Sample records for accelerated atherosclerosis development

  1. The Prebiotic Inulin Aggravates Accelerated Atherosclerosis in Hypercholesterolemic APOE*3-Leiden Mice.

    PubMed

    Hoving, Lisa R; de Vries, Margreet R; de Jong, Rob C M; Katiraei, Saeed; Pronk, Amanda; Quax, Paul H A; van Harmelen, Vanessa; Willems van Dijk, Ko

    2018-02-03

    The prebiotic inulin has proven effective at lowering inflammation and plasma lipid levels. As atherosclerosis is provoked by both inflammation and hyperlipidemia, we aimed to determine the effect of inulin supplementation on atherosclerosis development in hypercholesterolemic APOE*3-Leiden ( E3L ) mice. Male E3L mice were fed a high-cholesterol (1%) diet, supplemented with or without 10% inulin for 5 weeks. At week 3, a non-constrictive cuff was placed around the right femoral artery to induce accelerated atherosclerosis. At week 5, vascular pathology was determined by lesion thickness, vascular remodeling, and lesion composition. Throughout the study, plasma lipids were measured and in week 5, blood monocyte subtypes were determined using flow cytometry analysis. In contrast to our hypothesis, inulin exacerbated atherosclerosis development, characterized by increased lesion formation and outward vascular remodeling. The lesions showed increased number of macrophages, smooth muscle cells, and collagen content. No effects on blood monocyte composition were found. Inulin significantly increased plasma total cholesterol levels and total cholesterol exposure. In conclusion, inulin aggravated accelerated atherosclerosis development in hypercholesterolemic E3L mice, accompanied by adverse lesion composition and outward remodeling. This process was not accompanied by differences in blood monocyte composition, suggesting that the aggravated atherosclerosis development was driven by increased plasma cholesterol.

  2. The Prebiotic Inulin Aggravates Accelerated Atherosclerosis in Hypercholesterolemic APOE*3-Leiden Mice

    PubMed Central

    de Jong, Rob C. M.; Katiraei, Saeed; Pronk, Amanda; van Harmelen, Vanessa

    2018-01-01

    The prebiotic inulin has proven effective at lowering inflammation and plasma lipid levels. As atherosclerosis is provoked by both inflammation and hyperlipidemia, we aimed to determine the effect of inulin supplementation on atherosclerosis development in hypercholesterolemic APOE*3-Leiden (E3L) mice. Male E3L mice were fed a high-cholesterol (1%) diet, supplemented with or without 10% inulin for 5 weeks. At week 3, a non-constrictive cuff was placed around the right femoral artery to induce accelerated atherosclerosis. At week 5, vascular pathology was determined by lesion thickness, vascular remodeling, and lesion composition. Throughout the study, plasma lipids were measured and in week 5, blood monocyte subtypes were determined using flow cytometry analysis. In contrast to our hypothesis, inulin exacerbated atherosclerosis development, characterized by increased lesion formation and outward vascular remodeling. The lesions showed increased number of macrophages, smooth muscle cells, and collagen content. No effects on blood monocyte composition were found. Inulin significantly increased plasma total cholesterol levels and total cholesterol exposure. In conclusion, inulin aggravated accelerated atherosclerosis development in hypercholesterolemic E3L mice, accompanied by adverse lesion composition and outward remodeling. This process was not accompanied by differences in blood monocyte composition, suggesting that the aggravated atherosclerosis development was driven by increased plasma cholesterol. PMID:29401645

  3. Protective Effects of Hydroxychloroquine against Accelerated Atherosclerosis in Systemic Lupus Erythematosus

    PubMed Central

    Cauli, Alberto

    2018-01-01

    Cardiovascular (CV) morbidity and mortality are a challenge in management of patients with systemic lupus erythematosus (SLE). Higher risk of CV disease in SLE patients is mostly related to accelerated atherosclerosis. Nevertheless, high prevalence of traditional cardiovascular risk factors in SLE patients does not fully explain the increased CV risk. Despite the pathological bases of accelerated atherosclerosis are not fully understood, it is thought that this process is driven by the complex interplay between SLE and atherosclerosis pathogenesis. Hydroxychloroquine (HCQ) is a cornerstone in treatment of SLE patients and has been thought to exert a broad spectrum of beneficial effects on disease activity, prevention of damage accrual, and mortality. Furthermore, HCQ is thought to protect against accelerated atherosclerosis targeting toll-like receptor signaling, cytokine production, T-cell and monocyte activation, oxidative stress, and endothelial dysfunction. HCQ was also described to have beneficial effects on traditional CV risk factors, such as dyslipidemia and diabetes. In conclusion, despite lacking randomized controlled trials unambiguously proving the protection of HCQ against accelerated atherosclerosis and incidence of CV events in SLE patients, evidence analyzed in this review is in favor of its beneficial effect. PMID:29670462

  4. Angiotensin II–accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice

    PubMed Central

    Bruemmer, Dennis; Collins, Alan R.; Noh, Grace; Wang, Wei; Territo, Mary; Arias-Magallona, Sarah; Fishbein, Michael C.; Blaschke, Florian; Kintscher, Ulrich; Graf, Kristof; Law, Ronald E.; Hsueh, Willa A.

    2003-01-01

    Osteopontin (OPN) is expressed in atherosclerotic lesions, particularly in diabetic patients. To determine the role of OPN in atherogenesis, ApoE–/–OPN+/+, ApoE–/–OPN+/–, and ApoE–/–OPN–/– mice were infused with Ang II, inducing vascular OPN expression and accelerating atherosclerosis. Compared with ApoE–/–OPN+/+ mice, ApoE–/–OPN+/– and ApoE–/–OPN–/– mice developed less Ang II–accelerated atherosclerosis. ApoE–/– mice transplanted with bone marrow derived from ApoE–/–OPN–/– mice had less Ang II–induced atherosclerosis compared with animals receiving ApoE–/–OPN+/+ cells. Aortae from Ang II–infused ApoE–/–OPN–/– mice expressed less CD68, C-C-chemokine receptor 2, and VCAM-1. In response to intraperitoneal thioglycollate, recruitment of leukocytes in OPN–/– mice was impaired, and OPN–/– leukocytes exhibited decreased basal and MCP-1–directed migration. Furthermore, macrophage viability in atherosclerotic lesions from Ang II–infused ApoE–/–OPN–/– mice was decreased. Finally, Ang II–induced abdominal aortic aneurysm formation in ApoE–/–OPN–/– mice was reduced and associated with decreased MMP-2 and MMP-9 activity. These data suggest an important role for leukocyte-derived OPN in mediating Ang II–accelerated atherosclerosis and aneurysm formation. PMID:14597759

  5. Marked Acceleration of Atherosclerosis following Lactobacillus casei induced Coronary Arteritis in a Mouse Model of Kawasaki Disease

    PubMed Central

    Chen, Shuang; Lee, Young Ho; Crother, Timothy R.; Fishbein, Michael; Zhang, Wenxuan; Yilmaz, Atilla; Shimada, Kenichi; Schulte, Danica J; Lehman, Thomas J.A.; Shah, Prediman K.; Arditi, Moshe

    2012-01-01

    Objective To investigate if Lactobacillus casei cell wall extract (LCWE)-induced Kawasaki Disease (KD) accelerates atherosclerosis in hypercholesterolemic mice. Method and Resuslts Apoe−/− or Ldlr−/− mice were injected with LCWE (KD mice) or PBS, fed high fat diet for 8 weeks, and atherosclerotic lesions in aortic sinuses (AS), arch (AC) and whole aorta were assessed. KD mice had larger, more complex aortic lesions with abundant collagen, and both extracellular and intracellular lipid and foam cells, compared to lesions in control mice despite similar cholesterol levels. Both Apoe−/− KD and Ldlr−/− KD mice showed dramatic acceleration in atherosclerosis vs. controls, with increases in en face aortic atherosclerosis and plaque size in both the AS and AC plaques. Accelerated atherosclerosis was associated with increased circulating IL-12p40, IFN-γ, TNF-α, and increased macrophage, DC, and T cell recruitment in lesions. Furthermore, daily injections of the IL-1Ra, which inhibits LCWE induced KD vasculitis, prevented the acceleration of atherosclerosis. Conclusions Our results suggest an important pathophysiologic link between coronary arteritis/vasculitis in the KD mouse model and subsequent atherosclerotic acceleration, supporting the concept that a similar relation may also be present in KD patients. These results also suggest that KD in childhood may predispose to accelerated and early atherosclerosis as adults. PMID:22628430

  6. Increased Th9 cells and IL-9 levels accelerate disease progression in experimental atherosclerosis.

    PubMed

    Li, Qing; Ming, Tingting; Wang, Yuanmin; Ding, Shaowei; Hu, Chaojie; Zhang, Cuiping; Cao, Qi; Wang, Yiping

    2017-01-01

    Atherosclerosis (AS) is the number one killer in developed countries, and currently considered a chronic inflammatory disease. The central role of T cells in the pathogenesis of atherosclerosis is well documented. However, little is known about the newly described T cell subset-Th9 cells and their role in AS pathogenesis. Here, the amounts of Th9 cells as well as their key transcription factors and relevant cytokines during atherosclerosis were assessed in ApoE -/- mice and age-matched C57BL/6J mice. Significantly increased Th9 cell number, Th9 related cytokine (IL-9), and key transcription factor (PU.1) were found in ApoE -/- mice compared with age-matched C57BL/6J mice. Additionally, treatment with rIL-9 accelerated atherosclerotic development, which was attenuated by anti-IL-9 antibodies. These data suggested that both Th9 cells and related IL-9 play key roles in the pathogenesis of atherosclerosis, and antibodies against these antigens offer a novel therapeutic approach in AS treatment.

  7. Intimal hyperplasia induced by vascular intervention causes lipoprotein retention and accelerated atherosclerosis.

    PubMed

    Kijani, Siavash; Vázquez, Ana Maria; Levin, Malin; Borén, Jan; Fogelstrand, Per

    2017-07-01

    Accelerated atherosclerosis diminishes the long term patency of vascular interventions, such as percutaneous coronary intervention and implantation of saphenous vein grafts. However, the cause of this accelerated atherosclerosis is unclear. In this study, we tested the hypothesis that intimal hyperplasia formed following vascular intervention promotes retention of atherogenic lipoproteins. Intimal hyperplasia was surgically induced in the mouse common carotid artery. The surgery was combined with different mouse models of hypercholesterolemia to obtain different cholesterol levels and to control the onsets of hypercholesterolemia. Three weeks after surgery, samples were immunostained for apoB lipoproteins, smooth muscle cells and leukocytes. Already at mild hypercholesterolemia (193 mg/dL), pronounced apoB lipoprotein retention was found in the extracellular matrix in both intimal hyperplasia and the injured underlying media. In contrast, minimal retention was detected in the uninjured proximal region of the same vessel, or in vessels from mice with normal cholesterol levels (81 mg/dL). Induction of aggravated hypercholesterolemia 3 weeks after surgery, when a mature intimal hyperplasia had been formed, caused a very rapid development of atherosclerotic lesions. Mechanistically, we show that lipoprotein retention was almost exclusively dependent on electrostatic interactions to proteoglycan glycosaminoglycans, and the lipoprotein retention to intimal hyperplasia could be inhibited in vivo using glycosaminoglycan-binding antibodies. Thus, formation of intimal hyperplasia following vascular intervention makes the vessel wall highly susceptible for lipoprotein retention and accelerated atherosclerosis. The increased lipoprotein retention in intimal hyperplasia can be targeted by blocking the interaction between apoB lipoproteins and glycosaminoglycans in the extracellular matrix. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on

  8. Posttransplant Immune Activation: Innocent Bystander or Insidious Culprit of Posttransplant Accelerated Atherosclerosis.

    PubMed

    Ducloux, Didier; Bamoulid, Jamal; Crepin, Thomas; Rebibou, Jean-Michel; Courivaud, Cecile; Saas, Philippe

    2017-09-01

    Cardiovascular disease is a major cause of morbidity, disability, and mortality in kidney transplant patients. Cumulative reports indicate that the excessive risk of cardiovascular events is not entirely explained by the increased prevalence of traditional cardiovascular risk factors. Atherosclerosis is a chronic inflammatory disease, and it has been postulated that posttransplant immune disturbances may explain the gap between the predicted and observed risks of cardiovascular events. Although concordant data suggest that innate immunity contributes to the posttransplant accelerated atherosclerosis, only few arguments plead for a role of adaptive immunity. We report and discuss here consistent data demonstrating that CD8 + T cell activation is a frequent posttransplant immune feature that may have pro-atherogenic effects. Expansion of exhausted/activated CD8 + T cells in kidney transplant recipients is stimulated by several factors including cytomegalovirus infections, lymphodepletive therapy (e.g., antithymocyte globulins), chronic allogeneic stimulation, and a past history of renal insufficiency. This is observed in the setting of decreased thymic activity, a process also found in elderly individuals and reflecting accelerated immune senescence.

  9. Annexin A5 prevents post-interventional accelerated atherosclerosis development in a dose-dependent fashion in mice.

    PubMed

    Ewing, M M; Karper, J C; Sampietro, M L; de Vries, M R; Pettersson, K; Jukema, J W; Quax, P H A

    2012-04-01

    Activated cells in atherosclerotic lesions expose phosphatidylserine (PS) on their surface. Annexin A5 (AnxA5) binds to PS and is used for imaging atherosclerotic lesions. Recently, AnxA5 was shown to inhibit vascular inflammatory processes after vein grafting. Here, we report a therapeutic role for AnxA5 in post-interventional vascular remodeling in a mouse model mimicking percutaneous coronary intervention (PCI). Associations between the rs4833229 (OR = 1.29 (CI 95%), p(allelic) = 0.011) and rs6830321 (OR = 1.35 (CI 95%), p(allelic) = 0.003) SNPs in the AnxA5 gene and increased restenosis-risk in patients undergoing PCI were found in the GENDER study. To evaluate AnxA5 effects on post-interventional vascular remodeling and accelerated atherosclerosis development in vivo, hypercholesterolemic ApoE(-/-) mice underwent femoral arterial cuff placement to induce intimal thickening. Dose-dependent effects were investigated after 3 days (effects on inflammation and leukocyte recruitment) or 14 days (effects on remodeling) after cuff placement. Systemically administered AnxA5 in doses of 0.1, 0.3 and 1.0mg/kg compared to vehicle reduced early leukocyte and macrophage adherence up to 48.3% (p = 0.001) and diminished atherosclerosis development by 71.2% (p = 0.012) with a reduction in macrophage/foam cell presence. Moreover, it reduced the expression of the endoplasmic reticulum stress marker GRP78/BiP, indicating lower inflammatory activity of the cells present. AnxA5 SNPs could serve as markers for restenosis after PCI and AnxA5 therapeutically prevents vascular remodeling in a dose-dependent fashion, together indicating clinical potential for AnxA5 against post-interventional remodeling. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  10. Porphyromonas gingivalis Accelerates Inflammatory Atherosclerosis in the Innominate Artery of ApoE Deficient Mice

    PubMed Central

    Hayashi, Chie; Viereck, Jason; Hua, Ning; Phinikaridou, Alkystis; Madrigal, Andres G.; Gibson, Frank C.; Hamilton, James A.; Genco, Caroline A.

    2011-01-01

    Objective Studies in humans support a role for the oral pathogen Porphyromonas gingivalis in the development of inflammatory atherosclerosis. The goal of this study was to determine if P. gingivalis infection accelerates inflammation and atherosclerosis in the innominate artery of mice, an artery which has been reported to exhibit many features of human atherosclerotic disease, including plaque rupture. Methods and Results Apolipoprotein E-deficient (ApoE−/−) mice were orally infected with P. gingivalis, and Magnetic Resonance Imaging (MRI) was used to monitor the progression of atherosclerosis in live mice. P. gingivalis infected mice exhibited a statistically significant increase in atherosclerotic plaque in the innominate artery as compared to uninfected mice. Polarized light microscopy and immunohistochemistry revealed that the innominate arteries of infected mice had increased lipids, macrophages and T cells as compared to uninfected mice. Increases in plaque, total cholesterol esters and cholesterol monohydrate crystals, macrophages, and T cells were prevented by immunization with heat-killed P. gingivalis prior to pathogen exposure. Conclusions These are the first studies to demonstrate progression of inflammatory plaque accumulation in the innominate arteries by in-vivo MRI analysis following pathogen exposure, and to document protection from plaque progression in the innominate artery via immunization. PMID:21251656

  11. Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis

    PubMed Central

    Ng, Qimin; Sanda, Gregory E.; Dey, Amit K.; Teague, Heather L.; Sorokin, Alexander V.; Dagur, Pradeep K.; Silverman, Joanna I.; Harrington, Charlotte L.; Rodante, Justin A.; Rose, Shawn M.; Varghese, Nevin J.; Belur, Agastya D.; Goyal, Aditya; Gelfand, Joel M.; Springer, Danielle A.; Bleck, Christopher K.E.; Thomas, Crystal L.; Yu, Zu-Xi; Winge, Mårten C.G.; Kruth, Howard S.; Marinkovich, M. Peter; Joshi, Aditya A.; Playford, Martin P.; Mehta, Nehal N.

    2018-01-01

    Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12–/+/Srb1–/–/ApoER61H/H mouse and confirmed psoriasis accelerates atherogenesis (~7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis. PMID:29321372

  12. Oral activated charcoal adsorbent (AST-120) ameliorates extent and instability of atherosclerosis accelerated by kidney disease in apolipoprotein E-deficient mice

    PubMed Central

    Yamamoto, Suguru; Zuo, Yiqin; Ma, Ji; Yancey, Patricia G.; Hunley, Tracy E.; Motojima, Masaru; Fogo, Agnes B.; Linton, MacRae F.; Fazio, Sergio; Ichikawa, Iekuni

    2011-01-01

    Background. Accelerated atherosclerosis and increased cardiovascular events are not only more common in chronic kidney disease (CKD) but are more resistant to therapeutic interventions effective in the general population. The oral charcoal adsorbent, AST-120, currently used to delay start of dialysis, reduces circulating and tissue uremic toxins, which may contribute to vasculopathy, including atherosclerosis. We, therefore, investigated whether AST-120 affects CKD-induced atherosclerosis. Methods. Apolipoprotein E-deficient mice, a model of atherosclerosis, underwent uninephrectomy, subtotal nephrectomy or sham operation at 8 weeks of age and were treated with AST-120 after renal ablation. Atherosclerosis and its characteristics were assessed at 25 weeks of age. Results. Uninephrectomy and subtotal nephrectomised mice had significantly increased acceleration of atherosclerosis. AST-120 treatment dramatically reduced the atherosclerotic burden in mice with kidney damage, while there was no beneficial effect in sham-operated mice. The benefit was independent of blood pressure, serum total cholesterol or creatinine clearance. AST-120 significantly decreased necrotic areas and lessened aortic deposition of the uremic toxin indoxyl sulfate without affecting lesional macrophage or collagen content. Furthermore, AST-120 lessened aortic expression of monocyte chemoattractant protein-1, tumor necrosis factor-α and interleukin-1β messenger RNA. Conclusions. AST-120 lessens the extent of atherosclerosis induced by kidney injury and alters lesion characteristics in apolipoprotein E-deficient mice, resulting in plaques with a more stable phenotype with less necrosis and reduced inflammation. PMID:21245127

  13. 56Fe accelerates development of atherosclerosis in apoE -/-mice

    NASA Astrophysics Data System (ADS)

    Kucik, Dennis; Yu, Tao; Parks, Brian; Yu, Shaohua; Srivastava, Roshni; Gupta, Kiran; Wu, Xing; Khaled, Saman; Chang, Polly; Kabarowski, Janusz

    Exposure to radiation from a variety of sources is associated with increased risk of heart disease and stroke. For example, for women with early breast cancer, the benefit of radiotherapy can be nearly offset by the increased risk of mortality from cardiovascular disease. Head and neck cancer patients who undergo radiation treatment are at significantly elevated risk of stroke, even in a relatively young patient population that would not normally be at risk for atheroscle-rosis. Similarly, atomic bomb survivors had an increased incidence of mortality from coronary artery disease and stroke. Even radiation technologists working before 1950 (when occupational exposure was higher) had increased mortality due to circulatory diseases. Although much is known about the cardiovascular consequences these exposures to X-raus and gamma radiation, the response to the type of radiation likely to be encountered in prolonged space flight has not been determined. A key component of this cosmic radiation is 56Fe, which is particularly damaging to tissues. Using collimated beams, we selectively irradiated aortic arches and carotids (only) of the well-established apoE -/-atherosclerosis mouse model to test directly whether 56Fe exposure is a cardiovascular risk factor. Mice were sacrificed at 13 weeks post-irradiation and dissected, and aortas were divided into areas that had been targeted by the ion beam and those that were not. The area that was covered by plaques was then quantified. Plaque area at 13 weeks post-irradiation was significantly greater in targeted areas of mice that had received 5 Gy of 56Fe as compared to age-and sex-matched un-irradiated controls. In the carotid arteries and aortic roots, significantly greater atherosclerosis was apparent for a 2Gy exposure as well (the lowest dose tested). This demonstrates that even a single exposure to heavy ion radiation is capable of triggering events that culminate in cardiovascular disease, even long after the exposure has

  14. PKM2-dependent metabolic reprogramming in CD4+ T cells is crucial for hyperhomocysteinemia-accelerated atherosclerosis.

    PubMed

    Lü, Silin; Deng, Jiacheng; Liu, Huiying; Liu, Bo; Yang, Juan; Miao, Yutong; Li, Jing; Wang, Nan; Jiang, Changtao; Xu, Qingbo; Wang, Xian; Feng, Juan

    2018-06-01

    Inflammation mediated by activated T cells plays an important role in the initiation and progression of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis in ApoE -/- mice. Homocysteine (Hcy) activates T cells to secrete proinflammatory cytokines, especially interferon (IFN)-γ; however, the precise mechanisms remain unclear. Metabolic reprogramming is critical for T cell inflammatory activation and effector functions. Our previous study demonstrated that Hcy regulates T cell mitochondrial reprogramming by enhancing endoplasmic reticulum (ER)-mitochondria coupling. In this study, we further explored the important role of glycolysis-mediated metabolic reprogramming in Hcy-activated CD4 + T cells. Mechanistically, Hcy-activated CD4 + T cell increased the protein expression and activity of pyruvate kinase muscle isozyme 2 (PKM2), the final rate-limiting enzyme in glycolysis, via the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin signaling pathway. Knockdown of PKM2 by small interfering RNA reduced Hcy-induced CD4 + T cell IFN-γ secretion. Furthermore, we generated T cell-specific PKM2 knockout mice by crossing LckCre transgenic mice with PKM2 fl/fl mice and observed that Hcy-induced glycolysis and oxidative phosphorylation were both diminished in PKM2-deficient CD4 + T cells with reduced glucose and lipid metabolites, and subsequently reduced IFN-γ secretion. T cell-depleted apolipoprotein E-deficient (ApoE -/- ) mice adoptively transferred with PKM2-deficient CD4 + T cells, compared to mice transferred with control cells, showed significantly decreased HHcy-accelerated early atherosclerotic lesion formation. In conclusion, this work indicates that the PKM2-dependent glycolytic-lipogenic axis, a novel mechanism of metabolic regulation, is crucial for HHcy-induced CD4 + T cell activation to accelerate early atherosclerosis in ApoE -/- mice. Metabolic reprogramming is crucial for Hcy-induced CD4 + T cell inflammatory activation. Hcy activates

  15. [Atherosclerosis in inflammatory diseases].

    PubMed

    Páramo, José A; Rodríguez, José A; Orbe, Josune

    2007-05-19

    The recognition that inflammation is a hallmark of atherosclerotic disease and its complications has led to a series of studies reporting high prevalence of atherosclerosis in chronic inflammatory diseases. Indeed, chronic immune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, are associated with proinflammation, accelerated atherosclerosis and increased incidence of cardiovascular disease. Since the susceptibility towards cardiovascular events cannot be explained by classical risk factors, disease-specific pathways have been put forward as additional risk factors, potentially important for future prevention and treatment of atherosclerosis associated with chronic inflammatory diseases.

  16. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.

    PubMed

    Fuster, José J; MacLauchlan, Susan; Zuriaga, María A; Polackal, Maya N; Ostriker, Allison C; Chakraborty, Raja; Wu, Chia-Ling; Sano, Soichi; Muralidharan, Sujatha; Rius, Cristina; Vuong, Jacqueline; Jacob, Sophia; Muralidhar, Varsha; Robertson, Avril A B; Cooper, Matthew A; Andrés, Vicente; Hirschi, Karen K; Martin, Kathleen A; Walsh, Kenneth

    2017-02-24

    Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of Tet2 -mutant cells in atherosclerosis-prone, low-density lipoprotein receptor-deficient ( Ldlr -/- ) mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome-mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic TET2 mutations in blood cells play a causal role in atherosclerosis. Copyright © 2017, American Association for the Advancement of Science.

  17. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice

    PubMed Central

    Fuster, José J.; MacLauchlan, Susan; Zuriaga, María A.; Polackal, Maya N.; Ostriker, Allison C.; Chakraborty, Raja; Wu, Chia-Ling; Sano, Soichi; Muralidharan, Sujatha; Rius, Cristina; Vuong, Jacqueline; Jacob, Sophia; Muralidhar, Varsha; Robertson, Avril A. B.; Cooper, Matthew A.; Andrés, Vicente; Hirschi, Karen K.; Martin, Kathleen A.; Walsh, Kenneth

    2017-01-01

    Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of Tet2-mutant cells in atherosclerosis-prone, low-density lipoprotein receptor–deficient (Ldlr−/−) mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome–mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic TET2 mutations in blood cells play a causal role in atherosclerosis. PMID:28104796

  18. HIV-1-Associated Atherosclerosis: Unraveling the Missing Link.

    PubMed

    Kearns, Alison; Gordon, Jennifer; Burdo, Tricia H; Qin, Xuebin

    2017-06-27

    Cardiovascular disease, including atherosclerosis and atherosclerosis-associated complications, is an increasing cause of morbidity and mortality in human immunodeficiency virus (HIV) patients in the post-antiretroviral therapy era. HIV alone accelerates atherosclerosis. Antiretroviral therapy; HIV-associated comorbidities, such as dyslipidemia, drug abuse, and opportunistic infections; and lifestyle are risk factors for HIV-associated atherosclerosis. However, our current understanding of HIV-associated atherogenesis is very limited and has largely been obtained from clinical observation. There is a pressing need to experimentally unravel the missing link between HIV and atherosclerosis. Understanding these mechanisms will help to better develop and design novel therapeutic interventions for the treatment of HIV-associated cardiovascular disease. HIV mainly infects T cells and macrophages resulting in the induction of oxidative and endoplasmic reticulum stress, the formation of the inflammasome, and the dysregulation of autophagy. These mechanisms may contribute to HIV-associated atherogenesis. In this review, we will summarize our current understanding and propose potential mechanisms of HIV-associated atherosclerosis. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  19. Improved animal models for testing gene therapy for atherosclerosis.

    PubMed

    Du, Liang; Zhang, Jingwan; De Meyer, Guido R Y; Flynn, Rowan; Dichek, David A

    2014-04-01

    Gene therapy delivered to the blood vessel wall could augment current therapies for atherosclerosis, including systemic drug therapy and stenting. However, identification of clinically useful vectors and effective therapeutic transgenes remains at the preclinical stage. Identification of effective vectors and transgenes would be accelerated by availability of animal models that allow practical and expeditious testing of vessel-wall-directed gene therapy. Such models would include humanlike lesions that develop rapidly in vessels that are amenable to efficient gene delivery. Moreover, because human atherosclerosis develops in normal vessels, gene therapy that prevents atherosclerosis is most logically tested in relatively normal arteries. Similarly, gene therapy that causes atherosclerosis regression requires gene delivery to an existing lesion. Here we report development of three new rabbit models for testing vessel-wall-directed gene therapy that either prevents or reverses atherosclerosis. Carotid artery intimal lesions in these new models develop within 2-7 months after initiation of a high-fat diet and are 20-80 times larger than lesions in a model we described previously. Individual models allow generation of lesions that are relatively rich in either macrophages or smooth muscle cells, permitting testing of gene therapy strategies targeted at either cell type. Two of the models include gene delivery to essentially normal arteries and will be useful for identifying strategies that prevent lesion development. The third model generates lesions rapidly in vector-naïve animals and can be used for testing gene therapy that promotes lesion regression. These models are optimized for testing helper-dependent adenovirus (HDAd)-mediated gene therapy; however, they could be easily adapted for testing of other vectors or of different types of molecular therapies, delivered directly to the blood vessel wall. Our data also supports the promise of HDAd to deliver long

  20. Resveratrol, Wine, and Atherosclerosis

    PubMed Central

    Prasad, Kailash

    2012-01-01

    This review emphasizes the effects of resveratrol on factors involved in the mechanism of atherosclerosis and risk factors for atherosclerosis. The effects of wine and resveratrol on atherosclerosis are also discussed. Resveratrol is a potent antioxidant and an anti-inflammatory agent. It reduces the expression of cell adhesion molecules, monocyte colony stimulating factors, matrix metalloproteinases, and growth factors; and inhibits platelet aggregation and vascular smooth muscle cell proliferation. It reduces the serum levels of total cholesterol, triglycerides (TG), and raises high-density lipoprotein cholesterol, inhibits expression of C-reactive protein and lowers the levels of advanced glycation end products and its receptor in the vascular tissue. It lowers the risk factors for plaque rupture. Epidemiological data show that moderate consumption of alcohol has an inverse association with carotid atherosclerosis while high consumption has a positive association with carotid atherosclerosis. Wine reduces the extent of atherosclerosis in animal model. The antiatherosclerotic effect of wine is mainly due to it resveratrol content. Resveratrol reduces the extent of atherosclerosis in animal model of atherosclerosis (apolipoprotein [Apo] E-deficient and Apo E−/−/low-density lipoprotein receptor-deficient mice and macrophage). In rabbit model of atherosclerosis, both reduction and acceleration of atherosclerosis have been reported with resveratrol. There are no data for regression and slowing of progression of atherosclerosis. Robust clinical trials for suppression of atherosclerosis are lacking. In conclusion, resveratrol has potential but experimental studies in depth and robust clinical trials are lacking for this agent to be of any value in the primary and secondary prevention of coronary and peripheral artery disease. PMID:23450206

  1. Mercury accumulation and accelerated progression of carotid atherosclerosis: a population-based prospective 4-year follow-up study in men in eastern Finland.

    PubMed

    Salonen, J T; Seppänen, K; Lakka, T A; Salonen, R; Kaplan, G A

    2000-02-01

    Basic research and our previous studies have suggested that mercury exposure enhances lipid peroxidation and the risk of myocardial infarction, but there are no studies concerning the association between mercury accumulation and atherosclerosis. We therefore investigated whether high hair mercury content is associated with accelerated progression of carotid atherosclerosis, determined by ultrasonographic assessment of common carotid intima-media thickness (IMT), in a prospective study among 1014 men aged 42-60 years. In a linear regression model adjusting for other atherosclerotic risk factors, high hair mercury content was one of the strongest predictors of the 4-year increase in the mean IMT (P2.81 microg/g (fifths) had an IMT increase of 0.105, 0.102, 0.113, 0.107 and 0.140 mm/4 years, respectively (P=0.041 for heterogeneity between groups). The IMT increase was 0.034 mm/4 years (31.9%) greater in the highest fifth than in the other fifths (P<0.05 for the difference). These findings suggest that mercury accumulation in the human body is associated with accelerated progression of carotid atherosclerosis.

  2. Agonistic antibody to angiotensin II type 1 receptor accelerates atherosclerosis in ApoE-/- mice

    PubMed Central

    Li, Weijuan; Chen, Yaoqi; Li, Songhai; Guo, Xiaopeng; Zhou, Wenping; Zeng, Qiutang; Liao, Yuhua; Wei, Yumiao

    2014-01-01

    This study aimed to investigate the effects of agonistic antibody to angiotensin II type 1 receptor (AT1-AA) on atherosclerosis in male ApoE-/- mice which were employed to establish the animal models of AT1-AA in two ways. In the first group, mice were injected subcutaneously with conjugated AT1 peptide at multiple sites; in the second group, mice were infused with AT1-AA prepared from rabbits that were treated with AT1 peptide intraperitoneally. Mice in each group were further randomly divided into five subgroups and treated with AT1 peptide/AT1-AA, AT1 peptide/AT1-AA plus valsartan, AT1 peptide/AT1-AA plus fenofibrate, AT1 peptide/ AT1-AA plus pyrrolidine dithiocarbamate (PDTC) and control vehicle, respectively. Antibodies were detected in mice (except for mice in control group). Aortic atherosclerotic lesions were assessed by oil red O staining, while plasma CRP, TNF-α, nuclear factor-kappa B (NF-κB) and H2O2 were determined by ELISA. CCR2 (the receptor of MCP-1), macrophages, and smooth muscle cells were detected by immunohistochemistry. P47phox, MCP-1 and eNOS were detected by RT-PCR, while P47phox, NF-κB and MCP-1 were detected by Western blot assay. The aortic atherosclerotic lesions were significantly increased in AT1 peptide/AT1-AA treated mice, along with simultaneous increases in inflammatory parameters. However, mice treated with valsartan, fenofibrate or PDTC showed alleviated progression of atherosclerosis and reductions in inflammatory parameters. Thus, AT1-AA may accelerate aortic atherosclerosis in ApoE-/- mice, which is mediated, at least in part, by the inflammatory reaction involving nicotinamide-adenine dinucleotide phosphate oxidase, reactive oxygen species, and NF-κB. In addition, valsartan, fenofibrate and PDTC may inhibit the AT1-AA induced atherosclerosis. PMID:25628779

  3. Endothelium-specific insulin resistance leads to accelerated atherosclerosis in areas with disturbed flow patterns: a role for reactive oxygen species.

    PubMed

    Gage, Matthew C; Yuldasheva, Nadira Y; Viswambharan, Hema; Sukumar, Piruthivi; Cubbon, Richard M; Galloway, Stacey; Imrie, Helen; Skromna, Anna; Smith, Jessica; Jackson, Christopher L; Kearney, Mark T; Wheatcroft, Stephen B

    2013-09-01

    Systemic insulin resistance is associated with a portfolio of risk factors for atherosclerosis development. We sought to determine whether insulin resistance specifically at the level of the endothelium promotes atherosclerosis and to examine the potential involvement of reactive oxygen species. We cross-bred mice expressing a dominant negative mutant human insulin receptor specifically in the endothelium (ESMIRO) with ApoE(-/-) mice to examine the effect of endothelium-specific insulin resistance on atherosclerosis. ApoE(-/-)/ESMIRO mice had similar blood pressure, plasma lipids and whole-body glucose tolerance, but blunted endothelial insulin signalling, in comparison to ApoE(-/-) mice. Atherosclerosis was significantly increased in ApoE(-/-)/ESMIRO mice at the aortic sinus (226 ± 16 versus 149 ± 24 × 10(3) μm(2), P = 0.01) and lesser curvature of the aortic arch (12.4 ± 1.2% versus 9.4 ± 0.9%, P = 0.035). Relaxation to acetylcholine was blunted in aorta from ApoE(-/-)/ESMIRO mice (Emax 65 ± 41% versus 103 ± 6%, P = 0.02) and was restored by the superoxide dismutase mimetic MnTMPyP (Emax 112 ± 15% versus 65 ± 41%, P = 0.048). Basal generation of superoxide was increased 1.55 fold (P = 0.01) in endothelial cells from ApoE(-/-)/ESMIRO mice and was inhibited by the NADPH oxidase inhibitor gp91ds-tat (-12 ± 0.04%, P = 0.04), the NO synthase inhibitor L-NMMA (-8 ± 0.02%, P = 0.001) and the mitochondrial specific inhibitor rotenone (-23 ± 0.04%, P = 0.006). Insulin resistance specifically at the level of the endothelium leads to acceleration of atherosclerosis in areas with disturbed flow patterns such as the aortic sinus and the lesser curvature of the aorta. We have identified a potential role for increased generation of reactive oxygen species from multiple enzymatic sources in promoting atherosclerosis in this setting. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. [CHRONIC FLUORIDE INTOXICATION AS A RISK FACTOR FOR THE DEVELOPMENT OF ATHEROSCLEROSIS].

    PubMed

    Korotenko, O Yu; Panev, N I; Zakharenkov, V V; Filimonov, S N; Semenova, E A; Panev, R N

    2015-01-01

    In workers employed in the aluminum industry, the main harmful production factor is exposure to fluoride salts, which can cause chronic fluoride intoxication. For the assessment of the impact of chronic fluoride intoxication on the development of atherosclerosis, we conducted a comprehensive survey of 87 aluminum-metal makers with chronic fluoride intoxication and 43 aluminum-metal makers without occupational diseases, mean age--52.1 ± 0.4 years. There were considered the presence and severity of atherosclerosis of brachiocephalic arteries, and the arteries of the lower extremities in the studied group, there was evaluated the effect of other risk factors for atherosclerosis (smoking, presence of hypertension, diabetes, dyslipidemia). With the use of Doppler ultrasound of the arteries it was revealed that in metallurgists with chronic fluoride intoxication atherosclerosis was detected in 73.6% versus 55.8% in persons of the comparison group. The performed analysis of the prevalence of main risk factors for atherosclerosis showed that in metal makers with chronic fluoride intoxication in combination with atherosclerosis hypertension is more common (in 54.7%) than in metallurgists with chronic fluoride intoxication without atherosclerosis--only 26.1%. According to the frequency of occurrence of smoking, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia, there were no significant differences between the metallurgists with chronic fluoride intoxication, with and without atherosclerosis, and the control group, the increase in LDL cholesterol occurs significantly more often in metal-makers with chronic fluoride intoxication in combination with atherosclerosis if compared to workers without occupational diseases. Thus, chronic fluoride intoxication acts as a risk factor in the development of atherosclerosis: atherosclerosis in metal-makers with chronic fluoride intoxication occurs more frequently than in workers who do not have professional pathology

  5. Brazilian adult individuals with untreated isolated GH deficiency do not have accelerated subclinical atherosclerosis

    PubMed Central

    Costa, Ursula M M; Oliveira, Carla R P; Salvatori, Roberto; Barreto-Filho, José A S; Campos, Viviane C; Oliveira, Francielle T; Rocha, Ivina E S; Oliveira, Joselina L M; Silva, Wersley A; Aguiar-Oliveira, Manuel H

    2016-01-01

    GH and its principal mediator IGF1 have important effects on metabolic and cardiovascular (CV) status. While acquired GH deficiency (GHD) is often associated with increased CV risk, the consequences of congenital GHD are not known. We have described a large group of patients with isolated GHD (IGHD) due to a homozygous mutation (c.57+1G>A) in the GH releasing hormone receptor gene, and shown that adult GH-naïve individuals have no evidence of clinically evident premature atherosclerosis. To test whether subclinical atherosclerosis is anticipated in untreated IGHD, we performed a cross-sectional study of 25 IGHD and 27 adult controls matched for age and gender. A comprehensive clinical and biochemical panel and coronary artery calcium scores were evaluated by multi-detector tomography. Height, weight, IGF1, homeostasis model assessment of insulin resistance, creatinine and creatininekinase were lower in the IGHD group. Median and interquartile range of calcium scores distribution was similar in the two groups: IGHD 0(0) and control 0(4.9). The vast majority of the calcium scores (20 of 25 IGHD (80%) and 18 of 27 controls (66.6%)) were equal to zero (difference not significant). There was no difference in the calcium scores classification. None of IGHD subjects had minimal calcification, which were present in four controls. Three IGHD and four controls had mild calcification. There were two IGHD individuals with moderate calcification and one control with severe calcification. Our study provides evidence that subjects with congenital isolated lifetime and untreated severe IGHD do not have accelerated subclinical coronary atherosclerosis. PMID:26811426

  6. Atherosclerosis in epilepsy: its causes and implications.

    PubMed

    Hamed, Sherifa A

    2014-12-01

    Evidence from epidemiological, longitudinal, prospective, double-blinded clinical trials as well as case reports documents age-accelerated atherosclerosis with increased carotid artery intima media thickness (CA-IMT) in patients with epilepsy. These findings raise concern regarding their implications for age-accelerated cognitive and behavioral changes in midlife and risk of later age-related cognitive disorders including neurodegenerative processes such as Alzheimer's disease (AD). Chronic epilepsy, cerebral atherosclerosis, and age-related cognitive disorders including AD share many clinical manifestations (e.g. characteristic cognitive deficits), risk factors, and structural and pathological brain abnormalities. These shared risk factors include increased CA-IMT, hyperhomocysteinemia (HHcy), lipid abnormalities, weight gain and obesity, insulin resistance (IR), and high levels of inflammatory and oxidative stresses. The resulting brain structural and pathological abnormalities include decreased volume of the hippocampus, increased cortical thinning of the frontal lobe, ventricular expansion and increased white matter ischemic disease, total brain atrophy, and β-amyloid protein deposition in the brain. The knowledge that age-accelerated atherosclerosis may contribute to age-accelerated cognitive and behavioral abnormalities and structural brain pathologies in patients with chronic epilepsy represents an important research path to pursue future clinical and management considerations. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Macrophage Polarization by Angiotensin II-type 1 Receptor Aggravates Renal Injury-acceleration of Atherosclerosis

    PubMed Central

    Yamamoto, Suguru; Yancey, Patricia G.; Zuo, Yiqin; Ma, Li-Jun; Kaseda, Ryohei; Fogo, Agnes B.; Ichikawa, Iekuni; Linton, MacRae F.; Fazio, Sergio; Kon, Valentina

    2011-01-01

    Background Angiotensin II (AII) is a major determinant of atherosclerosis. Although macrophages are the most abundant cells in atherosclerotic plaques and express AII type 1 receptor (AT1), the pathophysiologic role of macrophage AT1 in atherogenesis remains uncertain. We examined the contribution of macrophage AT1 to accelerated atherosclerosis in an AII-responsive setting induced by uninephrectomy (UNx). Methods and Results AT1−/− or AT1+/+ marrow from apolipoprotein E deficient (apoE−/−) mice was transplanted into recipient apoE−/− mice with subsequent UNx or sham operation: apoE−/−/AT1+/+→apoE−/− + Sham; apoE−/−/AT1+/+→apoE−/− + UNx; apoE−/−/AT1−/−→apoE−/− + Sham; apoE−/−/AT1−/−→apoE−/− + UNx. No differences in body weight, blood pressure, lipid profile, and serum creatinine were observed between the two UNx groups. ApoE−/−/AT1+/+→apoE−/− + UNx had significantly more atherosclerosis (16907 ± 21473 vs 116071 ± 8180 μm2, p<0.05). By contrast, loss of macrophage AT1 which reduced local AT1 expression, prevented any effect of UNx on atherosclerosis (77174 ± 9947 vs 75714 ± 11333 μm2, p=NS). Although UNx did not affect total macrophage content in the atheroma, lesions in apoE−/−/AT1−/−→apoE−/− + UNx had fewer classically activated macrophage phenotype (M1) and more alternatively activated phenotype (M2). Further, UNx did not affect plaque necrosis or apoptosis in apoE−/−/AT1−/−→apoE−/− whereas it significantly increased both (by 2- and 6-fold, respectively) in apoE−/−/AT1+/+→apoE−/− mice. Instead, apoE−/−/AT1−/−→apoE−/− had 5-fold-increase in macrophage-associated apoptotic bodies, indicating enhanced efferocytosis. In vitro studies confirmed blunted susceptibility to apoptosis, especially in M2 macrophages, and a more efficient phagocytic function of AT1−/− macrophages vs AT1+/+. Conclusions AT1 receptor of bone marrow

  8. Atherosclerosis in the Erythrocebus patas, an old world monkey.

    PubMed Central

    Mahley, R. W.; Johnson, D. K.; Pucak, G. J.; Fry, D. L.

    1980-01-01

    Fifty monkeys of the species Erythrocebus patas were fed a control monkey chow, a semi-synthetic diet containing 25% lard, or a semisynthetic diet containing 25% lard and 0.5% cholesterol for 2 years. The patas monkeys had naturally occurring atherosclerosis that was greatly accelerated by feeding a diet containing cholesterol. The atherosclerosis involved the aorta, predominantly the abdominal portion, the coronary arteries, and various peripheral vessels. Histologically, the atherosclerosis was characterized by intimal proliferative lesions associated with intra- and extracellular lipid deposition. Complicated lesions that developed after 2 years on the cholesterol-containing diet were associated with lipid crystals, necrosis, mineralization, and encroachment upon the media. Adventitial reactions characterized by increased vascularity and the presence of inflammatory cells were seen. All of these observations have been described as components of the human atherosclerotic disease process. The similarity of the patas monkey atherosclerosis to human atherosclerosis, the relatively large size and easy handling of the animals, and the fact that previous studies have shown the lipoproteins of both control and cholesterol-fed monkeys to resemble human lipoproteins all contribute to making the patas monkey a useful model for the study of experimental atherosclerosis. Images Figure 1-5 Figure 6 Figure 7-10 Figure 11 Figure 12 PMID:6766672

  9. Acute Loss of Apolipoprotein E Triggers an Autoimmune Response That Accelerates Atherosclerosis.

    PubMed

    Centa, Monica; Prokopec, Kajsa E; Garimella, Manasa G; Habir, Katrin; Hofste, Lisa; Stark, Julian M; Dahdah, Albert; Tibbit, Chris A; Polyzos, Konstantinos A; Gisterå, Anton; Johansson, Daniel K; Maeda, Nobuyo N; Hansson, Göran K; Ketelhuth, Daniel F J; Coquet, Jonathan M; Binder, Christoph J; Karlsson, Mikael C I; Malin, Stephen

    2018-06-07

    Dyslipidemia is a component of the metabolic syndrome, an established risk factor for atherosclerotic cardiovascular disease, and is also observed in various autoimmune and chronic inflammatory conditions. However, there are limited opportunities to study the impact of acquired dyslipidemia on cardiovascular and immune pathology. We designed a model system that allows for the conversion to a state of acute hyperlipidemia in adult life, so that the consequences of such a transition could be observed, through conditionally deleting APOE (apolipoprotein E) in the adult mouse. The transition to hypercholesterolemia was accompanied by adaptive immune responses, including the expansion of T lymphocyte helper cell 1, T follicular helper cell, and T regulatory subsets and the formation of germinal centers. Unlike steady-state Apoe -deficientmice, abrupt loss of APOE induced rapid production of antibodies recognizing rheumatoid disease autoantigens. Genetic ablation of the germinal center reduced both autoimmunity and atherosclerosis, indicating that the immune response that follows loss of APOE is independent of atherosclerosis but nevertheless promotes plaque development. Our findings suggest that immune activation in response to hyperlipidemia could contribute to a wide range of inflammatory autoimmune diseases, including atherosclerosis. © 2018 American Heart Association, Inc.

  10. A dual enzymatic-biosensor for simultaneous determination of glucose and cholesterol in serum and peritoneal macrophages of diabetic mice: evaluation of the diabetes-accelerated atherosclerosis risk.

    PubMed

    Huang, Qilin; An, Yarui; Tang, Linlin; Jiang, Xiaoli; Chen, Hua; Bi, Wenji; Wang, Zhongchuan; Zhang, Wen

    2011-11-30

    In this paper, a novel dual enzymatic-biosensor is described for simultaneous determination of glucose and cholesterol in serum and peritoneal macrophages (PMs) of diabetic mice to evaluate the risk of diabetes-accelerated atherosclerosis. The biosensor was constructed by a three-step method. First, a poly-thionine (PTH) film was assembled on the surface of glassy carbon electrode by cyclic voltammetric electropolymerization of thionine, which serves as an electron transfer mediator (ETM). Second, gold nanoparticles (GNPs) were covered on the surface of PTH facilitating the electron transfer between glucose oxidase (GOx), cholesterol oxidase (ChOx) and electrode. Finally, the enzymes, GOx, cholesterol esterase (ChE), and ChOx, were covalently attached to the PTH layer through a chitosan (CH) linker. The PTH coupled with GNPs provides good selectivity, high sensitivity and little crosstalk for the dual enzymatic-biosensor. The developed biosensor had good electrocatalytic activity toward the oxidations of glucose and cholesterol, exhibiting a linear range from 0.008 mM to 6.0 mM for glucose with a detection limit of 2.0 μM, and a linear range from 0.002 mM to 1.0 mM for cholesterol with a detection limit of 0.6 μM. The results of the diabetic mice demonstrated that the cholesterol level did not change obviously with the increase of glucose level in serum, while the cholesterol level was induced with the increase of the glucose level in PMs. Previous studies have shown that the large accumulation of cholesterol in macrophage could lead to macrophage foam cell formation, which is the hallmark of early atherosclerosis. This study provides useful further evidences for the development of diabetes-accelerated atherosclerosis. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Prevention and treatment of atherosclerosis with flaxseed-derived compound secoisolariciresinol diglucoside.

    PubMed

    Prasad, Kailash; Jadhav, Ashok

    2016-01-01

    Atherosclerosis is the primary cause of coronary artery disease, heart attack, strokes, and peripheral vascular disease. Alternative/complimentary medicines, although are unacceptable by medical community, may be of great help in suppression, slowing of progression and regression of atherosclerosis. Numerous natural products are in use for therapy in spite of lack of evidence. This paper discusses the basic mechanism of atherosclerosis, risk factors for atherosclerosis, and prevention, slowing of progression and regression of atherosclerosis with flaxseed-derived secoisolariciresinol diglucoside (SDG). SDG content of flaxseed varies from 6mg/g to 18 mg/g. Flaxseed is the richest source of SDG. SDG possesses antioxidant, antihypertensive, antidiabetic, hypolipidemic, anti-inflammatory and antiatherogenic activities. SDG content of some commonly used food has been described. SDG in very low dose (15 mg/ kg) suppressed the development of hypercholesterolemic atherosclerosis by 73 % and this effect was associated with reduction in serum total cholesterol, LDL-C, and oxidative stress, and an increase in the levels HDL-C. A summary of the effects of flaxseed and its components on hypercholesterolemic atherosclerosis has been provided. Reduction in hypercholesterolemic atherosclerosis by flaxseed, CDC-flaxseed, flaxseed oil, flax lignan complex and SDG are 46 %, 69 %, 0 %, 34 % and 73 % respectively in dietary cholesterol -induced rabbit model of atherosclerosis. SDG slows the progression of atherosclerosis in animal model. Long-term use of SDG regresses hypercholesterolemic atherosclerosis. It is interesting that regular diet following high cholesterol diet accelerates in this animal model of atherosclerosis. In conclusion SDG suppresses, slow the progression and regresses the atherosclerosis. It could serve as an alternative medicine for the prevention, slowing of progression and regression of atherosclerosis and hence for the treatment of coronary artery disease

  12. Risk Factors for Atherosclerosis and the Development of Pre-Atherosclerotic Intimal Hyperplasia

    PubMed Central

    Cizek, Stephanie M.; Bedri, Shahinaz; Talusan, Paul; Silva, Nilsa; Lee, Hang; Stone, James R.

    2007-01-01

    Summary Intimal hyperplasia or thickening is considered to be the precursor lesion for atherosclerosis in humans; however the factors governing its formation are unclear. In the atherosclerosis-resistant internal thoracic artery, pre-atherosclerotic intimal hyperplasia routinely forms during adulthood after the 4th decade and is associated with at least two traditional risk factors for atherosclerosis: age and smoking. Background Intimal hyperplasia, or thickening, is considered to be the precursor lesion for atherosclerosis in humans; however, the factors governing its formation are unclear. To gain insight into the etiology of pre-atherosclerotic intimal hyperplasia, traditional risk factors for atherosclerosis were correlated with the intimal hyperplasia in an atherosclerosis-resistant vessel, the internal thoracic artery. Methods Paired internal thoracic arteries were obtained from 89 autopsies. Multivariate logistic regression and multiple regression models were used to examine the association of pre-atherosclerotic intimal hyperplasia with traditional risk factors for atherosclerosis: age, gender, hypertension, smoking, body mass index, diabetes, and hypercholesterolemia. Results Atherosclerotic lesions consisting of fatty streaks and/or type III intermediate lesions were identified in 19 autopsies. Only age >75 years was found to be significantly correlated with atherosclerotic lesion development (P=0.01). Multiple regression model of the intima/media ratio in all 89 cases revealed age >75 years (P<0.0001), age 51–75years (P=0.0012), smoking (P=0.008) and hypertension (P=0.02) to be significantly correlated with intimal thickness. In the 70 cases without atherosclerosis, only age 51–75 years (P=0.006) and smoking (P=0.028) were found to be significantly associated with pre-atherosclerotic intimal thickening. Conclusions In the atherosclerosis-resistant internal thoracic artery, pre-atherosclerotic intimal hyperplasia routinely forms during adulthood

  13. Effects of catechins and caffeine on the development of atherosclerosis in mice.

    PubMed

    Liu, Litong; Nagai, Izumi; Gao, Ying; Matsushima, Yoshibumi; Kawai, Yoshichika; Sayama, Kazutoshi

    2017-10-01

    Atherosclerosis is one of the diseases related to metabolic syndrome which is caused by obesity. Previous reports have shown that green tea and its components have anti-obesity effect. We examined whether catechins and caffeine can prevent the development of atherosclerosis by oral administration, singly or in combination to the atherosclerosis model mice. Results demonstrated that the number of atherosclerotic regions in the aorta was significantly reduced by the combined treatment, and the atherosclerotic area was also improved. Serum HDL-C increased by caffeine single treatment, but no effect on the TG and TC by any treatments. Moreover, ECG illuviated to atheromatous lesions in aorta and the illuviation was enhanced by caffeine. The mRNA expression levels of LOX-1 and TNF-α showed a tendency to suppress by the combined treatment. These results indicated that the combined administration of catechins and caffeine has the inhibitory effect on the development of atherosclerosis in mice.

  14. Effects of transplanted circulating endothelial progenitor cells and platelet microparticles in atherosclerosis development.

    PubMed

    Georgescu, Adriana; Alexandru, Nicoleta; Andrei, Eugen; Dragan, Emanuel; Cochior, Daniel; Dias, Sérgio

    2016-08-01

    Atherosclerosis is an inflammatory disease, in which risk factors such as hyperlipidemia and hypertension affect the arterial endothelium, resulting in dysfunction, cell damage or both. The number of circulating endothelial progenitor cells and microparticles provides invaluable outcome prediction for atherosclerosis disease. However, evidence for the therapeutic potential of endothelial progenitor cells and microparticles in atherosclerosis development is limited. Our study was designed to investigate the possible protective role of a cell therapy-based approach, using endothelial progenitor cells and the dual behaviour of circulating platelet microparticles, on atherosclerosis development in hypertensive-hypercholesterolemic hamster model. Consequently, control hamsters received four intravenous inoculations of: (1) 1×10(5) endothelial progenitor cells of healthy origins in one dose per month, during four months of diet-induced atherosclerosis, and after hypertensive-hypercholesterolemic diet for further four months; (2) in a second set of experiments, 1×10(5) endothelial progenitor cells of healthy origins or/and 1×10(5) platelet microparticles of atherosclerotic origins were inoculated every other month during hypertensive-hypercholesterolemic diet. Endothelial progenitor cell treatment had the following effects: (1) re-established plasmatic parameters: cholesterol and triglyceride concentrations, blood pressure, heart rate, cytokine and chemokine profiles, platelet microparticle pro-thrombotic activity and endothelial progenitor cell paracrine activity reflected by cytokine/chemokine detection; (2) reduced lipid, macrophage and microparticle accumulation in liver; (3) reduced atherosclerosis development, revealed by decreased lipid, macrophage and microparticle content of arterial wall; (4) induced the recruitment and incorporation of endothelial progenitor cells into liver and arterial wall; (5) improved arterial dysfunction by increasing contraction and

  15. Effect of long-term dietary sphingomyelin supplementation on atherosclerosis in mice

    PubMed Central

    Chung, Rosanna W. S.; Wang, Zeneng; Bursill, Christina A.; Wu, Ben J.; Barter, Philip J.

    2017-01-01

    Sphingomyelin (SM) levels in the circulation correlate positively with atherosclerosis burden. SM is a ubiquitous component of human diets, but it is unclear if dietary SM increases circulating SM levels. Dietary choline increases atherosclerosis by raising circulating trimethylamine N-oxide (TMAO) levels in mice and humans. As SM has a choline head group, we ask in this study if dietary SM accelerates atherosclerotic lesion development by increasing circulating SM and TMAO levels. Three studies were performed: (Study 1) C57BL/6 mice were maintained on a high fat diet with or without SM supplementation for 4 weeks prior to quantification of serum TMAO and SM levels; (Study 2) atherosclerosis was studied in apoE-/- mice after 16 weeks of a high fat diet without or with SM supplementation and (Study 3) apoE-/- mice were maintained on a chow diet for 19 weeks without or with SM supplementation and antibiotic treatment prior to quantification of atherosclerotic lesions and serum TMAO and SM levels. SM consumption did not increase circulating SM levels or atherosclerosis in high fat-fed apoE-/- mice. Serum TMAO levels in C57BL/6 mice were low and had no effect atherosclerosis lesion development. Dietary SM supplementation significantly reduced atherosclerotic lesion area in the aortic arch of chow-fed apoE-/- mice. This study establishes that dietary SM does not affect circulating SM levels or increase atherosclerosis in high fat-fed apoE-/- mice, but it is anti-atherogenic in chow-fed apoE-/- mice. PMID:29240800

  16. Ageing induced vascular smooth muscle cell senescence in atherosclerosis.

    PubMed

    Uryga, Anna K; Bennett, Martin R

    2016-04-15

    Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing include evidence of cell senescence, DNA damage (including telomere attrition), mitochondrial dysfunction, a pro-inflammatory secretory phenotype, defects in proteostasis, epigenetic changes, deregulated nutrient sensing, and exhaustion of progenitor cells. In this model, initial damage to DNA (genomic, telomeric, mitochondrial and epigenetic changes) results in a number of cellular responses (cellular senescence, deregulated nutrient sensing and defects in proteostasis). Ultimately, ongoing damage and attempts at repair by continued proliferation overwhelm reparative capacity, causing loss of specialised cell functions, cell death and inflammation. This review summarises the evidence for accelerated biological ageing in atherosclerosis, the functional consequences of cell ageing on cells comprising the plaque, and the causal role that VSMC senescence plays in atherogenesis. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  17. Local factors modify the dose dependence of 56Fe-induced atherosclerosis.

    NASA Astrophysics Data System (ADS)

    Kucik, Dennis; Gupta, Kiran; Wu, Xing; Yu, Tao; Chang, Polly; Kabarowski, Janusz; Yu, Shaohua

    2012-07-01

    Radiation exposure from a number of terrestrial sources is associated with an increased risk of cardiovascular disease, but evidence establishing whether high-LET radiation has similar effects has been lacking. We recently demonstrated that 600 MeV/n 56Fe induces atherosclerosis as well. Ten-week old male apolipoprotein-E deficient mice, a well-characterized atherosclerosis animal model, were exposed to 0 (control) 2, or 5Gy 56Fe targeted to the chest and neck. In these mice, 56Fe-induced atherosclerosis was similar in character to that induced by X-rays in the same mouse model and to that resulting from therapeutic radiation in cancer patients. Atherosclerosis was exacerbated by 56Fe only in targeted areas, however, suggesting a direct effect of the radiation on the arteries themselves. This is in contrast to some other risk factors, such as high cholesterol or tobacco use, which have systemic effects. The radiation dose required to accelerate development of atherosclerotic plaques, however, differed depending on the vessel that was irradiated and even the location within the vessel. For example, atherosclerosis in the aortic arch was accelerated only by the highest dose (5 Gy), while the carotid arteries and the aortic root showed effects at 2 Gy (a dose four- to eight-fold lower than the dose of X-rays that produces similar effects in this model). Since shear stress is disrupted in the area of the aortic root, it is likely that at least part of the site-specificity is due to additive or synergistic effects of radiation and local hydrodynamics. Other factors, such as local oxidative stress or gene expression may also have been involved. Since the pro-atherogenic effects of 56Fe depend on additional local factors, this suggests that radiation exposure, when unavoidable, might be mitigated by modification of factors unrelated to the radiation itself.

  18. Induction of atherosclerosis in mice and hamsters without germline genetic engineering.

    PubMed

    Bjørklund, Martin Maeng; Hollensen, Anne Kruse; Hagensen, Mette Kallestrup; Dagnaes-Hansen, Frederik; Christoffersen, Christina; Mikkelsen, Jacob Giehm; Bentzon, Jacob Fog

    2014-05-23

    Atherosclerosis can be achieved in animals by germline genetic engineering, leading to hypercholesterolemia, but such models are constrained to few species and strains, and they are difficult to combine with other powerful techniques involving genetic manipulation or variation. To develop a method for induction of atherosclerosis without germline genetic engineering. Recombinant adeno-associated viral vectors were engineered to encode gain-of-function proprotein convertase subtilisin/kexin type 9 mutants, and mice were given a single intravenous vector injection followed by high-fat diet feeding. Plasma proprotein convertase subtilisin/kexin type 9 and total cholesterol increased rapidly and were maintained at high levels, and after 12 weeks, mice had atherosclerotic lesions in the aorta. Histology of the aortic root showed progression of lesions to the fibroatheromatous stage. To demonstrate the applicability of this method for rapid analysis of the atherosclerosis susceptibility of a mouse strain and for providing temporal control over disease induction, we demonstrated the accelerated atherosclerosis of mature diabetic Akita mice. Furthermore, the versatility of this approach for creating atherosclerosis models also in nonmurine species was demonstrated by inducing hypercholesterolemia and early atherosclerosis in Golden Syrian hamsters. Single injections of proprotein convertase subtilisin/kexin type 9-encoding recombinant adeno-associated viral vectors are a rapid and versatile method to induce atherosclerosis in animals. This method should prove useful for experiments that are high-throughput or involve genetic techniques, strains, or species that do not combine well with current genetically engineered models. © 2014 American Heart Association, Inc.

  19. Vascular smooth muscle cell apoptosis is an early trigger for hypothyroid atherosclerosis.

    PubMed

    Wang, Pei; Xu, Tian-Ying; Guan, Yun-Feng; Zhao, Yan; Li, Zhi-Yong; Lan, Xiao-Hong; Wang, Xia; Yang, Peng-Yuan; Kang, Zhi-Min; Vanhoutte, Paul M; Miao, Chao-Yu

    2014-06-01

    Endothelial dysfunction is an initial and vascular smooth muscle cell (VSMC) apoptosis, a later step of atherosclerosis. Hypothyroidism accelerates atherosclerosis. However, the early events responsible for this pro-atherosclerotic effect are unclear. Rats were resistant to induction of atherosclerosis by high cholesterol diet alone, but became susceptible in hypothyroid state achieved by administration of propylthiouracil (PTU) for 6 weeks. VSMC dysfunction and apoptosis were obvious within 1 week after PTU treatment, without signs of endothelial dysfunction. This early VSMC damage was caused by hypothyroidism but not the high cholesterol diet. In ApoE knockout mice, PTU-induced hypothyroidism triggered early VSMC apoptosis, increased oxidative stress, and accelerated atherosclerosis development. Thyroid hormone supplementation (T4, 10, or 50 μg/kg) prevented atherogenic phenotypes in hypothyroid rats and mice. In rats, thyroidectomy caused severe hypothyroidism 5 days after operation, which also led to rapid VSMC dysfunction and apoptosis. In vitro studies did not show a direct toxic effect of PTU on VSMCs. In contrast, thyroid hormone (T3, 0.75 μg/L plus T4, 50 nmol/L) exerted a direct protection against VSMC apoptosis, which was reduced by knockdown of TRα1, rather than TRβ1 and TRβ2 receptors. TRα1-mediated inhibition of apoptotic signalling of JNKs and caspase-3 contributed to the anti-apoptotic action of thyroid hormone. These findings provide an in vivo example for VSMC apoptosis as an early trigger of hypothyroidism-associated atherosclerosis, and reveal activation of TRα1 receptors to prevent VSMC apoptosis as a therapeutic strategy in this disease. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  20. THE INFLUENCE OF INTRAVENOUSLY ADMINISTERED SURFACE-ACTIVE AGENTS ON THE DEVELOPMENT OF EXPERIMENTAL ATHEROSCLEROSIS IN RABBITS

    PubMed Central

    Kellner, Aaron; Correll, James W.; Ladd, Anthony T.

    1951-01-01

    A study was made of the relationship of blood lipids to the development of experimental atherosclerosis. Rabbits fed a diet containing cholesterol were found to develop hyperlipemia characterized by a great increase in blood cholesterol and a much lesser increase in blood phospholipids; after several weeks they manifested conspicuous atherosclerosis of the aorta, as has often been observed by others. Comparable rabbits fed the same diets containing added cholesterol were given in addition repeated intravenous injections of the surface-active agents Tween 80 and Triton A20; these animals developed hyperlipemia which was characterized by a great increase in blood cholesterol and an equivalent or even greater increase in phospholipids, and they had much less atherosclerosis than did the control rabbits fed cholesterol alone. In further experiments it was observed that repeated intravenous injections of Tween 80 did not result in resorption of previously induced atherosclerosis in rabbits. The findings are discussed in relation to the pathogenesis of natural and experimental atherosclerosis. PMID:14824410

  1. Hepatic JAK2 protects against atherosclerosis through circulating IGF-1

    PubMed Central

    Sivasubramaniyam, Tharini; Schroer, Stephanie A.; Li, Angela; Luk, Cynthia T.; Shi, Sally Yu; Besla, Rickvinder; Metherel, Adam H.; Kitson, Alex P.; Brunt, Jara J.; Lopes, Joshua; Wagner, Kay-Uwe; Bazinet, Richard P.; Bendeck, Michelle P.; Robbins, Clinton S.

    2017-01-01

    Atherosclerosis is considered both a metabolic and inflammatory disease; however, the specific tissue and signaling molecules that instigate and propagate this disease remain unclear. The liver is a central site of inflammation and lipid metabolism that is critical for atherosclerosis, and JAK2 is a key mediator of inflammation and, more recently, of hepatic lipid metabolism. However, precise effects of hepatic Jak2 on atherosclerosis remain unknown. We show here that hepatic Jak2 deficiency in atherosclerosis-prone mouse models exhibited accelerated atherosclerosis with increased plaque macrophages and decreased plaque smooth muscle cell content. JAK2’s essential role in growth hormone signalling in liver that resulted in reduced IGF-1 with hepatic Jak2 deficiency played a causal role in exacerbating atherosclerosis. As such, restoring IGF-1 either pharmacologically or genetically attenuated atherosclerotic burden. Together, our data show hepatic Jak2 to play a protective role in atherogenesis through actions mediated by circulating IGF-1 and, to our knowledge, provide a novel liver-centric mechanism in atheroprotection. PMID:28724798

  2. Fluorescence spectroscopic detection of virus-induced atherosclerosis

    NASA Astrophysics Data System (ADS)

    Yan, Wei-dong; Perk, Masis; Nation, Patric N.; Power, Robert F.; Liu, Liying; Jiang, Xiuyan; Lucas, Alexandra

    1994-07-01

    Laser-induced fluorescence (LF) has been developed as a diagnostic tool for the detection of atherosclerosis. We have examined the use of LF for the identification of accelerated atherosclerotic plaque growth induced by Marek's Disease Virus (MDV) infection in White Leghorn rooster chicks (R) as well as plaque regression after treatment. Twenty-eight newborn R were infected with 12,000 cfu of MDV. Twelve parallel control R had saline injection. LF spectra were recorded from the arteries in vitro with a CeramOptec laser angioplasty catheter during 308 nm XeCl excimer laser excitation. Significant differences were detected at 440 to 475, 525, 550, 600, and 650 nm in MDV-R (p<0.05). In a subsequent study, 60 R were infected with 5,000 cfu of MDV, and were then treated with either Pravastatin (PRV) or placebo at 3 months post infection. These PRV-R were followed for 6 months to detect changes in atherosclerotic plaque development. PRV reduced intimal proliferation produced by MDV infection on histological examination (PRV-R 128.0+/- 44.0 micrometers , placebo-R 412.2+/- 91.5 micrometers , pequals0.007). MDV infected, PRV treated R were examined for LF changes that correlated with decreased atherosclerosis. There was an associated significant increase in LF intensity in PRV-R at 405 to 425 nm (p<0.001). In conclusion, LF can detect intimal proliferation in virus- induced atherosclerosis and atherosclerotic plaque regression after PRV therapy.

  3. A Rabbit Model for Testing Helper-Dependent Adenovirus-Mediated Gene Therapy for Vein Graft Atherosclerosis.

    PubMed

    Bi, Lianxiang; Wacker, Bradley K; Bueren, Emma; Ham, Ervin; Dronadula, Nagadhara; Dichek, David A

    2017-12-15

    Coronary artery bypass vein grafts are a mainstay of therapy for human atherosclerosis. Unfortunately, the long-term patency of vein grafts is limited by accelerated atherosclerosis. Gene therapy, directed at the vein graft wall, is a promising approach for preventing vein graft atherosclerosis. Because helper-dependent adenovirus (HDAd) efficiently transduces grafted veins and confers long-term transgene expression, HDAd is an excellent candidate for delivery of vein graft-targeted gene therapy. We developed a model of vein graft atherosclerosis in fat-fed rabbits and demonstrated long-term (≥20 weeks) persistence of HDAd genomes after graft transduction. This model enables quantitation of vein graft hemodynamics, wall structure, lipid accumulation, cellularity, vector persistence, and inflammatory markers on a single graft. Time-course experiments identified 12 weeks after transduction as an optimal time to measure efficacy of gene therapy on the critical variables of lipid and macrophage accumulation. We also used chow-fed rabbits to test whether HDAd infusion in vein grafts promotes intimal growth and inflammation. HDAd did not increase intimal growth, but had moderate-yet significant-pro-inflammatory effects. The vein graft atherosclerosis model will be useful for testing HDAd-mediated gene therapy; however, pro-inflammatory effects of HdAd remain a concern in developing HDAd as a therapy for vein graft disease.

  4. Combined therapy of dietary fish oil and stearoyl-CoA desaturase 1 inhibition prevents the metabolic syndrome and atherosclerosis.

    PubMed

    Brown, J Mark; Chung, Soonkyu; Sawyer, Janet K; Degirolamo, Chiara; Alger, Heather M; Nguyen, Tam M; Zhu, Xuewei; Duong, My-Ngan; Brown, Amanda L; Lord, Caleb; Shah, Ramesh; Davis, Matthew A; Kelley, Kathryn; Wilson, Martha D; Madenspacher, Jennifer; Fessler, Michael B; Parks, John S; Rudel, Lawrence L

    2010-01-01

    Stearoyl-CoA desaturase 1 (SCD1) is a critical regulator of energy metabolism and inflammation. We have previously reported that inhibition of SCD1 in hyperlipidemic mice fed a saturated fatty acid (SFA)-enriched diet prevented development of the metabolic syndrome, yet surprisingly promoted severe atherosclerosis. In this study we tested whether dietary fish oil supplementation could prevent the accelerated atherosclerosis caused by SCD1 inhibition. LDLr(-/-), ApoB(100/100) mice were fed diets enriched in saturated fat or fish oil in conjunction with antisense oligonucleotide (ASO) treatment to inhibit SCD1. As previously reported, in SFA-fed mice, SCD1 inhibition dramatically protected against development of the metabolic syndrome, yet promoted atherosclerosis. In contrast, in mice fed fish oil, SCD1 inhibition did not result in augmented macrophage inflammatory response or severe atherosclerosis. In fact, the combined therapy of dietary fish oil and SCD1 ASO treatment effectively prevented both the metabolic syndrome and atherosclerosis. SCD1 ASO treatment in conjunction with dietary fish oil supplementation is an effective combination therapy to comprehensively combat the metabolic syndrome and atherosclerosis in mice.

  5. 2013 Russell Ross memorial lecture in vascular biology: cellular and molecular mechanisms of diabetes mellitus-accelerated atherosclerosis.

    PubMed

    Bornfeldt, Karin E

    2014-04-01

    Adults with diabetes mellitus are much more likely to have cardiovascular disease than those without diabetes mellitus. Genetically engineered mouse models have started to provide important insight into the mechanisms whereby diabetes mellitus promotes atherosclerosis. Such models have demonstrated that diabetes mellitus promotes formation of atherosclerotic lesions, progression of lesions into advanced hemorrhaged lesions, and that it prevents lesion regression. The proatherosclerotic effects of diabetes mellitus are driven in part by the altered function of myeloid cells. The protein S100A9 and the receptor for advanced glycation end-products are important modulators of the effect of diabetes mellitus on myelopoiesis, which might promote monocyte accumulation in lesions. Furthermore, myeloid cell expression of the enzyme acyl-CoA synthetase 1 (ACSL1), which converts long-chain fatty acids into their acyl-CoA derivatives, has emerged as causal to diabetes mellitus-induced lesion initiation. The protective effects of myeloid ACSL1-deficiency in diabetic mice, but not in nondiabetic mice, indicate that myeloid cells are activated by diabetes mellitus through mechanisms that play minor roles in the absence of diabetes mellitus. The roles of reactive oxygen species and insulin resistance in diabetes mellitus-accelerated atherosclerosis are also discussed, primarily in relation to endothelial cells. Translational studies addressing whether the mechanisms identified in mouse models are equally important in humans with diabetes mellitus will be paramount.

  6. Rate of atherosclerosis progression in ApoE-/- mice long after discontinuation of cola beverage drinking.

    PubMed

    Otero-Losada, Matilde; Cao, Gabriel; Mc Loughlin, Santiago; Rodríguez-Granillo, Gastón; Ottaviano, Graciela; Milei, José

    2014-01-01

    This study was conducted in order to evaluate the effect of cola beverages drinking on atherosclerosisand test the hypothesis whether cola beverages consumption at early life stages might affect the development and progression of atherosclerosis later in life. ApoE-/- C57BL/6J mice (8 week-old) were randomized in 3 groups (n = 20 each) according to free accessto water (W), sucrose sweetened carbonated cola drink(C) or aspartame-acesulfame K sweetened carbonated 'light' cola drink (L)for the next 8 weeks. Drinking treatment was ended by switching C and L groups to drinking water. Four mice per group and time were sequentially euthanized: before treatment (8 weeks-old), at the end of treatment (16 weeks-old) and after treatment discontinuation (20 weeks-old, 24 weeks-old, 30 week-old mice). Aortic roots and livers were harvested, processed for histology and serial cross-sections were stained. Aortic plaque area was analyzed and plaque/media-ratio was calculated. Early consumption of cola drinks accelerated atherosclerotic plaque progression favoring the interaction between macrophages and myofibroblasts, without the participation of either T lymphocytes or proliferative activity. Plaque/media-ratio varied according to drink treatment (F2,54 = 3.433, p<0.04) and mice age (F4,54 = 5.009, p<0.03) and was higher in C and L groups compared with age-matched W group (p<0.05 at 16 weeks and 20 weeks, p<0.01 at 24 weeks and 30 weeks). Natural evolution of atherosclerosis in ApoE-/- mice (W group) evidenced atherosclerosis acceleration in parallel with a rapid increase in liver inflammation around the 20 weeks of age. Cola drinking within the 8-16 weeks of age accelerated atherosclerosis progression in ApoE-/- mice favoring aortic plaque enlargement (inward remodeling) over media thinning all over the study time. Data suggest that cola drinking at early life stages may predispose to atherosclerosis progression later in life in ApoE-/- mice.

  7. miR-146a deficiency in hematopoietic cells is not involved in the development of atherosclerosis.

    PubMed

    Del Monte, Alberto; Arroyo, Ana B; Andrés-Manzano, María J; García-Barberá, Nuria; Caleprico, María S; Vicente, Vicente; Roldán, Vanessa; González-Conejero, Rocío; Martínez, Constantino; Andrés, Vicente

    2018-01-01

    Atherosclerosis involves activation of the IRAK1/TRAF6/NF-κB inflammatory cascade, which is negatively regulated by miR146a. Previous studies showed that the TT genotype of rs2431697, located near the miR-146a gene, drives lower miR-146a transcription and predicts adverse cardiovascular events in anticoagulated atrial fibrillation patients. Moreover, systemic miR-146a administration protects mice from atherosclerosis. Here we evaluated the ability of miR-146a expression in the hematopoietic component to regulate atherosclerosis in low-density lipoprotein receptor-null mice (Ldlr-/-). Lethally-irradiated Ldlr-/- mice transplanted with bone marrow from wild-type or miR-146a-null mice were fed an atherogenic diet for 8 and 20 weeks. Irak1, Traf6 and MIR146A expression were quantified in thoracic aorta by qRT-PCR and Western blot. Aortic plaque size and composition were characterized by Oil-Red staining and immunohistochemistry and leukocyte recruitment by intravital microscopy. Blood cell counts were similar in fat-fed Ldlr-/-mice with or without hematopoietic miR-146a expression. However, plasma cholesterol decreased in fat-fed Ldlr-/-mice transplanted with bone marrow deficient for miR-146a. Finally, aortic atherosclerosis burden and recruitment of leukocytes into the vessel wall were undistinguishable between the two groups, despite higher levels of Irak1 and Traf6 mRNA and protein in the aorta of fat-fed mice lacking hematopoietic miR-146a expression. miR-146a deficiency exclusively in hematopoietic cells modulates cholesterol levels in plasma and the expression of its targets in the artery wall of fat-fed Ldlr-/- mice, but does not accelerate atherosclerosis. Atheroprotection upon systemic miR-146a administration may therefore be caused by specific effects on vascular cells.

  8. Progress and future opportunities in the development of vaccines against atherosclerosis.

    PubMed

    Govea-Alonso, Dania O; Beltrán-López, Josué; Salazar-González, Jorge A; Vargas-Morales, Juan; Rosales-Mendoza, Sergio

    2017-04-01

    Atherosclerosis represents a serious global health problem that demands new therapeutic and prophylactic interventions. Considering that atherosclerosis has autoimmune and inflammatory components, immunotherapy is a possible focus to treat this disease. Areas covered: Based on the analysis of the current biomedical literature, this review describes the status on the development of vaccines against atherosclerosis. Several targets have been identified including sequences of apolipoprotein B100 (ApoB100), cholesteryl ester transfer protein (CETP), heat shock proteins (HSP), extracellular matrix proteins, T cell receptor β chain variable region 31 (TRBV31), the major outer membrane protein (MOMP), and the outer membrane protein 5 (Pomp5) from Chlamydia pneumoniae. Humoral and cellular immunities to these targets have been associated with therapeutic effects in murine models and humans. The evaluation of some candidates in clinical trials is ongoing. Expert commentary: New research paths based on the use of next generation vaccine production platforms are envisioned.

  9. Changes of lysosomes in the earliest stages of the development of atherosclerosis.

    PubMed

    Bobryshev, Yuri V; Shchelkunova, Tatyana A; Morozov, Ivan A; Rubtsov, Petr M; Sobenin, Igor A; Orekhov, Alexander N; Smirnov, Alexander N

    2013-05-01

    One of hypotheses of atherosclerosis is based on a presumption that the zones prone to the development of atherosclerosis contain lysosomes which are characterized by enzyme deficiency and thus, are unable to dispose of lipoproteins. The present study was undertaken to investigate the characteristics and changes of lysosomes in the earliest stages of the development of atherosclerosis. Electron microscopic immunocytochemistry revealed that there were certain changes in the distribution of CD68 antigen in lysosomes along the 'normal intima-initial lesion-fatty streak' sequence. There were no significant changes found in the key mRNAs encoding for the components of endosome/lysosome compartment in initial atherosclerotic lesions, but in fatty streaks, the contents of EEA1 and Rab5a mRNAs were found to be diminished while the contents of CD68 and p62 mRNAs were increased, compared with the intact tissue. The study reinforces a view that changes occurring in lysosomes play a role in atherogenesis from the very earlier stages of the disease. © 2013 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  10. Rate of Atherosclerosis Progression in ApoE−/− Mice Long After Discontinuation of Cola Beverage Drinking

    PubMed Central

    Otero-Losada, Matilde; Cao, Gabriel; Mc Loughlin, Santiago; Rodríguez-Granillo, Gastón; Ottaviano, Graciela; Milei, José

    2014-01-01

    This study was conducted in order to evaluate the effect of cola beverages drinking on atherosclerosisand test the hypothesis whether cola beverages consumption at early life stages might affect the development and progression of atherosclerosis later in life. ApoE−/− C57BL/6J mice (8 week-old) were randomized in 3 groups (n = 20 each) according to free accessto water (W), sucrose sweetened carbonated cola drink(C) or aspartame-acesulfame K sweetened carbonated ‘light’ cola drink (L)for the next 8 weeks. Drinking treatment was ended by switching C and L groups to drinking water. Four mice per group and time were sequentially euthanized: before treatment (8weeks-old), at the end of treatment (16 weeks-old) and after treatment discontinuation (20 weeks-old, 24 weeks-old, 30 week-old mice). Aortic roots and livers were harvested, processed for histology and serial cross-sections were stained. Aortic plaque area was analyzed and plaque/media-ratio was calculated. Early consumption of cola drinks accelerated atherosclerotic plaque progression favoring the interaction between macrophages and myofibroblasts, without the participation of either T lymphocytes or proliferative activity. Plaque/media-ratio varied according to drink treatment (F2,54 = 3.433, p<0.04) and mice age (F4,54 = 5.009, p<0.03) and was higher in C and L groups compared with age-matched W group (p<0.05 at 16 weeks and 20 weeks, p<0.01 at 24 weeks and 30 weeks). Natural evolution of atherosclerosis in ApoE−/− mice (W group) evidenced atherosclerosis acceleration in parallel with a rapid increase in liver inflammation around the 20 weeks of age. Cola drinking within the 8–16 weeks of age accelerated atherosclerosis progression in ApoE−/− mice favoring aortic plaque enlargement (inward remodeling) over media thinning all over the study time. Data suggest that cola drinking at early life stages may predispose to atherosclerosis progression later in life in ApoE−/− mice

  11. Novel anti-inflammatory therapies for the treatment of atherosclerosis.

    PubMed

    Khan, Razi; Spagnoli, Vincent; Tardif, Jean-Claude; L'Allier, Philippe L

    2015-06-01

    The underlying role of inflammation in atherosclerosis has been characterized. However, current treatment of coronary artery disease (CAD) predominantly consists of targeted reductions in serum lipoprotein levels rather than combating the deleterious effects of acute and chronic inflammation. Vascular inflammation acts by a number of different molecular and cellular pathways to contribute to atherogenesis. Over the last decades, both basic studies and clinical trials have provided evidence for the potential benefits of treatment of inflammation in CAD. During this period, development of pharmacotherapies directed towards inflammation in atherosclerosis has accelerated quickly. This review will highlight specific therapies targeting interleukin-1β (IL-1β), P-selectin and 5-lipoxygenase (5-LO). It will also aim to examine the anti-inflammatory effects of serpin administration, colchicine and intravenous HDL-directed treatment of CAD. We summarize the mechanistic rationale and evidence for these novel anti-inflammatory treatments at both the experimental and clinical levels. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. [Epigenetics in atherosclerosis].

    PubMed

    Guardiola, Montse; Vallvé, Joan C; Zaina, Silvio; Ribalta, Josep

    2016-01-01

    The association studies based on candidate genes carried on for decades have helped in visualizing the influence of the genetic component in complex diseases such as atherosclerosis, also showing the interaction between different genes and environmental factors. Even with all the knowledge accumulated, there is still some way to go to decipher the individual predisposition to disease, and if we consider the great influence that environmental factors play in the development and progression of atherosclerosis, epigenetics is presented as a key element in trying to expand our knowledge on individual predisposition to atherosclerosis and cardiovascular disease. Epigenetics can be described as the discipline that studies the mechanisms of transcriptional regulation, independent of changes in the sequence of DNA, and mostly induced by environmental factors. This review aims to describe what epigenetics is and how epigenetic mechanisms are involved in atherosclerosis. Copyright © 2015 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

  13. Regulation of programmed cell death or apoptosis in atherosclerosis.

    PubMed

    Geng, Y J

    1997-01-01

    Intimal thickening caused by accumulation of cells, lipids, and connective tissue characterizes atherosclerosis, an arterial disease that leads to cardiac and cerebral infarction. Apoptosis, or genetically programmed cell death, is important for the development and morphogenesis of organs and tissues. As in other tissues, cells of cardiovascular tissues can undergo apoptosis. Increased apoptosis has been found in both human and animal atherosclerotic lesions, mediating tissue turnover and lesion development. In addition to vascular cells, many activated immune cells, mainly macrophages and T cells, are present in atherosclerotic lesions, where these cells produce biologically active substances such as the proinflammatory cytokines tumor necrosis factor, interleukin-1 (IL-1), and interferon-gamma. Simultaneous exposure to these cytokines may trigger apoptosis of vascular smooth muscle cells. The products of death-regulating genes including Fas/Fas ligand, members of IL-1 beta cysteinyl protease (caspase) family, the tumor suppressive gene p53, and the protooncogene c-myc have been found in vascular cells and may participate in the regulation of vascular apoptosis during the development of atherosclerosis. Abnormal occurrence of apoptosis may take place in atherosclerotic lesions, including attenuation or acceleration of the apoptotic death process. The former may cause an increase in the cellularity of the lesions, and the latter can reduce cellular components important for maintaining the integrity and stability of the plaques. Clarification of the molecular mechanism that regulates apoptosis may help design a new strategy for treatment of patients with atherosclerosis and its major complications, heart attack and stroke.

  14. Cyanotic congenital heart disease and atherosclerosis.

    PubMed

    Tarp, Julie Bjerre; Jensen, Annette Schophuus; Engstrøm, Thomas; Holstein-Rathlou, Niels-Henrik; Søndergaard, Lars

    2017-06-01

    Improved treatment options in paediatric cardiology and congenital heart surgery have resulted in an ageing population of patients with cyanotic congenital heart disease (CCHD). The risk of acquired heart disease such as atherosclerosis increases with age.Previous studies have speculated whether patients with CCHD are protected against atherosclerosis. Results have shown that the coronary arteries of patients with CCHD are free from plaques and stenosis. Decreased carotid intima-media thickness and low total plasma cholesterol may indicate a reduced risk of later development of atherosclerosis. However, the evidence is still sparse and questionable, and a reasonable explanation for the decreased risk of developing atherosclerosis in patients with CCHD is still missing.This review provides an overview of what is known about the prevalence and potential causes of the reduced risk of atherosclerosis in patients with CCHD. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  15. BAFF Receptor mAb Treatment Ameliorates Development and Progression of Atherosclerosis in Hyperlipidemic ApoE−/− Mice

    PubMed Central

    Kyaw, Tin; Cui, Peng; Tay, Christopher; Kanellakis, Peter; Hosseini, Hamid; Liu, Edgar; Rolink, Antonius G.; Tipping, Peter

    2013-01-01

    Aims Option to attenuate atherosclerosis by depleting B2 cells is currently limited to anti-CD20 antibodies which deplete all B-cell subtypes. In the present study we evaluated the capacity of a monoclonal antibody to B cell activating factor-receptor (BAFFR) to selectively deplete atherogenic B2 cells to prevent both development and progression of atherosclerosis in the ApoE−/− mouse. Methods and Results To determine whether the BAFFR antibody prevents atherosclerosis development, we treated ApoE−/− mice with the antibody while feeding them a high fat diet (HFD) for 8 weeks. Mature CD93− CD19+ B2 cells were reduced by treatment, spleen B-cell zones disrupted and spleen CD20 mRNA expression decreased while B1a cells and non-B cells were spared. Atherosclerosis was ameliorated in the hyperlipidemic mice and CD19+ B cells, CD4+ and CD8+ T cells were reduced in atherosclerotic lesions. Expressions of proinflammatory cytokines, IL1β, TNFα, and IFNγ in the lesions were also reduced, while MCP1, MIF and VCAM-1 expressions were unaffected. Plasma immunoglobulins were reduced, but MDA-oxLDL specific antibodies were unaffected. To determine whether anti-BAFFR antibody ameliorates progression of atherosclerosis, we first fed ApoE−/− mice a HFD for 6 weeks, and then instigated anti-BAFFR antibody treatment for a further 6 week-HFD. CD93− CD19+ B2 cells were selectively decreased and atherosclerotic lesions were reduced by this treatment. Conclusion Anti-BAFFR monoclonal antibody selectively depletes mature B2 cells while sparing B1a cells, disrupts spleen B-cell zones and ameliorates atherosclerosis development and progression in hyperlipidemic ApoE−/− mice. Our findings have potential for clinical translation to manage atherosclerosis-based cardiovascular diseases. PMID:23560095

  16. Omega-3 fatty acid supplement prevents development of intracranial atherosclerosis.

    PubMed

    Shen, Jiamei; Hafeez, Adam; Stevenson, James; Yang, Jianjie; Yin, Changbin; Li, Fengwu; Wang, Sainan; Du, Huishan; Ji, Xunming; Rafols, Jose A; Geng, Xiaokun; Ding, Yuchuan

    2016-10-15

    Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and, in particular, has been implicated as a leading cause of recurrent ischemic stroke. We adapted a rat model of atherosclerosis to study brain intracranial atherosclerosis, and further investigated the effect of omega-3 fatty acids (O3FA) in attenuating development of ICAS. Adult male Sprague-Dawley rats were divided into control normal-cholesterol or high-cholesterol diet groups with or without O3FA for up to 6weeks. During the first 2weeks, NG-nitro-l-arginine methyl ester (l-NAME, 3mg/mL) was added to the drinking water of the high-cholesterol groups. The rats received supplementation with O3FA (5mg/kg/day) by gavages. Blood lipids including low density lipoprotein (LDL), cholesterol (CHO), triglycerides (TG) and high density lipoprotein (HDL) were measured at 3 and 6weeks. The lumen of middle cerebral artery (MCA) and the thickness of the vessel wall were assessed. Inflammatory molecular markers were assessed by Western blot. A high-cholesterol diet exhibited a significant increase in the classic blood markers (LDL, CHO, and TG) for atherosclerosis, as well as a decrease in HDL. These markers were found to be progressively more severe with time. Lumen stenosis and intimal thickening were increased in MCA. O3FA showed attenuation of blood lipids with an absence of morphological changes. O3FA significantly reduced the inflammatory marker CD68 in MCA and prevented monocyte chemotactic protein (MCP-1) and interferon-γ (IFN-γ) expression in the brain. O3FA similarly decreased inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6), markers affiliated with monocyte activity in atherosclerosis. Furthermore, O3FA significantly inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1), a marker for endothelial activation. Lastly, O3FA increased ATP-binding cassette transporter A1 (ABCA1) protein expression via

  17. Atherosclerosis in chronic kidney disease: the role of macrophages

    PubMed Central

    Kon, Valentina; Linton, MacRae F.; Fazio, Sergio

    2013-01-01

    Patients with chronic kidney disease (CKD) are at increased risk of atherosclerotic cardiovascular disease and loss of renal parenchyma accelerates atherosclerosis in animal models. Macrophages are central to atherogenesis because they regulate cholesterol traffic and inflammation in the arterial wall. CKD influences macrophage behavior at multiple levels, rendering them proatherogenic. Even at normal creatinine levels, macrophages from uninephrectomized Apoe−/− mice are enriched in cholesterol owing to downregulation of cholesterol transporter ATP-binding cassette subfamily A member 1 levels and activation of nuclear factor κB, which leads to impaired cholesterol efflux. Interestingly, treatment with an angiotensin-II-receptor blocker (ARB) improves these effects. Moreover, atherosclerotic aortas from Apoe−/− mice transplanted into renal-ablated normocholesterolemic recipients show plaque progression and increased macrophage content instead of the substantial regression seen in recipient mice with intact kidneys. ARBs reduce atherosclerosis development in mice with partial renal ablation. These results, combined with the clinical benefits of angiotensin-converting-enzyme (ACE) inhibitors and ARBs in patients with CKD, suggest an important role for the angiotensin system in the enhanced susceptibility to atherosclerosis seen across the spectrum of CKD. The role of macrophages could explain why these therapies may be effective in end-stage renal disease, one of the few conditions in which statins show no clinical benefit. PMID:21102540

  18. Ultrasound Imaging for Risk Assessment in Atherosclerosis

    PubMed Central

    Steinl, David C.; Kaufmann, Beat A.

    2015-01-01

    Atherosclerosis and its consequences like acute myocardial infarction or stroke are highly prevalent in western countries, and the incidence of atherosclerosis is rapidly rising in developing countries. Atherosclerosis is a disease that progresses silently over several decades before it results in the aforementioned clinical consequences. Therefore, there is a clinical need for imaging methods to detect the early stages of atherosclerosis and to better risk stratify patients. In this review, we will discuss how ultrasound imaging can contribute to the detection and risk stratification of atherosclerosis by (a) detecting advanced and early plaques; (b) evaluating the biomechanical consequences of atherosclerosis in the vessel wall; (c) assessing plaque neovascularization and (d) imaging the expression of disease-relevant molecules using molecular imaging. PMID:25938969

  19. PDGFRβ signaling regulates local inflammation and synergizes with hypercholesterolemia to promote atherosclerosis

    PubMed Central

    He, Chaoyong; Medley, Shayna C.; Hu, Taishan; Hinsdale, Myron E.; Lupu, Florea; Virmani, Renu; Olson, Lorin E.

    2015-01-01

    Platelet-derived growth factor (PDGF) is a mitogen and chemoattractant for vascular smooth muscle cells (VSMCs). However, the direct effects of PDGF receptor β (PDGFRβ) activation on VSMCs have not been studied in the context of atherosclerosis. Here, we present a new mouse model of atherosclerosis with an activating mutation in PDGFRβ. Increased PDGFRβ signaling induces chemokine secretion and leads to leukocyte accumulation in the adventitia and media of the aorta. Furthermore, PDGFRβD849V amplifies and accelerates atherosclerosis in hypercholesterolemic ApoE−/− or Ldlr−/− mice. Intriguingly, increased PDGFRβ signaling promotes advanced plaque formation at novel sites in the thoracic aorta and coronary arteries. However, deletion of the PDGFRβ-activated transcription factor STAT1 in VSMCs alleviates inflammation of the arterial wall and reduces plaque burden. These results demonstrate that PDGFRβ pathway activation has a profound effect on vascular disease and support the conclusion that inflammation in the outer arterial layers is a driving process for atherosclerosis. PMID:26183159

  20. Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease: A Scientific Statement From the American Heart Association.

    PubMed

    Goldstein, Benjamin I; Carnethon, Mercedes R; Matthews, Karen A; McIntyre, Roger S; Miller, Gregory E; Raghuveer, Geetha; Stoney, Catherine M; Wasiak, Hank; McCrindle, Brian W

    2015-09-08

    In the 2011 "Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents," several medical conditions among youth were identified that predispose to accelerated atherosclerosis and early cardiovascular disease (CVD), and risk stratification and management strategies for youth with these conditions were elaborated. Major depressive disorder (MDD) and bipolar disorder (BD) among youth satisfy the criteria set for, and therefore merit inclusion among, Expert Panel tier II moderate-risk conditions. The combined prevalence of MDD and BD among adolescents in the United States is ≈10%, at least 10 times greater than the prevalence of the existing moderate-risk conditions combined. The high prevalence of MDD and BD underscores the importance of positioning these diseases alongside other pediatric diseases previously identified as moderate risk for CVD. The overall objective of this statement is to increase awareness and recognition of MDD and BD among youth as moderate-risk conditions for early CVD. To achieve this objective, the primary specific aims of this statement are to (1) summarize evidence that MDD and BD are tier II moderate-risk conditions associated with accelerated atherosclerosis and early CVD and (2) position MDD and BD as tier II moderate-risk conditions that require the application of risk stratification and management strategies in accordance with Expert Panel recommendations. In this scientific statement, there is an integration of the various factors that putatively underlie the association of MDD and BD with CVD, including pathophysiological mechanisms, traditional CVD risk factors, behavioral and environmental factors, and psychiatric medications. © 2015 American Heart Association, Inc.

  1. Anti-cytokine therapy for prevention of atherosclerosis.

    PubMed

    Kirichenko, Tatiana V; Sobenin, Igor A; Nikolic, Dragana; Rizzo, Manfredi; Orekhov, Alexander N

    2016-10-15

    Currently a chronic inflammation is considered to be the one of the most important reasons of the atherosclerosis progression. A huge amount of researches over the past few decades are devoted to study the various mechanisms of inflammation in the development of atherosclerotic lesions. To review current capabilities of anti-inflammatory therapy for the prevention and treatment of atherosclerosis and its clinical manifestations. Appropriate articles on inflammatory cytokines in atherosclerosis and anti-inflammatory prevention of atherosclerosis were searched in PubMed Database from their respective inceptions until October 2015. "The role of inflammatory cytokines in the development of atherosclerotic lesions" describes available data on the possible inflammatory mechanisms of the atherogenesis with a special attention to the role of cytokines. "Modern experience of anti-inflammatory therapy for the treatment of atherosclerosis" describes modern anti-inflammatory preparations with anti-atherosclerotic effect including natural preparations. In "the development of anti-inflammatory herbal preparation for atherosclerosis prevention" an algorithm is demonstrated that includes screening of anti-cytokine activity of different natural products, the development of the most effective combination and estimation of its effect in cell culture model, in animal model of the acute aseptic inflammation and in a pilot clinical trial. A natural preparation "Inflaminat" based on black elder berries (Sambucus nigra L.), violet tricolor herb (Viola tricolor L.) and calendula flowers (Calendula officinalis L.) possessing anti-cytokine activity was developed using the designed algorithm. The results of the following 2-year double blind placebo-controlled clinical study show that "Inflaminat" reduces carotid IMT progression, i.e. has anti-atherosclerotic effect. Anti-cytokine therapy may be a promising direction in moderation of atherogenesis, especially when it begins on the early stages

  2. Animal Models of Atherosclerosis

    PubMed Central

    Getz, Godfrey S.; Reardon, Catherine A.

    2012-01-01

    Atherosclerosis is a chronic inflammatory disorder that is the underlying cause of most cardiovascular disease. Both cells of the vessel wall and cells of the immune system participate in atherogenesis. This process is heavily influenced by plasma lipoproteins, genetics and the hemodynamics of the blood flow in the artery. A variety of small and large animal models have been used to study the atherogenic process. No model is ideal as each has its own advantages and limitations with respect to manipulation of the atherogenic process and modeling human atherosclerosis or lipoprotein profile. Useful large animal models include pigs, rabbits and non-human primates. Due in large part to the relative ease of genetic manipulation and the relatively short time frame for the development of atherosclerosis, murine models are currently the most extensively used. While not all aspects of murine atherosclerosis are identical to humans, studies using murine models have suggested potential biological processes and interactions that underlie this process. As it becomes clear that different factors may influence different stages of lesion development, the use of mouse models with the ability to turn on or delete proteins or cells in tissue specific and temporal manner will be very valuable. PMID:22383700

  3. Effects of intra-abdominal sepsis on atherosclerosis in mice.

    PubMed

    Kaynar, Ata Murat; Yende, Sachin; Zhu, Lin; Frederick, Daniel R; Chambers, Robin; Burton, Christine L; Carter, Melinda; Stolz, Donna Beer; Agostini, Brittani; Gregory, Alyssa D; Nagarajan, Shanmugam; Shapiro, Steven D; Angus, Derek C

    2014-09-03

    and vascular cell adhesion molecule 1) and the adhesion assay, a functional measure of endothelial activation, were elevated at 72 hours and 120 hours in mice that underwent CLP versus sham-operations (all at P <0.05). Using a combination of existing murine models for atherosclerosis and sepsis, we found that CLP, a model of intra-abdominal sepsis, accelerates atheroma development. Accelerated atheroma burden was associated with prolonged systemic, endothelial and intimal inflammation and was not explained by ongoing infection. These findings support observations in humans and demonstrate the feasibility of a long-term follow-up murine model of sepsis.

  4. Photoacoustic tomography: applications for atherosclerosis imaging

    NASA Astrophysics Data System (ADS)

    Sangha, Gurneet S.; Goergen, Craig J.

    2016-08-01

    Atherosclerosis is a debilitating condition that increases a patient’s risk for intermittent claudication, limb amputation, myocardial infarction, and stroke, thereby causing approximately 50% of deaths in the western world. Current diagnostic imaging techniques, such as ultrasound, digital subtraction angiography, computed tomography angiography, magnetic resonance angiography, and optical imaging remain suboptimal for detecting development of early stage plaques. This is largely due to the lack of compositional information, penetration depth, and/or clinical efficiency of these traditional imaging techniques. Photoacoustic imaging has emerged as a promising modality that could address some of these limitations to improve the diagnosis and characterization of atherosclerosis-related diseases. Photoacoustic imaging uses near-infrared light to induce acoustic waves, which can be used to recreate compositional images of tissue. Recent developments in photoacoustic techniques show its potential in noninvasively characterizing atherosclerotic plaques deeper than traditional optical imaging approaches. In this review, we discuss the significance and development of atherosclerosis, current and novel clinical diagnostic methods, and recent works that highlight the potential of photoacoustic imaging for both experimental and clinical studies of atherosclerosis.

  5. AIBP reduces atherosclerosis by promoting reverse cholesterol transport and ameliorating inflammation in apoE-/- mice.

    PubMed

    Zhang, Min; Zhao, Guo-Jun; Yao, Feng; Xia, Xiao-Dan; Gong, Duo; Zhao, Zhen-Wang; Chen, Ling-Yan; Zheng, Xi-Long; Tang, Xiao-Er; Tang, Chao-Ke

    2018-06-01

    ApoA-1 binding protein (AIBP) is a secreted protein that interacts with apoA-I and accelerates cholesterol efflux from cells. We have recently reported that AIBP promotes apoA-1 binding to ABCA1 in the macrophage cell membrane, partially through 115-123 amino acids. However, the effects of AIBP on the development of atherosclerosis in vivo remain unknown. ApoE -/- mice with established atherosclerotic plaques were infected with rAAV-AIBP or rAAV-AIBP(Δ115-123), respectively. AIBP-treated mice showed reduction of atherosclerotic lesion formation, increase in circulating HDL levels and enhancement of reverse cholesterol transport to the plasma, liver, and feces. AIBP increased ABCA1 protein levels in aorta and peritoneal macrophages. Furthermore, AIBP could diminish atherosclerotic plaque macrophage content and the expression of chemotaxis-related factors. In addition, AIBP prevented macrophage inflammation by inactivating NF-κB and promoted the expression of M2 markers like Mrc-1 and Arg-1. However, lack of 115-123 amino acids of AIBP(Δ115-123) had no such preventive effects on the progression of atherosclerosis. Our observations demonstrate that AIBP inhibits atherosclerosis progression and suggest that it may be an effective target for prevention of atherosclerosis. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. No effect of C-reactive protein on early atherosclerosis development in apolipoprotein E*3-leiden/human C-reactive protein transgenic mice.

    PubMed

    Trion, A; de Maat, M P M; Jukema, J W; van der Laarse, A; Maas, M C; Offerman, E H; Havekes, L M; Szalai, A J; Princen, H M G; Emeis, J J

    2005-08-01

    C-reactive protein (CRP) has been associated with risk of cardiovascular disease. It is not clear whether CRP is causally involved in the development of atherosclerosis. Mouse CRP is not expressed at high levels under normal conditions and increases in concentration only several-fold during an acute phase response. Because the dynamic range of human CRP is much larger, apolipoprotein E*3-Leiden (E3L) transgenic mice carrying the human CRP gene offer a unique model to study the role(s) of CRP in atherosclerosis development. Atherosclerosis development was studied in 15 male and 15 female E3L/CRP mice; E3L transgenic littermates were used as controls. The mice were fed a hypercholesterolemic diet to induce atherosclerosis development. Cholesterol exposure did not differ between E3L/CRP and E3L mice. Plasma CRP levels were on average 10.2+/-6.5 mg/L in male E3L/CRP mice, 0.2+/-0.1 mg/L in female E3L/CRP mice, and undetectable in E3L mice. Quantification of atherosclerosis showed that lesion area in E3L/CRP mice was not different from that in E3L mice. This study demonstrates that mildly elevated levels of CRP in plasma do not contribute to the development of early atherosclerosis in hypercholesterolemic E3L/CRP mice.

  7. Interaction between allergic asthma and atherosclerosis

    PubMed Central

    Liu, Conglin; Zhang, Jingying; Shi, Guo-Ping

    2015-01-01

    Prior studies have established an essential role of mast cells in allergic asthma and atherosclerosis. Mast cell deficiency or inactivation protects mice from allergen-induced airway hyper-responsiveness and diet-induced atherosclerosis, suggesting that mast cells share pathologic activities in both diseases. Allergic asthma and atherosclerosis are inflammatory diseases that contain similar sets of elevated numbers of inflammatory cells in addition to mast cells in the airway and arterial wall, such as macrophages, monocytes, T cells, eosinophils, and smooth muscle cells. Emerging evidence from experimental models and human studies points to a potential interaction between the two seemingly unrelated diseases. Patients or mice with allergic asthma have a high risk of developing atherosclerosis or vice versa, despite the fact that asthma is a Th2-oriented disease, whereas Th1 immunity promotes atherosclerosis. In addition to the preferred Th1/Th2 responses that may differentiate the two diseases, mast cells and many other inflammatory cells also contribute to their pathogenesis by much more than just T cell immunity. Here we summarize the different roles of airway and arterial wall inflammatory cells and vascular cells in asthma and atherosclerosis, and propose an interaction between the two diseases, although limited investigations are available to delineate the molecular and cellular mechanisms by which one disease increases the risk of the other. Results from mouse allergic asthma and atherosclerosis models and from human population studies lead to the hypothesis that patients with atherosclerosis may benefit from anti-asthmatic medications, or that the therapeutic regimens targeting atherosclerosis may also alleviate allergic asthma. PMID:26608212

  8. Deficiency of ABCA1 and ABCG1 in Macrophages Increases Inflammation and Accelerates Atherosclerosis in Mice

    PubMed Central

    Westerterp, Marit; Murphy, Andrew J.; Wang, Mi; Pagler, Tamara A.; Vengrenyuk, Yuliya; Kappus, Mojdeh S.; Gorman, Darren J.; Nagareddy, Prabhakara R.; Zhu, Xuewei; Abramowicz, Sandra; Parks, John S.; Welch, Carrie; Fisher, Edward A.; Wang, Nan; Yvan-Charvet, Laurent; Tall, Alan R.

    2013-01-01

    Rationale Plasma HDL levels are inversely correlated with atherosclerosis. Although it is widely assumed that this is due to the ability of HDL to promote cholesterol efflux from macrophage foam cells, direct experimental support for this hypothesis is lacking. Objective To assess the role of macrophage cholesterol efflux pathways in atherogenesis. Methods and Results We developed MAC-ABCDKO mice with efficient deletion of the ATP Binding Cassette Transporters A1 and G1 (ABCA1 and ABCG1) in macrophages but not in hematopoietic stem or progenitor populations. MAC-ABCDKO bone marrow (BM) was transplanted into Ldlr-/- recipients. On the chow diet, these mice had similar plasma cholesterol and blood monocyte levels but increased atherosclerosis compared to controls. On the Western type diet (WTD), MAC-ABCDKO BM transplanted Ldlr-/- mice had disproportionate atherosclerosis, considering they also had lower VLDL/LDL cholesterol levels than controls. ABCA1/G1 deficient macrophages in lesions showed increased inflammatory gene expression. Unexpectedly, WTD-fed MAC-ABCDKO BM transplanted Ldlr-/- mice displayed monocytosis and neutrophilia in the absence of HSPC proliferation. Mechanistic studies revealed increased expression of M-CSF and G-CSF in splenic macrophage foam cells, driving BM monocyte and neutrophil production. Conclusion These studies 1) show that macrophage deficiency of ABCA1/G1 is pro-atherogenic likely by promoting plaque inflammation and 2) uncover a novel positive feedback loop in which cholesterol-laden splenic macrophages signal BM progenitors to produce monocytes, with suppression by macrophage cholesterol efflux pathways. PMID:23572498

  9. Atherosclerosis (image)

    MedlinePlus

    Atherosclerosis is a disease of the arteries in which fatty material is deposited in the vessel wall, ... muscle leads to symptoms such as chest pain. Atherosclerosis shows no symptoms until a complication occurs.

  10. Macrophage Apoptosis and Efferocytosis in the Pathogenesis of Atherosclerosis

    PubMed Central

    Linton, MacRae F.; Babaev, Vladimir R.; Huang, Jiansheng; Linton, Edward F.; Tao, Huan; Yancey, Patricia G.

    2017-01-01

    Macrophage apoptosis and the ability of macrophages to clean up dead cells, a process called efferocytosis, are crucial determinants of atherosclerosis lesion progression and plaque stability. Environmental stressors initiate endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR). Unresolved ER stress with activation of the UPR initiates apoptosis. Macrophages are resistant to apoptotic stimuli, because of activity of the PI3K/Akt pathway. Macrophages express 3 Akt isoforms, Akt1, Akt2 and Akt3, which are products of distinct but homologous genes. Akt displays isoform-specific effects on atherogenesis, which vary with different vascular cell types. Loss of macrophage Akt2 promotes the anti-inflammatory M2 phenotype and reduces atherosclerosis. However, Akt isoforms are redundant with regard to apoptosis. c-Jun NH2-terminal kinase (JNK) is a pro-apoptotic effector of the UPR, and the JNK1 isoform opposes anti-apoptotic Akt signaling. Loss of JNK1 in hematopoietic cells protects macrophages from apoptosis and accelerates early atherosclerosis. IκB kinase α (IKKα, a member of the serine/threonine protein kinase family) plays an important role in mTORC2-mediated Akt signaling in macrophages, and IKKα deficiency reduces macrophage survival and suppresses early atherosclerosis. Efferocytosis involves the interaction of receptors, bridging molecules, and apoptotic cell ligands. Scavenger receptor class B type I is a critical mediator of macrophage efferocytosis via the Src/PI3K/Rac1 pathway in atherosclerosis. Agonists that resolve inflammation offer promising therapeutic potential to promote efferocytosis and prevent atherosclerotic clinical events. PMID:27725526

  11. Irgm1 promotes M1 but not M2 macrophage polarization in atherosclerosis pathogenesis and development.

    PubMed

    Fang, Shaohong; Xu, Yanwen; Zhang, Yun; Tian, Jiangtian; Li, Ji; Li, Zhaoying; He, Zhongze; Chai, Ruikai; Liu, Fang; Zhang, Tongshuai; Yang, Shuang; Pei, Chunying; Liu, Xinxin; Lin, Peng; Xu, Hongwei; Yu, Bo; Li, Hulun; Sun, Bo

    2016-08-01

    Atherosclerosis is a chronic inflammatory vascular disease related to macrophages uptake of low-density lipoprotein and their subsequent transformation into foam cells. M1 (inflammatory)/M2 (anti-inflammatory) balance was suggested to impact disease progression. In this study, we investigated whether the immunity related GTPase (Irgm1) regulates macrophage polarization during atherosclerosis development. We used apolipoprotein E (ApoE) knockout and Irgm1 haplodeficient mice and induced atherosclerosis with high-cholesterol diet for the indicated months. Atherosclerotic arteries were collected from patients undergoing vascular surgery, to determine the lesional expression of Irgm1 and distribution of M1/M2 populations. Our results showed that IRGM/Irgm1 expression was increased in atherosclerotic artery samples (1.7-fold, p=0.0045) compared with non-atherosclerotic arteries, which was consistent with findings in the murine experimental atherosclerosis model (1.9-fold, p=0.0002). IRGM/Irgm1 expression was mostly found in lesional M1 macrophages. Haplodeficiency of Irgm1 in ApoE(-/-) mice resulted in reduced infiltrating M1 macrophages in atheroma (94%, p=0.0002) and delayed development of atherosclerotic plaques. In vitro experiments also confirmed that Irgm1 haplodeficiency reduced iNOS expression of polarized M1 macrophages (81%, p=0.0034), with negligible impact on the M2 phenotype. Moreover, we found that Irgm1 haplodeficiency in mice significantly reduced expression level of M1 function-related transcription factors, interferon regulatory factor (Irf) 5 and Irf8, but not Irf4, an M2-related transcription factor. This study shows that Irgm1/IRGM participates in the polarization of M1 macrophage and promotes development of atheroma in murine experimental atherosclerosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Thymic Stromal Lymphopoietin Attenuates the Development of Atherosclerosis in ApoE−/− Mice

    PubMed Central

    Yu, Kunwu; Zhu, Pengfei; Dong, Qian; Zhong, Yucheng; Zhu, Zhengfeng; Lin, Yingzhong; Huang, Ying; Meng, Kai; Ji, Qingwei; Yi, Guiwen; Zhang, Wei; Wu, Bangwei; Mao, Yi; Cheng, Peng; Zhao, Xiaoqi; Mao, Xiaobo; Zeng, Qiutang

    2013-01-01

    Background Thymic stromal lymphopoietin (TSLP) is a cytokine with multiple effects on the body. For one thing, TSLP induces Th2 immunoreaction and facilitates allergic reaction; for another, it promotes the differentiation of naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) and maintains immune tolerance. However, the exact role of TSLP in atherosclerosis remains unknown. Methods and Results In vitro, we examined the phenotype of TSLP‐conditioned bone marrow dendritic cells (TSLP‐DCs) of apolipoprotein E–deficient (ApoE−/−) mice and their capacity to induce the differentiation of Tregs. Our results indicated that TSLP‐DCs obtained the characteristics of tolerogenic dendritic cells and increased a generation of CD4+ latency‐associated peptide (LAP)+ Tregs and nTregs when cocultured with naive T cells. In addition, the functional relevance of TSLP and TSLP‐DCs in the development of atherosclerosis was also determined. Interestingly, we found that TSLP was almost absent in cardiovascular tissue of ApoE−/− mice, and TSLP administration increased the levels of antioxidized low‐density lipoprotein IgM and IgG1, but decreased the levels of IgG2a in plasma. Furthermore, mice treated with TSLP and TSLP‐DCs developed significantly fewer (32.6% and 28.2%, respectively) atherosclerotic plaques in the aortic root compared with controls, along with increased numbers of CD4+LAP+ Tregs and nTregs in the spleen and decreased inflammation in the aorta, which could be abrogated by anti‐TGF‐β antibody. Conclusions Our results revealed a protective role for TSLP in atherosclerosis that is possibly mediated by reestablishing a tolerogenic immune response, which may represent a novel possibility for treatment or prevention of atherosclerosis. PMID:23985377

  13. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype

    PubMed Central

    Cardilo-Reis, Larissa; Gruber, Sabrina; Schreier, Sabine M; Drechsler, Maik; Papac-Milicevic, Nikolina; Weber, Christian; Wagner, Oswald; Stangl, Herbert; Soehnlein, Oliver; Binder, Christoph J

    2012-01-01

    Atherosclerotic lesions are characterized by the accumulation of oxidized LDL (OxLDL) and the infiltration of macrophages and T cells. Cytokine expression in the microenvironment of evolving lesions can profoundly contribute to plaque development. While the pro-atherogenic effect of T helper (Th) 1 cytokines, such as IFN-γ, is well established, the role of Th2 cytokines is less clear. Therefore, we characterized the role of the Th2 cytokine interleukin (IL)-13 in murine atherosclerosis. Here, we report that IL-13 administration favourably modulated the morphology of already established atherosclerotic lesions by increasing lesional collagen content and reducing vascular cell adhesion molecule-1 (VCAM-1)-dependent monocyte recruitment, resulting in decreased plaque macrophage content. This was accompanied by the induction of alternatively activated (M2) macrophages, which exhibited increased clearance of OxLDL compared to IFN-γ-activated (M1) macrophages in vitro. Importantly, deficiency of IL-13 results in accelerated atherosclerosis in LDLR−/− mice without affecting plasma cholesterol levels. Thus, IL-13 protects from atherosclerosis and promotes a favourable plaque morphology, in part through the induction of alternatively activated macrophages. PMID:23027612

  14. Strong correlation between early stage atherosclerosis and electromechanical coupling of aorta

    NASA Astrophysics Data System (ADS)

    Liu, X. Y.; Yan, F.; Niu, L. L.; Chen, Q. N.; Zheng, H. R.; Li, J. Y.

    2016-03-01

    Atherosclerosis is the underlying cause of cardiovascular diseases that are responsible for many deaths in the world, and the early diagnosis of atherosclerosis is highly desirable. The existing imaging methods, however, are not capable of detecting the early stage of atherosclerosis development due to their limited spatial resolution. Using piezoresponse force microscopy (PFM), we show that the piezoelectric response of an aortic wall increases as atherosclerosis advances, while the stiffness of the aorta shows a less evident correlation with atherosclerosis. Furthermore, we show that there is strong correlation between the coercive electric field necessary to switch the polarity of the artery and the development of atherosclerosis. Thus by measuring the electromechanical coupling of the aortic wall, it is possible to probe atherosclerosis at the early stage of its development, not only improving the spatial resolution by orders of magnitude, but also providing comprehensive quantitative information on the biomechanical properties of the artery.

  15. Insulin resistance, metabolic stress, and atherosclerosis

    PubMed Central

    Pansuria, Meghana; Xi, Hang; Li, Le; Yang, Xiao-Feng; Wang, Hong

    2012-01-01

    Atherosclerosis, a pathological process that underlies the development of cardiovascular disease, is the primary cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia and insulin resistance (IR), in which target tissues fail to respond to insulin. Systemic IR is associated with impaired insulin signaling in the metabolic tissues and vasculature. Insulin receptor is highly expressed in the liver, muscle, pancreas, and adipose tissue. It is also expressed in vascular cells. It has been suggested that insulin signaling in vascular cells regulates cell proliferation and vascular function. In this review, we discuss the association between IR, metabolic stress, and atherosclerosis with focus on 1) tissue and cell distribution of insulin receptor and its differential signaling transduction and 2) potential mechanism of insulin signaling impairment and its role in the development of atherosclerosis and vascular function in metabolic disorders including hyperglycemia, hypertension, dyslipidemia, and hyperhomocysteinemia. We propose that insulin signaling impairment is the foremost biochemical mechanism underlying increased cardiovascular morbidity and mortality in atherosclerosis, T2DM, and metabolic syndrome. PMID:22202099

  16. Influence of coronary artery disease and subclinical atherosclerosis related polymorphisms on the risk of atherosclerosis in rheumatoid arthritis.

    PubMed

    López-Mejías, Raquel; Corrales, Alfonso; Vicente, Esther; Robustillo-Villarino, Montserrat; González-Juanatey, Carlos; Llorca, Javier; Genre, Fernanda; Remuzgo-Martínez, Sara; Dierssen-Sotos, Trinidad; Miranda-Filloy, José A; Huaranga, Marco A Ramírez; Pina, Trinitario; Blanco, Ricardo; Alegre-Sancho, Juan J; Raya, Enrique; Mijares, Verónica; Ubilla, Begoña; Ferraz-Amaro, Iván; Gómez-Vaquero, Carmen; Balsa, Alejandro; López-Longo, Francisco J; Carreira, Patricia; González-Álvaro, Isidoro; Ocejo-Vinyals, J Gonzalo; Rodríguez-Rodríguez, Luis; Fernández-Gutiérrez, Benjamín; Castañeda, Santos; Martín, Javier; González-Gay, Miguel A

    2017-01-06

    A genetic component influences the development of atherosclerosis in the general population and also in rheumatoid arthritis (RA). However, genetic polymorphisms associated with atherosclerosis in the general population are not always involved in the development of cardiovascular disease (CVD) in RA. Accordingly, a study in North-American RA patients did not show the association reported in the general population of coronary artery disease with a series of relevant polymorphisms (TCF21, LPA, HHIPL1, RASD1-PEMT, MRPS6, CYP17A1-CNNM2-NT5C2, SMG6-SRR, PHACTR1, WDR12 and COL4A1-COL4A2). In the present study, we assessed the potential association of these polymorphisms with CVD in Southern European RA patients. We also assessed if polymorphisms implicated in the increased risk of subclinical atherosclerosis in non-rheumatic Caucasians (ZHX2, PINX1, SLC17A4, LRIG1 and LDLR) may influence the risk for CVD in RA. 2,609 Spanish patients were genotyped by TaqMan assays. Subclinical atherosclerosis was determined in 1,258 of them by carotid ultrasonography (assessment of carotid intima media thickness and presence/absence of carotid plaques). No statistically significant differences were found when each polymorphism was assessed according to the presence/absence of cardiovascular events and subclinical atherosclerosis, after adjustment for potential confounder factors. Our results do not show an association between these 15 polymorphisms and atherosclerosis in RA.

  17. Influence of coronary artery disease and subclinical atherosclerosis related polymorphisms on the risk of atherosclerosis in rheumatoid arthritis

    PubMed Central

    López-Mejías, Raquel; Corrales, Alfonso; Vicente, Esther; Robustillo-Villarino, Montserrat; González-Juanatey, Carlos; Llorca, Javier; Genre, Fernanda; Remuzgo-Martínez, Sara; Dierssen-Sotos, Trinidad; Miranda-Filloy, José A.; Huaranga, Marco A. Ramírez; Pina, Trinitario; Blanco, Ricardo; Alegre-Sancho, Juan J.; Raya, Enrique; Mijares, Verónica; Ubilla, Begoña; Ferraz-Amaro, Iván; Gómez-Vaquero, Carmen; Balsa, Alejandro; López-Longo, Francisco J.; Carreira, Patricia; González-Álvaro, Isidoro; Ocejo-Vinyals, J. Gonzalo; Rodríguez-Rodríguez, Luis; Fernández-Gutiérrez, Benjamín; Castañeda, Santos; Martín, Javier; González-Gay, Miguel A.

    2017-01-01

    A genetic component influences the development of atherosclerosis in the general population and also in rheumatoid arthritis (RA). However, genetic polymorphisms associated with atherosclerosis in the general population are not always involved in the development of cardiovascular disease (CVD) in RA. Accordingly, a study in North-American RA patients did not show the association reported in the general population of coronary artery disease with a series of relevant polymorphisms (TCF21, LPA, HHIPL1, RASD1-PEMT, MRPS6, CYP17A1-CNNM2-NT5C2, SMG6-SRR, PHACTR1, WDR12 and COL4A1-COL4A2). In the present study, we assessed the potential association of these polymorphisms with CVD in Southern European RA patients. We also assessed if polymorphisms implicated in the increased risk of subclinical atherosclerosis in non-rheumatic Caucasians (ZHX2, PINX1, SLC17A4, LRIG1 and LDLR) may influence the risk for CVD in RA. 2,609 Spanish patients were genotyped by TaqMan assays. Subclinical atherosclerosis was determined in 1,258 of them by carotid ultrasonography (assessment of carotid intima media thickness and presence/absence of carotid plaques). No statistically significant differences were found when each polymorphism was assessed according to the presence/absence of cardiovascular events and subclinical atherosclerosis, after adjustment for potential confounder factors. Our results do not show an association between these 15 polymorphisms and atherosclerosis in RA. PMID:28059143

  18. Oral microbiota in patients with atherosclerosis.

    PubMed

    Fåk, Frida; Tremaroli, Valentina; Bergström, Göran; Bäckhed, Fredrik

    2015-12-01

    Recent evidence suggests that the microbiota may be considered as an environmental factor that contributes to the development of atherosclerosis. Periodontal disease has been associated with cardio- and cerebrovascular events, and inflammation in the periodontium is suggested to increase the systemic inflammatory level of the host, which may in turn influence plaque composition and rupture. We previously showed that bacteria from the oral cavity and the gut could be found in atherosclerotic plaques. To elucidate whether the oral microbiota composition differed between patients with asymptomatic and symptomatic atherosclerosis we performed pyrosequencing of the oral microbiota of 92 individuals including patients with asymptomatic and symptomatic atherosclerosis and control individuals without carotid plaques or previous stroke or myocardial infarction. The overall microbial structure was similar in controls and atherosclerosis patients, but patients with symptomatic atherosclerosis had higher relative abundance of Anaeroglobus (mean 0.040% (SD 0.049)) than the control group (0.010% (SD 0.028)) (P = 0.03). Using linear regression analysis, we found that Parvimonas associated positively with uCRP and Capnocytophaga, Catonella and Lactobacillus associated with blood lipid markers. In conclusion, abundance of Anaeroglobus in the oral cavity could be associated with symptomatic atherosclerosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Distinct effects of glucose and glucosamine on vascular endothelial and smooth muscle cells: Evidence for a protective role for glucosamine in atherosclerosis

    PubMed Central

    Duan, Wenlan; Paka, Latha; Pillarisetti, Sivaram

    2005-01-01

    Accelerated atherosclerosis is one of the major vascular complications of diabetes. Factors including hyperglycemia and hyperinsulinemia may contribute to accelerated vascular disease. Among the several mechanisms proposed to explain the link between hyperglycemia and vascular dysfunction is the hexosamine pathway, where glucose is converted to glucosamine. Although some animal experiments suggest that glucosamine may mediate insulin resistance, it is not clear whether glucosamine is the mediator of vascular complications associated with hyperglycemia. Several processes may contribute to diabetic atherosclerosis including decreased vascular heparin sulfate proteoglycans (HSPG), increased endothelial permeability and increased smooth muscle cell (SMC) proliferation. In this study, we determined the effects of glucose and glucosamine on endothelial cells and SMCs in vitro and on atherosclerosis in apoE null mice. Incubation of endothelial cells with glucosamine, but not glucose, significantly increased matrix HSPG (perlecan) containing heparin-like sequences. Increased HSPG in endothelial cells was associated with decreased protein transport across endothelial cell monolayers and decreased monocyte binding to subendothelial matrix. Glucose increased SMC proliferation, whereas glucosamine significantly inhibited SMC growth. The antiproliferative effect of glucosamine was mediated via induction of perlecan HSPG. We tested if glucosamine affects atherosclerosis development in apoE-null mice. Glucosamine significantly reduced the atherosclerotic lesion in aortic root. (P < 0.05) These data suggest that macrovascular disease associated with hyperglycemia is unlikely due to glucosamine. In fact, glucosamine by increasing HSPG showed atheroprotective effects. PMID:16207378

  20. Curcuma oil attenuates accelerated atherosclerosis and macrophage foam-cell formation by modulating genes involved in plaque stability, lipid homeostasis and inflammation.

    PubMed

    Singh, Vishal; Rana, Minakshi; Jain, Manish; Singh, Niharika; Naqvi, Arshi; Malasoni, Richa; Dwivedi, Anil Kumar; Dikshit, Madhu; Barthwal, Manoj Kumar

    2015-01-14

    In the present study, the anti-atherosclerotic effect and the underlying mechanism of curcuma oil (C. oil), a lipophilic fraction from turmeric (Curcuma longa L.), was evaluated in a hamster model of accelerated atherosclerosis and in THP-1 macrophages. Male golden Syrian hamsters were subjected to partial carotid ligation (PCL) or FeCl3-induced arterial oxidative injury (Ox-injury) after 1 week of treatment with a high-cholesterol (HC) diet or HC diet plus C. oil (100 and 300 mg/kg, orally). Hamsters fed with the HC diet were analysed at 1, 3 and 5 weeks following carotid injury. The HC diet plus C. oil-fed group was analysed at 5 weeks. In hyperlipidaemic hamsters with PCL or Ox-injury, C. oil (300 mg/kg) reduced elevated plasma and aortic lipid levels, arterial macrophage accumulation, and stenosis when compared with those subjected to arterial injury alone. Similarly, elevated mRNA transcripts of matrix metalloproteinase-2 (MMP-2), MMP-9, cluster of differentiation 45 (CD45), TNF-α, interferon-γ (IFN-γ), IL-1β and IL-6 were reduced in atherosclerotic arteries, while those of transforming growth factor-β (TGF-β) and IL-10 were increased after the C. oil treatment (300 mg/kg). The treatment with C. oil prevented HC diet- and oxidised LDL (OxLDL)-induced lipid accumulation, decreased the mRNA expression of CD68 and CD36, and increased the mRNA expression of PPARα, LXRα, ABCA1 and ABCG1 in both hyperlipidaemic hamster-derived peritoneal and THP-1 macrophages. The administration of C. oil suppressed the mRNA expression of TNF-α, IL-1β, IL-6 and IFN-γ and increased the expression of TGF-β in peritoneal macrophages. In THP-1 macrophages, C. oil supplementation prevented OxLDL-induced production of TNF-α and IL-1β and increased the levels of TGF-β. The present study shows that C. oil attenuates arterial injury-induced accelerated atherosclerosis, inflammation and macrophage foam-cell formation.

  1. Compound K Attenuates the Development of Atherosclerosis in ApoE−/− Mice via LXRα Activation

    PubMed Central

    Zhou, Li; Zheng, Yu; Li, Zhuoying; Bao, Lingxia; Dou, Yin; Tang, Yuan; Zhang, Jianxiang; Zhou, Jianzhi; Liu, Ya; Jia, Yi; Li, Xiaohui

    2016-01-01

    Background: Atherosclerosis is a fundamental pathological process responded to some serious cardiovascular events. Although the cholesterol-lowering drugs are widely prescribed for atherosclerosis therapy, it is still the leading cause of death in the developed world. Here we measured the effects of compound K in atherosclerosis formation and investigated the probably mechanisms of the anti-antherosclerosis roles of compound K. Methods: We treated the atherosclerotic model animals (apoE−/− mice on western diet) with compound K and measured the size of atherosclerotic lesions, inflammatory cytokine levels and serum lipid profile. Peritoneal macrophages were collected in vitro for the foam cell and inflammasome experiments. Results: Our results show that treatment with compound K dose-dependently attenuates the formation of atherosclerotic plaques by 55% through activation of reverse cholesterol transport pathway, reduction of systemic inflammatory cytokines and inhibition of local inflammasome activity. Compound K increases the cholesterol efflux of macrophage-derived foam cells, and reduces the inflammasome activity in cholesterol crystal stimulated macrophages. The activation of LXRα may contribute to the athero-protective effects of compound K. Conclusion: These observations provide evidence for an athero-protective effect of compound K via LXRα activation, and support its further evaluation as a potential effective modulator for the prevention and treatment of atherosclerosis. PMID:27399689

  2. Animal Models in Cardiovascular Research: Hypertension and Atherosclerosis

    PubMed Central

    Ng, Chun-Yi; Jaarin, Kamsiah

    2015-01-01

    Hypertension and atherosclerosis are among the most common causes of mortality in both developed and developing countries. Experimental animal models of hypertension and atherosclerosis have become a valuable tool for providing information on etiology, pathophysiology, and complications of the disease and on the efficacy and mechanism of action of various drugs and compounds used in treatment. An animal model has been developed to study hypertension and atherosclerosis for several reasons. Compared to human models, an animal model is easily manageable, as compounding effects of dietary and environmental factors can be controlled. Blood vessels and cardiac tissue samples can be taken for detailed experimental and biomolecular examination. Choice of animal model is often determined by the research aim, as well as financial and technical factors. A thorough understanding of the animal models used and complete analysis must be validated so that the data can be extrapolated to humans. In conclusion, animal models for hypertension and atherosclerosis are invaluable in improving our understanding of cardiovascular disease and developing new pharmacological therapies. PMID:26064920

  3. Increased atherosclerosis in mice with increased vascular biglycan content.

    PubMed

    Thompson, Joel C; Tang, Tao; Wilson, Patricia G; Yoder, Meghan H; Tannock, Lisa R

    2014-07-01

    The response to retention hypothesis of atherogenesis proposes that atherosclerosis is initiated via the retention of atherogenic lipoproteins by vascular proteoglycans. Co-localization studies suggest that of all the vascular proteoglycans, biglycan is the one most closely co-localized with LDL. The goal of this study was to determine if over-expression of biglycan in hyperlipidemic mice would increase atherosclerosis development. Transgenic mice were developed by expressing biglycan under control of the smooth muscle actin promoter, and were crossed to the LDL receptor deficient (C57BL/6 background) atherosclerotic mouse model. Biglycan transgenic and non-transgenic control mice were fed an atherogenic Western diet for 4-12 weeks. LDL receptor deficient mice overexpressing biglycan under control of the smooth muscle alpha actin promoter had increased atherosclerosis development that correlated with vascular biglycan content. Increased vascular biglycan content predisposes to increased lipid retention and increased atherosclerosis development. Published by Elsevier Ireland Ltd.

  4. Gugulipid causes hypercholesterolemia leading to endothelial dysfunction, increased atherosclerosis, and premature death by ischemic heart disease in male mice

    PubMed Central

    Contreras-Duarte, Susana; Amigo, Ludwig; Sepúlveda, Esteban; Boric, Mauricio; Quiñones, Verónica; Busso, Dolores; Rigotti, Attilio

    2017-01-01

    For proper cholesterol metabolism, normal expression and function of scavenger receptor class B type I (SR-BI), a high-density lipoprotein (HDL) receptor, is required. Among the factors that regulate overall cholesterol homeostasis and HDL metabolism, the nuclear farnesoid X receptor plays an important role. Guggulsterone, a bioactive compound present in the natural product gugulipid, is an antagonist of this receptor. This natural product is widely used globally as a natural lipid-lowering agent, although its anti-atherogenic cardiovascular benefit in animal models or humans is unknown. The aim of this study was to determine the effects of gugulipid on cholesterol homeostasis and development of mild and severe atherosclerosis in male mice. For this purpose, we evaluated the impact of gugulipid treatment on liver histology, plasma lipoprotein cholesterol, endothelial function, and development of atherosclerosis and/or ischemic heart disease in wild-type mice; apolipoprotein E knockout mice, a model of atherosclerosis without ischemic complications; and SR-B1 knockout and atherogenic–diet-fed apolipoprotein E hypomorphic (SR-BI KO/ApoER61h/h) mice, a model of lethal ischemic heart disease due to severe atherosclerosis. Gugulipid administration was associated with histological abnormalities in liver, increased alanine aminotransferase levels, lower hepatic SR-BI content, hypercholesterolemia due to increased HDL cholesterol levels, endothelial dysfunction, enhanced atherosclerosis, and accelerated death in animals with severe ischemic heart disease. In conclusion, our data show important adverse effects of gugulipid intake on HDL metabolism and atherosclerosis in male mice, suggesting potential and unknown deleterious effects on cardiovascular health in humans. In addition, these findings reemphasize the need for rigorous preclinical and clinical studies to provide guidance on the consumption of natural products and regulation of their use in the general population

  5. Non-proinflammatory and responsive nanoplatforms for targeted treatment of atherosclerosis.

    PubMed

    Dou, Yin; Chen, Yue; Zhang, Xiangjun; Xu, Xiaoqiu; Chen, Yidan; Guo, Jiawei; Zhang, Dinglin; Wang, Ruibing; Li, Xiaohui; Zhang, Jianxiang

    2017-10-01

    Atherosclerosis is the leading cause of many fatal cardiovascular and cerebrovascular diseases. Whereas nanomedicines are promising for targeted therapy of atherosclerosis, great challenges remain in development of effective, safe, and translational nanotherapies for its treatment. Herein we hypothesize that non-proinflammatory nanomaterials sensitive to low pH or high reactive oxygen species (ROS) may serve as effective platforms for triggerable delivery of anti-atherosclerotic therapeutics in cellular and tissue microenvironments of inflammation. To demonstrate this hypothesis, an acid-labile material of acetalated β-cyclodextrin (β-CD) (Ac-bCD) and a ROS-sensitive β-CD material (Ox-bCD) were separately synthesized by chemical modification of β-CD, which were formed into responsive nanoparticles (NPs). Ac-bCD NP was rapidly hydrolyzed in mildly acidic buffers, while hydrolysis of Ox-bCD NP was selectively accelerated by H 2 O 2 . Using an anti-atherosclerotic drug rapamycin (RAP), we found stimuli-responsive release of therapeutic molecules from Ac-bCD and Ox-bCD nanotherapies. Compared with non-responsive poly(lactide-co-glycolide) (PLGA)-based NP, Ac-bCD and Ox-bCD NPs showed negligible inflammatory responses in vitro and in vivo. By endocytosis in cells and intracellularly releasing cargo molecules in macrophages, responsive nanotherapies effectively inhibited macrophage proliferation and suppressed foam cell formation. After intraperitoneal (i.p.) delivery in apolipoprotein E-deficient (ApoE -/- ) mice, fluorescence imaging showed accumulation of NPs in atherosclerotic plaques. Flow cytometry analysis indicated that the lymphatic translocation mediated by neutrophils and monocytes/macrophages may contribute to atherosclerosis targeting of i.p. administered NPs, in addition to targeting via the leaky blood vessels. Correspondingly, i.p. treatment with different nanotherapies afforded desirable efficacies. Particularly, both pH and ROS

  6. Computational modelling of atherosclerosis.

    PubMed

    Parton, Andrew; McGilligan, Victoria; O'Kane, Maurice; Baldrick, Francina R; Watterson, Steven

    2016-07-01

    Atherosclerosis is one of the principle pathologies of cardiovascular disease with blood cholesterol a significant risk factor. The World Health Organization estimates that approximately 2.5 million deaths occur annually because of the risk from elevated cholesterol, with 39% of adults worldwide at future risk. Atherosclerosis emerges from the combination of many dynamical factors, including haemodynamics, endothelial damage, innate immunity and sterol biochemistry. Despite its significance to public health, the dynamics that drive atherosclerosis remain poorly understood. As a disease that depends on multiple factors operating on different length scales, the natural framework to apply to atherosclerosis is mathematical and computational modelling. A computational model provides an integrated description of the disease and serves as an in silico experimental system from which we can learn about the disease and develop therapeutic hypotheses. Although the work completed in this area to date has been limited, there are clear signs that interest is growing and that a nascent field is establishing itself. This article discusses the current state of modelling in this area, bringing together many recent results for the first time. We review the work that has been done, discuss its scope and highlight the gaps in our understanding that could yield future opportunities. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  7. BAFF Neutralization Aggravates Atherosclerosis.

    PubMed

    Tsiantoulas, Dimitrios; Sage, Andrew P; Göderle, Laura; Ozsvar-Kozma, Maria; Murphy, Deirdre; Porsch, Florentina; Pasterkamp, Gerard; Menche, Jörg; Schneider, Pascal; Mallat, Ziad; Binder, Christoph J

    2018-06-01

    Background -Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause of death globally and is caused by the buildup of a plaque in the arterial wall. Genomic data showed that the B cell activating factor receptor (BAFFR) pathway, which is specifically essential for the survival of conventional B lymphocytes (B-2 cells), is a key driver of coronary heart disease. Deletion or antibody-mediated blockade of BAFFR ablates B-2 cells and decreases experimental atherosclerosis. Anti-BAFF immunotherapy is approved for treatment of autoimmune systemic lupus erythematosus and can therefore be expected to limit their associated cardiovascular risk. However, direct effects of anti-BAFF immunotherapy on atherosclerosis remain unknown. Methods -To investigate the effect of BAFF neutralization in atherosclerosis, we treated Apoe -/- and Ldlr -/- mice with a well-characterized blocking anti-BAFF antibody. Moreover, to investigate the mechanism by which BAFF impacts atherosclerosis, we studied atherosclerosis-prone mice that lack the alternative receptor for BAFF, transmembrane activator and CAML interactor (TACI). Results -We demonstrate here that anti-BAFF antibody treatment increased atherosclerosis in mice, despite efficient depletion of mature B-2 cells, suggesting a unique mechanism of action. Indeed, myeloid cell specific deletion TACI, also results in increased atherosclerosis, while B cell-specific TACI deletion had no effect. Mechanistically, BAFF-TACI signaling represses macrophage IRF7-dependent (but not NF-kB dependent) TLR9 responses including proatherogenic CXCL10 production. Conclusions -These data identify a novel B cell independent anti-inflammatory role for BAFF in atherosclerosis and may have important clinical implications.

  8. Simultaneous Increases in Proliferation and Apoptosis of Vascular Smooth Muscle Cells Accelerate Diabetic Mouse Venous Atherosclerosis

    PubMed Central

    Liu, Shuying; Zhang, Zhengyu; Wang, Jingjing; Zhou, Yuhuan; Liu, Kefeng; Huang, Jintao; Chen, Dadi; Wang, Junmei; Li, Chaohong

    2015-01-01

    Aims This study was designed to demonstrate simultaneous increases in proliferation and apoptosis of vascular smooth muscle cells (VSMCs) leading to accelerated vein graft remodeling and to explore the underlying mechanisms. Methods Vein grafts were performed in non-diabetic and diabetic mice. The cultured quiescent VSMCs were subjected to mechanical stretch stress (SS) and/or advanced glycosylation end products (AGEs). Harvested vein grafts and treated VSMCs were used to detect cell proliferation, apoptosis, mitogen-activated protein kinases (MAPKs) activation and SM-α-actin expression. Results Significantly thicker vessel walls and greater increases in proliferation and apoptosis were observed in diabetic vein grafts than those in non-diabetic. Both SS and AGEs were found to induce different activation of three members of MAPKs and simultaneous increases in proliferation and apoptosis of VSMCs, and combined treatment with both had a synergistic effect. VSMCs with strong SM-α-actin expression represented more activated JNKs or p38MAPK, and cell apoptosis, while the cells with weak SM-α-actin expression demonstrated preferential activation of ERKs and cell proliferation. In contrast, inhibition of MAPKs signals triggered significant decreases in VSMC proliferation, and apoptosis. Treatment of the cells with RNA interference of receptor of AGEs (RAGE) also resulted in significant decreases in both proliferation and apoptosis. Conclusions Increased pressure-induced SS triggers simultaneous increases in proliferation and apoptosis of VSMCs in the vein grafts leading to vein arterializations, which can be synergistically accelerated by high glucose-induced AGEs resulting in vein graft atherosclerosis. Either SS or AGEs and their combination induce simultaneous increases in proliferation and apoptosis of VSMCs via different activation of three members of MAPKs resulting from different VSMC subtypes classified by SM-α-actin expression levels. PMID:26488175

  9. Fine particulate matter air pollution and atherosclerosis: Mechanistic insights.

    PubMed

    Bai, Yuntao; Sun, Qinghua

    2016-12-01

    Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous plaque in the arteries. Its etiology is very complicated and its risk factors primarily include genetic defects, smoking, hyperlipidemia, hypertension, lack of exercise, and infection. Recent studies suggest that fine particulate matter (PM2.5) air pollution may also contribute to the development of atherosclerosis. The present review integrates current experimental evidence with mechanistic pathways whereby PM2.5 exposure can promote the development of atherosclerosis. PM2.5-mediated enhancement of atherosclerosis is likely due to its pro-oxidant and pro-inflammatory effects, involving multiple organs, different cell types, and various molecular mediators. Studies about the effects of PM2.5inhalation on atherosclerosis may yield a better understanding of the link between air pollution and major cardiovascular diseases, and provide useful information for policy makers to determine acceptable levels of PM2.5 air quality. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Prevention of atherosclerosis with dietary antioxidants: fact or fiction?

    PubMed

    Duell, P B

    1996-04-01

    The notion that oxidation of lipids and lipoproteins may contribute to the pathogenesis of atherosclerosis is supported by a large body of evidence. It is hypothesized that dietary antioxidants may help prevent development and progression of atherosclerosis. The available evidence helps substantiate this hypothesis but is not yet conclusive. The results of several ongoing large randomized intervention trials will provide valuable information about the efficacy and safety of supplemental dietary antioxidants in prevention of atherosclerosis.

  11. [Atherosclerosis, oxidative stress and physical activity. Review].

    PubMed

    Calderón, Juan Camilo; Fernández, Ana Zita; María de Jesús, Alina Isabel

    2008-09-01

    Atherosclerosis and related diseases have emerged as the leading cause of morbidity and mortality in the western world and, therefore, as a problem of public health. Free radicals and reactive oxygen species have been suggested to be part of the pathophysiology of these diseases. It is well known that physical activity plays an important role as a public health measure by reducing the risk of developing atherosclerosis-related cardiovascular events in the general population. It is also known that physical activity increases in some tissues, the reactive oxygen species production. In this review the atherosclerosis-oxidative stress-physical activity relationship is focused on the apparent paradox by which physical activity reduces atherosclerosis and cardiovascular risk in parallel with the activation of an apparently damaging mechanism which is an increased oxidative stress. A hypothesis including the experimental and clinical evidence is presented to explain the aforementioned paradox.

  12. Phosphatidylserine in atherosclerosis.

    PubMed

    Darabi, Maryam; Kontush, Anatol

    2016-08-01

    It is now widely acknowledged that phosphatidylserine is a multifunctional bioactive lipid. In this review, we focus on the function of phosphatidylserine in modulating cholesterol metabolism, influencing inflammatory response and regulating coagulation system, and discuss promising phosphatidylserine-based therapeutic approaches and detection techniques in atherosclerosis. Phosphatidylserine has been suggested to play important roles in physiological processes, such as apoptosis, inflammation, and coagulation. Recent data demonstrate atheroprotective potential of phosphatidylserine, reflecting its capacity to inhibit inflammation, modulate coagulation, and enhance HDL functionality. Furthermore, modern lipidomic approaches have enabled the investigation of phosphatidylserine properties relevant to the lipid-based drug delivery and development of reconstituted HDL. Studies of phosphatidylserine in relation to atherosclerosis represent an area of opportunity. Additional research elucidating mechanisms underlying experimentally observed atheroprotective effects of phosphatidylserine is required to fully explore therapeutic potential of this naturally occurring phospholipid in cardiovascular disease.

  13. Roles of Cells from the Arterial Vessel Wall in Atherosclerosis.

    PubMed

    Wang, Di; Wang, Zhiyan; Zhang, Lili; Wang, Yi

    2017-01-01

    Atherosclerosis has been identified as a chronic inflammatory disease of the arterial vessel wall. Accumulating evidence indicates that different cells from the tunica intima, media, adventitia, and perivascular adipose tissue not only comprise the intact and normal arterial vessel wall but also participate all in the inflammatory response of atherosclerosis via multiple intricate pathways. For instance, endothelial dysfunction has historically been considered to be the initiator of the development of atherosclerosis. The migration and proliferation of smooth muscle cells also play a pivotal role in the progression of atherosclerosis. Additionally, the fibroblasts from the adventitia and adipocytes from perivascular adipose tissue have received considerable attention given their special functions that contribute to atherosclerosis. In addition, numerous types of cytokines produced by different cells from the arterial vessel wall, including endothelium-derived relaxing factors, endothelium-derived contracting factors, tumor necrosis factors, interleukin, adhesion molecules, interferon, and adventitium-derived relaxing factors, have been implicated in atherosclerosis. Herein, we summarize the possible roles of different cells from the entire arterial vessel wall in the pathogenesis of atherosclerosis.

  14. Atherosclerosis in ancient Egyptian mummies: the Horus study.

    PubMed

    Allam, Adel H; Thompson, Randall C; Wann, L Samuel; Miyamoto, Michael I; Nur El-Din, Abd El-Halim; El-Maksoud, Gomaa Abd; Al-Tohamy Soliman, Muhammad; Badr, Ibrahem; El-Rahman Amer, Hany Abd; Sutherland, M Linda; Sutherland, James D; Thomas, Gregory S

    2011-04-01

    The purpose of this study was to determine whether ancient Egyptians had atherosclerosis. The worldwide burden of atherosclerotic disease continues to rise and parallels the spread of diet, lifestyles, and environmental risk factors associated with the developed world. It is tempting to conclude that atherosclerotic cardiovascular disease is exclusively a disease of modern society and did not affect our ancient ancestors. We performed whole body, multislice computed tomography scanning on 52 ancient Egyptian mummies from the Middle Kingdom to the Greco-Roman period to identify cardiovascular structures and arterial calcifications. We interpreted images by consensus reading of 7 imaging physicians, and collected demographic data from historical and museum records. We estimated age at the time of death from the computed tomography skeletal evaluation. Forty-four of 52 mummies had identifiable cardiovascular (CV) structures, and 20 of these had either definite atherosclerosis (defined as calcification within the wall of an identifiable artery, n = 12) or probable atherosclerosis (defined as calcifications along the expected course of an artery, n = 8). Calcifications were found in the aorta as well as the coronary, carotid, iliac, femoral, and peripheral leg arteries. The 20 mummies with definite or probable atherosclerosis were older at time of death (mean age 45.1 ± 9.2 years) than the mummies with CV tissue but no atherosclerosis (mean age 34.5 ± 11.8 years, p < 0.002). Two mummies had evidence of severe arterial atherosclerosis with calcifications in virtually every arterial bed. Definite coronary atherosclerosis was present in 2 mummies, including a princess who lived between 1550 and 1580 BCE. This finding represents the earliest documentation of coronary atherosclerosis in a human. Definite or probable atherosclerosis was present in mummies who lived during virtually every era of ancient Egypt represented in this study, a time span of >2,000 years

  15. Work schedules and 11-year progression of carotid atherosclerosis in middle-aged Finnish men.

    PubMed

    Wang, Aolin; Arah, Onyebuchi A; Kauhanen, Jussi; Krause, Niklas

    2015-01-01

    This study investigated the relationship between different work schedules and progression of carotid atherosclerosis, an early indicator of cardiovascular disease (CVD). We studied 621 men, aged 42-60 years, in the prospective Kuopio Ischemic Heart Disease Risk Factor Study cohort. Using multivariable regressions adjusting for 22 covariates including total time worked during follow-up, we evaluated the associations of baseline work schedules with 11-year progression of ultrasonographically assessed carotid intima-media thickness (IMT), and their variation by preexisting CVD. Standard daytime work, weekend shifts, and evening/night/rotating shifts were associated with 31%, 37%, and 33% increases in IMT, respectively. Compared to daytime workers, weekend workers experienced a faster progression of carotid atherosclerosis [relative change ratio (RCR) = 1.05, 95% CI: 1.00-1.09)]. This ratio was higher among men who had preexisting CVD. Weekend shifts, more than standard daytime work, appear to accelerate carotid atherosclerosis progression among middle-aged Finnish men, especially those with pre-existing CVD. © 2014 Wiley Periodicals, Inc.

  16. Influence of Erythrocyte Membrane Stability in Atherosclerosis.

    PubMed

    da Silva Garrote-Filho, Mario; Bernardino-Neto, Morun; Penha-Silva, Nilson

    2017-04-01

    The purpose of this study is to show how an excess of cholesterol in the erythrocyte membrane contributes stochastically to the progression of atherosclerosis, leading to damage in blood rheology and O 2 transport, deposition of cholesterol (from trapped erythrocytes) in an area of intraplaque hemorrhage, and local exacerbation of oxidative stress. Cholesterol contained in the membrane of erythrocytes trapped in an intraplaque hemorrhage contributes to the growth of the necrotic nucleus. There is even a relationship between the amount of cholesterol in the erythrocyte membrane and the severity of atherosclerosis. In addition, the volume variability among erythrocytes, measured by RDW, is predictive of a worsening of this disease. Erythrocytes contribute to the development of atherosclerosis in several ways, especially when trapped in intraplate hemorrhage. These erythrocytes are oxidized and phagocytosed by macrophages. The cholesterol present in the membrane of these erythrocytes subsequently contributes to the growth of the atheroma plaque. In addition, when they rupture, erythrocytes release hemoglobin, which leads to the generation of free radicals. Finally, increased RDW may predict the worsening of atherosclerosis, due to the effects of inflammation and oxidative stress on erythropoiesis and erythrocyte volume. A better understanding of erythrocyte participation in atherosclerosis may contribute to the improvement of the prevention and treatment strategies of this disease.

  17. MicroRNAs in the pathobiology of atherosclerosis

    PubMed Central

    Laffont, Benoit; Rayner, Katey J

    2017-01-01

    MicroRNAs are short non-coding RNAs, expressed in humans and involved in sequence-specific post-transcriptional regulation of gene expression. They have emerged as key players in a wide array of biological processes, and changes in their expression and/or function have been associated with plethora of human diseases. Atherosclerosis and its related clinical complications, such as myocardial infarction or stroke, represent the leading cause of death in the western world. Accumulating experimental evidence has revealed a key role for microRNAs in regulating cellular and molecular processes related to atherosclerosis development, ranging from risk factors, to plaque initiation and progression, up to atherosclerotic plaque rupture. In this review, we will focus on how microRNAs can influence atherosclerosis biology, as well as the potential clinical applications of microRNAs which are being developed as both targets and therapeutics for a growing industry hoping to harness the power of RNA-guided gene regulation to fight disease and infection. PMID:28232017

  18. A review of plant-based compounds and medicinal plants effective on atherosclerosis

    PubMed Central

    Sedighi, Mehrnoosh; Bahmani, Mahmoud; Asgary, Sedigheh; Beyranvand, Fatemeh; Rafieian-Kopaei, Mahmoud

    2017-01-01

    Atherosclerosis is one of the most important cardiovascular diseases that involve vessels through the development of fatty streaks and plaques. Plant-based compounds can help treat or prevent atherosclerosis through affecting the involved factors. The main purpose of this review article is to investigate and introduce medicinal plants and their potential activities regarding antioxidant properties, effective on lipids level and development of plaque, atherosclerosis, and progression of atherosclerosis as well as the development of cardiovascular disease and ischemia. To search for the relevant articles indexed in Information Sciences Institute, PubMed, Scientific Information Database, IranMedex, and Scopus between 1980 and 2013, with further emphasis on those indexed from 2004 to 2015, we used these search terms: atherosclerosis, antioxidant, cholesterol, inflammation, and the medicinal plants below. Then, the articles with inclusion criteria were used in the final analysis of the findings. Plant-based active compounds, including phenols, flavonoids, and antioxidants, can be effective on atherosclerosis predisposing factors and hence in preventing this disease and associated harmful complications, especially through reducing cholesterol, preventing increase in free radicals, and ultimately decreasing vascular plaque and vascular resistance. Hence, medicinal plants can contribute to treating atherosclerosis and preventing its progression through reducing cholesterolemia, free radicals, inflammation, vascular resistance, and certain enzymes. They, alone or in combination with hypocholesterolemic drugs, can therefore be useful for patients with hyperlipidemia and its complications. PMID:28461816

  19. A review of plant-based compounds and medicinal plants effective on atherosclerosis.

    PubMed

    Sedighi, Mehrnoosh; Bahmani, Mahmoud; Asgary, Sedigheh; Beyranvand, Fatemeh; Rafieian-Kopaei, Mahmoud

    2017-01-01

    Atherosclerosis is one of the most important cardiovascular diseases that involve vessels through the development of fatty streaks and plaques. Plant-based compounds can help treat or prevent atherosclerosis through affecting the involved factors. The main purpose of this review article is to investigate and introduce medicinal plants and their potential activities regarding antioxidant properties, effective on lipids level and development of plaque, atherosclerosis, and progression of atherosclerosis as well as the development of cardiovascular disease and ischemia. To search for the relevant articles indexed in Information Sciences Institute, PubMed, Scientific Information Database, IranMedex, and Scopus between 1980 and 2013, with further emphasis on those indexed from 2004 to 2015, we used these search terms: atherosclerosis, antioxidant, cholesterol, inflammation, and the medicinal plants below. Then, the articles with inclusion criteria were used in the final analysis of the findings. Plant-based active compounds, including phenols, flavonoids, and antioxidants, can be effective on atherosclerosis predisposing factors and hence in preventing this disease and associated harmful complications, especially through reducing cholesterol, preventing increase in free radicals, and ultimately decreasing vascular plaque and vascular resistance. Hence, medicinal plants can contribute to treating atherosclerosis and preventing its progression through reducing cholesterolemia, free radicals, inflammation, vascular resistance, and certain enzymes. They, alone or in combination with hypocholesterolemic drugs, can therefore be useful for patients with hyperlipidemia and its complications.

  20. Atherosclerosis and leukocyte-endothelial adhesive interactions are increased following acute myocardial infarction in apolipoprotein E deficient mice.

    PubMed

    Wright, Andrew P; Öhman, Miina K; Hayasaki, Takanori; Luo, Wei; Russo, Hana M; Guo, Chiao; Eitzman, Daniel T

    2010-10-01

    To determine the effect of myocardial infarction (MI) on progression of atherosclerosis in apolipoprotein E deficient (ApoE-/-) mice. MI was induced following left anterior descending coronary artery (LAD) ligation in wild-type (WT) (n=9) and ApoE-/- (n=25) mice. Compared to sham-operated animals, MI mice demonstrated increased intravascular leukocyte rolling and firm adhesion by intravital microscopy, reflecting enhanced systemic leukocyte-endothelial interactions. To determine if MI was associated with accelerated atherogenesis, LAD ligation was performed in ApoE-/- mice. Six weeks following surgery, atherosclerosis was quantitated throughout the arterial tree by microdissection and Oil-Red-O staining. There was 1.6-fold greater atherosclerotic burden present in ApoE-/- MI mice compared to sham-operated mice. Acute MI accelerates atherogenesis in mice. These results may be related to the increased risk of recurrent ischemic coronary events following MI in humans. Published by Elsevier Ireland Ltd.

  1. Statins attenuate the development of atherosclerosis and endothelial dysfunction induced by exposure to urban particulate matter (PM{sub 10})

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Miyata, Ryohei; Hiraiwa, Kunihiko; Cheng, Jui Chih

    Exposure to ambient air particulate matter (particles less than 10 μm or PM{sub 10}) has been shown to be an independent risk factor for the development and progression of atherosclerosis. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have well-established anti-inflammatory properties. The aim of this study was to determine the impact of statins on the adverse functional and morphological changes in blood vessels induced by PM{sub 10}. New Zealand White rabbits fed with a high fat diet were subjected to balloon injury to their abdominal aorta followed by PM{sub 10}/saline exposure for 4 weeks ± lovastatin (5 mg/kg/day) treatment. PM{submore » 10} exposure accelerated balloon catheter induced plaque formation and increased intimal macrophages and lipid accumulation while lovastatin attenuated these changes and promoted smooth muscle cell recruitment into plaques. PM{sub 10} impaired vascular acetylcholine (Ach) responses and increased vasoconstriction induced by phenylephrine as assessed by wire myograph. Supplementation of nitric oxide improved the impaired Ach responses. PM{sub 10} increased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in blood vessels and increased the plasma levels of endothelin-1 (ET-1). Incubation with specific inhibitors for iNOS, COX-2 or ET-1 in the myograph chambers significantly improved the impaired vascular function. Lovastatin decreased the expression of these mediators in atherosclerotic lesions and improved endothelial dysfunction. However, lovastatin was unable to reduce blood lipid levels to the baseline level in rabbits exposed to PM{sub 10}. Taken together, statins protect against PM{sub 10}-induced cardiovascular disease by reducing atherosclerosis and improving endothelial function via their anti-inflammatory properties. - Highlights: • Coarse particulate matter (PM{sub 10}) accelerated balloon injury-induced plaque formation. • Lovastatin decreased

  2. Therapies targeting innate immunity for fighting inflammation in atherosclerosis.

    PubMed

    Mendel, Itzhak; Yacov, Niva; Harats, Dror; Breitbart, Eyal

    2015-01-01

    Atherosclerosis is a smoldering disease of the vasculature that can lead to the occlusion of the arteries, resulting in ischemia of the heart and brain. For many years, the asserted underlying mechanism of atherosclerosis, supported by its epidemiology, was based on the "cholesterol hypothesis" that people with high blood cholesterol are at higher risk of developing cardiovascular disease. This hypothesis instigated a vigorous search for treatment that yielded the generation of statins, which specifically reduce LDL cholesterol. Since then, statins have revolutionized the way people are treated for the prevention of atherosclerosis. Nonetheless, despite this potent class of drugs, cardiovascular disease continues to be the leading cause of death in many parts of the world, suggesting that additional mechanisms are involved in disease pathogenesis. Intensive research has revealed that the atherosclerotic plaque is enriched with leukocytes, and that macrophages constitute the majority of immune cells in the lesion. Monocytes/macrophages are now recognized as the prime immune cells involved in the development of atherosclerosis and are implicated to affect the size, composition and vulnerability of the atherosclerotic plaque. While many of the macrophage-derived pro-inflammatory mechanisms associated with atherogenesis have been characterized, such as cell adhesion, cytokine production and protease secretion, there is a dearth of drugs that specifically target innate immunity for treating patients with atherosclerosis. This review presents pre-clinical studies, and in most cases following clinical trials with antagonists and agonists that have been designed to counteract inflammation in atherosclerosis and associated diseases, highlighting targets expressed predominantly in monocytes.

  3. Efficacy of bioactive compounds from extra virgin olive oil to modulate atherosclerosis development.

    PubMed

    Lou-Bonafonte, José M; Arnal, Carmen; Navarro, María A; Osada, Jesús

    2012-07-01

    As olive oil is the main source of calories in the Mediterranean diet, a great deal of research has been devoted to characterizing its role in atherosclerosis. Virgin olive oil is an oily matrix that contains hydrocarbons, mainly squalene; triterpenes such as uvaol, erythrodiol, oleanolic, and maslinic acid; phytosterols; and a wide range of phenolic compounds comprising simple phenols, flavonoids, secoiridoids, and lignans. In this review, we analyze the studies dealing with atherosclerosis and olive oil in several species. A protective role of virgin olive oil against atherosclerosis has been shown in ApoE-deficient mice and hamsters. In the former animal, sex, dose, and dietary cholesterol are modulators of the outcome. Contradictory findings have been reported for rabbits, a circumstance that could be due to the profusion of experimental designs, differing in terms of doses and animal strains, as well as sources of olive oils. This role has yet to be fully validated in humans. Minor components of olive oil have been shown to be involved in atherosclerosis protection. Nevertheless, evidence of the potential of isolated compounds or the right combination of them to achieve the antiatherosclerotic effect of virgin olive oil is inconclusive and will undoubtedly require further experimental support. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Development of Acceleration Sensor and Acceleration Evaluation System for Super-Low-Range Frequencies

    NASA Astrophysics Data System (ADS)

    Asano, Shogo; Matsumoto, Hideki

    2001-05-01

    This paper describes the development process for acceleration sensors used on automobiles and an acceleration evaluation system designed specifically for acceleration at super-low-range frequencies. The features of the newly developed sensor are as follows. 1) Original piezo-bimorph design based on a disc-center-fixed structure achieves pyroeffect cancelling and stabilization of sensor characteristics and enables the detection of the acceleration of 0.0009 G at the super-low-range-frequency of 0.03 Hz. 2) The addition of a self-diagnostic function utilizing the characteristics of piezoceramics enables constant monitoring of sensor failure. The frequency range of acceleration for accurate vehicle motion control is considered to be from DC to about 50 Hz. However, the measurement of acceleration in the super-low-range frequency near DC has been difficult because of mechanical and electrical noise interruption. This has delayed the development of the acceleration sensor for automotive use. We have succeeded in the development of an acceleration evaluation system for super-low-range frequencies from 0.015 Hz to 2 Hz with detection of the acceleration range from 0.0002 G (0.2 gal) to 1 G, as well as the development of a piezoelectric-type acceleration sensor for automotive use.

  5. Myocardin: A novel player in atherosclerosis.

    PubMed

    Xia, Xiao-Dan; Zhou, Zhen; Yu, Xiao-Hua; Zheng, Xi-Long; Tang, Chao-Ke

    2017-02-01

    Myocardin (MYOCD) the most important coactivator of serum response factor (SRF), plays a critical role specifically in the development of cardiac myocytes and vascular smooth muscle cells (VSMCs). Binding of Myocardin to the SRF on the CArG box-containing target genes can transcriptionally activate a variety of downstream muscle-specific genes, such as Sm22α, Acta2, Myh11, and several other signaling pathways. Myocardin expression represents a contractile and differentiated SMC phenotype. Loss of Myocardin, however, represents a synthetic and dedifferentiated phenotype, a hallmark in atherosclerosis. Growing evidence shows that Myocardin is involved in lipid metabolism and vascular inflammation, the primary pathogenesis of atherosclerosis. Moreover, Myocardin expression level is altered in atherosclerotic patients and animal models, suggesting more extensive and important roles for Myocardin in atherosclerosis. In the current review, we summarized recent progress on the regulation and signaling of Myocardin, and highlighted its impacts on atherosclerotic disease. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice.

    PubMed

    Westerterp, Marit; Murphy, Andrew J; Wang, Mi; Pagler, Tamara A; Vengrenyuk, Yuliya; Kappus, Mojdeh S; Gorman, Darren J; Nagareddy, Prabhakara R; Zhu, Xuewei; Abramowicz, Sandra; Parks, John S; Welch, Carrie; Fisher, Edward A; Wang, Nan; Yvan-Charvet, Laurent; Tall, Alan R

    2013-05-24

    Plasma high-density lipoprotein levels are inversely correlated with atherosclerosis. Although it is widely assumed that this is attributable to the ability of high-density lipoprotein to promote cholesterol efflux from macrophage foam cells, direct experimental support for this hypothesis is lacking. To assess the role of macrophage cholesterol efflux pathways in atherogenesis. We developed mice with efficient deletion of the ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) in macrophages (MAC-ABC(DKO) mice) but not in hematopoietic stem or progenitor populations. MAC-ABC(DKO) bone marrow (BM) was transplanted into Ldlr(-/-) recipients. On the chow diet, these mice had similar plasma cholesterol and blood monocyte levels but increased atherosclerosis compared with controls. On the Western-type diet, MAC-ABC(DKO) BM-transplanted Ldlr(-/-) mice had disproportionate atherosclerosis, considering they also had lower very low-density lipoprotein/low-density lipoprotein cholesterol levels than controls. ABCA1/G1-deficient macrophages in lesions showed increased inflammatory gene expression. Unexpectedly, Western-type diet-fed MAC-ABC(DKO) BM-transplanted Ldlr(-/-) mice displayed monocytosis and neutrophilia in the absence of hematopoietic stem and multipotential progenitor cells proliferation. Mechanistic studies revealed increased expressions of machrophage colony stimulating factor and granulocyte colony stimulating factor in splenic macrophage foam cells, driving BM monocyte and neutrophil production. These studies show that macrophage deficiency of ABCA1/G1 is proatherogenic likely by promoting plaque inflammation and uncover a novel positive feedback loop in which cholesterol-laden splenic macrophages signal BM progenitors to produce monocytes, with suppression by macrophage cholesterol efflux pathways.

  7. Proliferating macrophages prevail in atherosclerosis.

    PubMed

    Randolph, Gwendalyn J

    2013-09-01

    Macrophages accumulate in atherosclerotic lesions during the inflammation that is part of atherosclerosis development and progression. A new study in mice indicates that the accumulation of macrophages in atherosclerotic plaques depends on local macrophage proliferation rather than the recruitment of circulating monocytes.

  8. Immune cell screening of a nanoparticle library improves atherosclerosis therapy

    PubMed Central

    Baxter, Samantha; Menon, Arjun; Alaarg, Amr; Sanchez-Gaytan, Brenda L.; Fay, Francois; Zhao, Yiming; Ouimet, Mireille; Braza, Mounia S.; Longo, Valerie A.; Abdel-Atti, Dalya; Duivenvoorden, Raphael; Calcagno, Claudia; Storm, Gert; Tsimikas, Sotirios; Moore, Kathryn J.; Swirski, Filip K.; Nahrendorf, Matthias; Fisher, Edward A.; Pérez-Medina, Carlos; Fayad, Zahi A.; Reiner, Thomas; Mulder, Willem J. M.

    2016-01-01

    Immunological complexity in atherosclerosis warrants targeted treatment of specific inflammatory cells that aggravate the disease. With the initiation of large phase III trials investigating immunomodulatory drugs for atherosclerosis, cardiovascular disease treatment enters a new era. We here propose a radically different approach: implementing and evaluating in vivo a combinatorial library of nanoparticles with distinct physiochemical properties and differential immune cell specificities. The library’s nanoparticles are based on endogenous high-density lipoprotein, which can preferentially deliver therapeutic compounds to pathological macrophages in atherosclerosis. Using the apolipoprotein E-deficient (Apoe−/−) mouse model of atherosclerosis, we quantitatively evaluated the library’s immune cell specificity by combining immunological techniques and in vivo positron emission tomography imaging. Based on this screen, we formulated a liver X receptor agonist (GW3965) and abolished its liver toxicity while still preserving its therapeutic function. Screening the immune cell specificity of nanoparticles can be used to develop tailored therapies for atherosclerosis and other inflammatory diseases. PMID:27791119

  9. Suppression of atherosclerosis by synthetic REV-ERB agonist

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.

    2015-05-08

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks comparedmore » to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.« less

  10. Beijing ambient particle exposure accelerates atherosclerosis in ApoE knockout mice.

    PubMed

    Chen, Tian; Jia, Guang; Wei, Yongjie; Li, Jiucun

    2013-11-25

    Air pollution is associated with significant adverse health effects including increased cardiovascular morbidity and mortality. However research on the cardiovascular effect of "real-world" exposure to ambient particulate matter (PM) in susceptible animal model is very limited. In this study, we aimed to investigate the association between Beijing ambient particle exposure and the atherosclerosis development in the apolipoprotein E knockout mice (ApoE(-/-) mice). Two parallel exposure chambers were used for whole body exposure among ApoE knockout mice. One of the chambers was supplied with untreated ambient air (PM group) and the other chamber was treated with ambient air filtered by high-efficiency particulate air (HEPA) filter (FA group). Twenty mice were divided into two groups and exposed to ambient PM (n=10 for PM group) or filtered air (n=10 for FA group) for two months from January 18th to March 18th, 2010. During the exposure, the mass concentrations of PM2.5 and PM10 in the two chambers were continuously monitored. Additionally, a receptor source apportionment model of chemical mass balance using 19 organic tracers was applied to determine the contributions of sources on the PM2.5 in terms of natural gas, diesel vehicle, gasoline vehicle, coal burning, vegetable debris, biomass burning and cooking. At the end of the two-month exposure, biomarkers of oxidative stress, inflammation and lipid metabolism in bronchoalveolar lavage fluid (BAL) and blood samples were determined and the plaque area on the aortic endothelium was quantified. In the experiment, the concentrations of PM10 and PM2.5 in PM chamber were 99.45μg/m(3) and 61.0μg/m(3) respectively, while PM2.5 in FA chamber was 17.6μg/m(3). Source apportionment analysis by organic tracers showed that gasoline vehicle (39.9%) and coal burning (24.3%) emission were the two major sources contributing to the mass concentration of PM2.5 in Beijing. Among the ApoE knockout mice, the PM group were significantly

  11. Histone deacetylases and atherosclerosis.

    PubMed

    Zheng, Xia-xia; Zhou, Tian; Wang, Xin-An; Tong, Xiao-hong; Ding, Jia-wang

    2015-06-01

    Atherosclerosis is the most common pathological process that leads to cardiovascular diseases, a disease of large- and medium-sized arteries that is characterized by a formation of atherosclerotic plaques consisting of necrotic cores, calcified regions, accumulated modified lipids, smooth muscle cells (SMCs), endothelial cells, leukocytes, and foam cells. Recently, the question about how to suppress the occurrence of atherosclerosis and alleviate the progress of cardiovascular disease becomes the hot topic. Accumulating evidence suggests that histone deacetylases(HDACs) play crucial roles in arteriosclerosis. This review summarizes the effect of HDACs and HDAC inhibitors(HDACi) on the progress of atherosclerosis. Copyright © 2015. Published by Elsevier Ireland Ltd.

  12. Suppression of atherosclerosis by synthetic REV-ERB agonist

    PubMed Central

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    2015-01-01

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. PMID:25800870

  13. High-methionine diets accelerate atherosclerosis by HHcy-mediated FABP4 gene demethylation pathway via DNMT1 in ApoE(-/-) mice.

    PubMed

    Yang, An-Ning; Zhang, Hui-Ping; Sun, Yue; Yang, Xiao-Ling; Wang, Nan; Zhu, Guangrong; Zhang, Hui; Xu, Hua; Ma, Sheng-Chao; Zhang, Yue; Li, Gui-Zhong; Jia, Yue-Xia; Cao, Jun; Jiang, Yi-Deng

    2015-12-21

    Homocysteine (Hcy) is an independent risk factor for atherosclerosis, but the underlying molecular mechanisms are not known. We investigated the effects of Hcy on fatty acid-binding protein 4 (FABP4), and tested our hypothesis that Hcy-induced atherosclerosis is mediated by increased FABP4 expression and decreased methylation. The FABP4 expression and DNA methylation was assessed in the aorta of ApoE(-/-) mice fed high-methionine diet for 20weeks. Over-expression of FABP4 enhanced accumulation of total cholesterol and cholesterol ester in foam cells. The up-regulation of DNA methyltransferase 1 (DNMT1) promoted the methylation process and decreased FABP4 expression. These data suggest that FABP4 plays a key role in Hcy-mediated disturbance of lipid metabolism and that DNMT1 may be a novel therapeutic target in Hcy-related atherosclerosis. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  14. Atherosclerosis affecting vision: therapy.

    PubMed

    Eggers, H

    1966-05-01

    The visual consequences and the pathogenesis and therapy of atherosclerosis are discussed. Atherosclerosis apparently is the result of hepatic failure to produce a stable suspension of cholesterol esters in the plasma. In some instances this represents an inherent metabolic defect. Usually it represents improper diet, namely, the excessive intake of saturated fatty acids and the inadequate intake of polyunsaturated fatty acids. Excessive ingestion of carbohydrates, insufficient physical exercise and reduced thyroid function are contributing causes. The final common denominators leading to tissue injury and destruction are vascular insufficiency and hypoxia. Hypertension is a separate disease, often concurrent with atherosclerosis. In diabetes, also a separate disease, atherosclerosis is one of the sequelae. Therapy primarily consists of the reduction or elimination of meat and milk fats from the diet, and the inclusion or increase of marine fats and vegetable oils. Simultaneously, carbohydrate intake is restricted. Adequate thyroid function, a normal hemoglobin level, and sufficient physical exercise are important. A supplementary intake of vitamins B6 and E, and of lipotropic substances is recommended.

  15. Pro-inflammatory effects of the mushroom Agaricus blazei and its consequences on atherosclerosis development.

    PubMed

    Gonçalves, Juliana L; Roma, Eric H; Gomes-Santos, Ana Cristina; Aguilar, Edenil C; Cisalpino, Daniel; Fernandes, Luciana R; Vieira, Angélica T; Oliveira, Dirce R; Cardoso, Valbert N; Teixeira, Mauro M; Alvarez-Leite, Jacqueline I

    2012-12-01

    Extracts of the mushroom Agaricus blazei (A. blazei) have been described as possessing immunomodulatory and potentially cancer-protective activities. However, these effects of A. blazei as a functional food have not been fully investigated in vivo. Using apolipoprotein E-deficient (ApoE(-/-)) mice, an experimental model of atherosclerosis, we evaluated the effects of 6 or 12 weeks of A. blazei supplementation on the activation of immune cells in the spleen and blood and on the development of atherosclerosis. Food intake, weight gain, blood lipid profile, and glycemia were similar between the groups. To evaluate leukocyte homing and activation, mice were injected with (99m)Tc-radiolabeled leukocytes, which showed enhanced leukocyte migration to the spleen and heart of A. blazei-supplemented animals. Analysis of the spleen showed higher levels of activation of neutrophils, NKT cells, and monocytes as well as increased production of TNF-α and IFN-γ. Circulating NKT cells and monocytes were also more activated in the supplemented group. Atherosclerotic lesion areas were larger in the aorta of supplemented mice and exhibited increased numbers of macrophages and neutrophils and a thinner fibrous cap. A. blazei-induced transcriptional upregulation of molecules linked to macrophage activation (CD36, TLR4), neutrophil chemotaxy (CXCL1), leukocyte adhesion (VCAM-1), and plaque vulnerability (MMP9) were seen after 12 weeks of supplementation. This is the first in vivo study showing that the immunostimulatory effect of A. blazei has proatherogenic repercussions. A. blazei enhances local and systemic inflammation, upregulating pro-inflammatory molecules, and enhancing leukocyte homing to atherosclerosis sites without affecting the lipoprotein profile.

  16. Infectious burden and atherosclerosis: A clinical issue

    PubMed Central

    Sessa, Rosa; Pietro, Marisa Di; Filardo, Simone; Turriziani, Ombretta

    2014-01-01

    Atherosclerotic cardiovascular diseases, chronic inflammatory diseases of multifactorial etiology, are the leading cause of death worldwide. In the last decade, more infectious agents, labeled as “infectious burden”, rather than any single pathogen, have been showed to contribute to the development of atherosclerosis through different mechanisms. Some microorganisms, such as Chlamydia pneumoniae (C. pneumoniae), human cytomegalovirus, etc. may act directly on the arterial wall contributing to endothelial dysfunction, foam cell formation, smooth muscle cell proliferation, platelet aggregation as well as cytokine, reactive oxygen specie, growth factor, and cellular adhesion molecule production. Others, such as Helicobacter pylori (H. pylori), influenza virus, etc. may induce a systemic inflammation which in turn may damage the vascular wall (e.g., by cytokines and proteases). Moreover, another indirect mechanism by which some infectious agents (such as H. pylori, C. pneumoniae, periodontal pathogens, etc.) may play a role in the pathogenesis of atherosclerosis is molecular mimicry. Given the complexity of the mechanisms by which each microorganism may contribute to atherosclerosis, defining the interplay of more infectious agents is far more difficult because the pro-atherogenic effect of each pathogen might be amplified. Clearly, continued research and a greater awareness will be helpful to improve our knowledge on the complex interaction between the infectious burden and atherosclerosis. PMID:25032197

  17. Reversal of coronary atherosclerosis: Role of life style and medical management.

    PubMed

    Parsons, Christine; Agasthi, Pradyumna; Mookadam, Farouk; Arsanjani, Reza

    2018-05-17

    Atherosclerotic coronary artery disease continues to be a major global health burden in developing and developed nations. Newer imaging techniques afford an accurate assessment of plaque burden and characteristics as well as the effects of treatment. Lifestyle interventions and pharmacotherapy remain the mainstay of non-interventional treatment of coronary atherosclerosis, with reversal seen in many studies. In addition, control of modifiable risk factors can be beneficial. As a better understanding of atherosclerosis pathophysiology is achieved, new therapeutic targets and combination therapies may join the armamentarium that promotes regression of atherosclerotic plaque. We present a review of the literature regarding lifestyle and medical therapies that can promote the reversal of coronary atherosclerosis. Copyright © 2018. Published by Elsevier Inc.

  18. Defining the Relationship Between Biomarkers of Oxidation and Inflammatory Stress and the Risk for Atherosclerosis in Astronauts During and After Long-Duration Spaceflight

    NASA Technical Reports Server (NTRS)

    Lee, Stuart M. C.; Stenger, Michael B.; Smith, Scott M.; Zwart, Sara R.

    2016-01-01

    Future human space travel will consist primarily of long-duration missions onboard the International Space Station (ISS) or exploration-class missions to Mars, its moons, or nearby asteroids. These missions will expose astronauts to increased risk of oxidative and inflammatory damage from a variety of sources, including radiation, psychological stress, reduced physical activity, diminished nutritional status, and hyperoxic exposure during extravehicular activity. Evidence exists that increased oxidative damage and inflammation can accelerate the development of atherosclerosis.

  19. Gammadelta (γδ) T lymphocytes do not impact the development of early atherosclerosis.

    PubMed

    Cheng, Hsin-Yuan; Wu, Runpei; Hedrick, Catherine C

    2014-06-01

    Gammadelta (γδ) T cells are a subset of pro-inflammatory innate-like T lymphocytes that serve as a bridge between innate and adaptive immunity. γδ T cells are highly enriched in cholesterol compared to αβ T cells. In this study, we aimed to identify the role of γδ T cells in atherosclerosis, a cholesterol and inflammation-driven disease. We found that the percentages of γδ T cells are increased in ApoE(-/-) mice fed a Western diet. We generated TCRδ(-/-)ApoE(-/-) mice and fed them either rodent chow or a Western diet for ten weeks for the assessment of atherosclerosis. The atherosclerotic lesion size in diet-fed TCRδ(-/-)ApoE(-/-) mice was similar to that of diet-fed ApoE(-/-) mice. There were no differences in cytokine production or numbers of αβ T cells in aorta of TCRδ(-/-)ApoE(-/-) mice. Plasma lipoprotein profiles were unchanged by the absence of γδ T cells. Our data suggest that γδ T cells do not contribute to early atherosclerotic plaque development. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Insights into Atherosclerosis Using Nanotechnology

    PubMed Central

    Linton, MacRae F.; Fazio, Sergio; Haselton, Frederick R.

    2010-01-01

    A developing forefront in vascular disease research is the application of nanotechnology, the engineering of devices at the molecular scale, for diagnostic and therapeutic applications in atherosclerosis. Promising research in this field over the past decade has resulted in the preclinical validation of nanoscale devices that target cellular and molecular components of the atherosclerotic plaque, including one of its prominent cell types, the macrophage. Nanoscale contrast agents targeting constituents of plaque biology have been adapted for application in multiple imaging modalities, leading toward more detailed diagnostic readouts, whereas nanoscale drug delivery devices can be tailored for site-specific therapeutic activity. This review highlights recent progress in utilizing nanotechnology for the clinical management of atherosclerosis, drawing upon recent preclinical studies relevant to diagnosis and treatment of the plaque and promising future applications. PMID:20425261

  1. Weight-loss changes PPAR expression, reduces atherosclerosis and improves cardiovascular function in obese insulin-resistant mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Verreth, Wim; Verhamme, Peter; Pelat, Michael

    2003-09-01

    Weight-loss in obese insulin-resistant, but not in insulin-sensitive, persons reduces CHD risk. It is not known to what extent changes in the adipose gene expression profile are important for reducing CHD risk. We studied the effect of diet restriction-induced weight-loss on gene expression in adipose tissue, atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia and insulin-resistance are associated with hypertension, impaired left ventricle function and accelerated atherosclerosis in those mice. Diet restriction during 12 weeks caused a 45% weight-loss and changes in the gene expression in adipose tissue of PPARa and PPAR? and ofmore » key genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. These changes were associated with increased insulin-sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. Thus, induction of PPARa and PPAR? in adipose tissue is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight-loss. Our observations point to the critical role of PPARs in the pathogenesis of cardiovascular features of the metabolic syndrome.« less

  2. A multicentre, randomized, double-blind placebo-controlled trial evaluating rosiglitazone for the prevention of atherosclerosis progression after coronary artery bypass graft surgery in patients with type 2 diabetes. Design and rationale of the VeIn-Coronary aTherOsclerosis and Rosiglitazone after bypass surgerY (VICTORY) trial

    PubMed Central

    Bertrand, Olivier F; Poirier, Paul; Rodés-Cabau, Josep; Rinfret, Stéphane; Title, Lawrence; Dzavik, Vladimir; Natarajan, Madhu; Angel, Juan; Batalla, Nuria; Alméras, Natalie; Costerousse, Olivier; De Larochellière, Robert; Roy, Louis; Després, Jean-Pierre

    2009-01-01

    BACKGROUND: The number of patients with coronary artery disease and type 2 diabetes will increase dramatically over the next decade. Diabetes has been related to accelerated atherosclerosis and many patients with diabetes will require coronary artery bypass graft (CABG) surgery utilizing saphenous vein grafts. After CABG, accelerated atherosclerosis in saphenous vein grafts leads to graft failure in approximately 50% of cases over a 10-year period. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, has been shown to improve multiple metabolic parameters in patients with type 2 diabetes. However, its role in the prevention of atherosclerosis progression is uncertain. STUDY DESIGN: VeIn-Coronary aTherOsclerosis and Rosiglitazone after bypass surgerY (VICTORY) is a cardiometabolic trial in which patients with type 2 diabetes, one to 10 years after CABG, will be randomly assigned to receive rosiglitazone (up to 8 mg/day) or a placebo after qualifying angiography and intravascular ultrasound of a segment of one vein graft with or without a native anastomosed coronary artery. A comprehensive set of athero-thrombo-inflammatory markers will be serially assessed during the 12-month follow-up period. Body fat distribution and body composition will be assessed by computed tomography and dual energy x-ray absorptiometry, respectively, at baseline, six months and 12 months follow-up. For atherosclerosis progression evaluation, repeat angiography and intravascular ultrasound will be performed after 12 months follow-up. The primary end point of the study will be the change in atherosclerotic plaque volume in a 40 mm or longer segment of one vein graft. CONCLUSIONS: The VICTORY trial is the first cardiometabolic study to evaluate the antiatherosclerotic and metabolic effects of rosiglitazone in post-CABG patients with type 2 diabetes. PMID:19746240

  3. Intracranial atherosclerosis: current concepts.

    PubMed

    Arenillas, Juan F

    2011-01-01

    The most relevant ideas discussed in this article are described here. Intracranial atherosclerotic disease (ICAD) represents the most common cause of ischemic stroke worldwide. Its importance in whites may have been underestimated. New technical developments, such as high-resolution MRI, allow direct assessment of the intracranial atherosclerotic plaque, which may have a profound impact on ICAD diagnosis and therapy in the near future. Early detection of ICAD may allow therapeutic intervention while the disease is still asymptomatic. The Barcelonès Nord and Maresme Asymptomatic Intracranial Atherosclerosis Study is presented here. The main prognostic factors that characterize the patients who are at a higher risk for ICAD recurrence are classified and discussed. The best treatment for ICAD remains to be established. The Stenting Versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Study is currently ongoing to address this crucial issue. These and other topics will be discussed at the Fifth International Intracranial Atherosclerosis Conference (Valladolid, Spain, autumn 2011).

  4. Imaging Atherosclerosis

    PubMed Central

    Tarkin, Jason M.; Dweck, Marc R.; Evans, Nicholas R.; Takx, Richard A.P.; Brown, Adam J.; Tawakol, Ahmed; Fayad, Zahi A.

    2016-01-01

    Advances in atherosclerosis imaging technology and research have provided a range of diagnostic tools to characterize high-risk plaque in vivo; however, these important vascular imaging methods additionally promise great scientific and translational applications beyond this quest. When combined with conventional anatomic- and hemodynamic-based assessments of disease severity, cross-sectional multimodal imaging incorporating molecular probes and other novel noninvasive techniques can add detailed interrogation of plaque composition, activity, and overall disease burden. In the catheterization laboratory, intravascular imaging provides unparalleled access to the world beneath the plaque surface, allowing tissue characterization and measurement of cap thickness with micrometer spatial resolution. Atherosclerosis imaging captures key data that reveal snapshots into underlying biology, which can test our understanding of fundamental research questions and shape our approach toward patient management. Imaging can also be used to quantify response to therapeutic interventions and ultimately help predict cardiovascular risk. Although there are undeniable barriers to clinical translation, many of these hold-ups might soon be surpassed by rapidly evolving innovations to improve image acquisition, coregistration, motion correction, and reduce radiation exposure. This article provides a comprehensive review of current and experimental atherosclerosis imaging methods and their uses in research and potential for translation to the clinic. PMID:26892971

  5. STAT4 deficiency reduces the development of atherosclerosis in mice.

    PubMed

    Taghavie-Moghadam, Parésa L; Gjurich, Breanne N; Jabeen, Rukhsana; Krishnamurthy, Purna; Kaplan, Mark H; Dobrian, Anca D; Nadler, Jerry L; Galkina, Elena V

    2015-11-01

    Atherosclerosis is a chronic inflammatory process that leads to plaque formation in large and medium sized vessels. T helper 1 (Th1) cells constitute the majority of plaque infiltrating pro-atherogenic T cells and are induced via IFNγ-dependent activation of T-box (Tbet) and/or IL-12-dependent activation of signal transducer and activator of transcription 4 (STAT4). We thus aimed to define a role for STAT4 in atherosclerosis. STAT4-deficiency resulted in a ∼71% reduction (p < 0.001) in plaque burden in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice fed chow diet and significantly attenuated atherosclerosis (∼31%, p < 0.01) in western diet fed Stat4(-/-)Apoe(-/-) mice. Surprisingly, reduced atherogenesis in Stat4(-/-)Apoe(-/-) mice was not due to attenuated IFNγ production in vivo by Th1 cells, suggesting an at least partially IFNγ-independent pro-atherogenic role of STAT4. STAT4 is expressed in T cells, but also detected in macrophages (MΦs). Stat4(-/-)Apoe(-/-)in vitro differentiated M1 or M2 MΦs had reduced cytokine production compare to Apoe(-/-) M1 and M2 MΦs that was accompanied by reduced induction of CD69, I-A(b), and CD86 in response to LPS stimulation. Stat4(-/-)Apoe(-/-) MΦs expressed attenuated levels of CCR2 and demonstrated reduced migration toward CCL2 in a transwell assay. Importantly, the percentage of aortic CD11b(+)F4/80(+)Ly6C(hi) MΦs was reduced in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice. Thus, this study identifies for the first time a pro-atherogenic role of STAT4 that is at least partially independent of Th1 cell-derived IFNγ, and primarily involving the modulation of MΦ responses. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  6. Defining the Relationship Between Biomarkers of Oxidative and Inflammatory Stress and the Risk for Atherosclerosis in Astronauts During and After Long-Duration Spaceflight

    NASA Technical Reports Server (NTRS)

    Lee, S. M. C.; Martin, D. S.; Smith, S. M.; Zwart, S. R.; Laurie, S. S; Ribeiro, L. C.; Stenger, M. B.

    2017-01-01

    Current human space travel consists primarily of long-duration missions onboard the International Space Station (ISS), but in the future may include exploration-class missions to nearby asteroids, Mars, or its moons. These missions will expose astronauts to increased risk of oxidative and inflammatory damage from a variety of sources, including radiation, psychological stress, reduced physical activity, diminished nutritional status, and hyperoxic exposure during extravehicular activity. Evidence exists that increased oxidative stress and inflammation can accelerate the development of atherosclerosis.

  7. [Transdisciplinary Approach for Sarcopenia. Sarcopenia and atherosclerosis].

    PubMed

    Kohara, Katsuhiko

    2014-10-01

    Risk factors for sarcopenia, including aging, inflammation, oxidative stress, and sedentary life style, are also known as risks for atherosclerosis. Sarcopenia and atherosclerosis relate each other. We found that sarcopenia, especially sarcopenic visceral obesity in male subjects, was associated with higher arterial stiffness and central blood pressure. We also observed that leptin resistance may underlie the link between sarcopenia, sarcopenic obesity and atherosclerosis. In epidemiological studies, it has been demonstrated sarcopenic indices were associated with cardiovascular death. These findings indicate that sarcopenia could be regarded as risk factor for atherosclerosis and cardiovascular events.

  8. Assessment of relationship on excess fluoride intake from drinking water and carotid atherosclerosis development in adults in fluoride endemic areas, China.

    PubMed

    Liu, Hui; Gao, Yanhui; Sun, Liyan; Li, Mang; Li, Bingyun; Sun, Dianjun

    2014-03-01

    Cross-sectional analysis was conducted to access the relationships between developing carotid artery atherosclerosis through consuming high fluoride in drinking water and its possible mechanism, using the baseline data collected from 585 study subjects. In the cross sectional analysis, subjects were divided into four groups based on the concentrations of fluoride in their drinking water. The range of fluoride concentrations was: normal group (less than 1.20 mg/L), mild group (1.21-2.00 mg/L), moderate group (2.01-3.00 mg/L), and high concentration group (more than 3.01 mg/L). The prevalence rate of carotid artery atherosclerosis in the subjects in each group was found to be 16.13%, 27.22%, 27.10%, and 29.69%, respectively. Significant difference between the prevalence of carotid artery atherosclerosis in the mild, moderate and high fluoride exposure group and in the normal group was observed (P<0.05). In addition, it was found that elevated intercellular cell adhesion molecule-1 (ICAM-1) and reduced glutathione peroxidases (GPx) was associated with carotid artery atherosclerosis in fluoride endemic areas. The findings of the research study revealed a significant positive relationship between excess fluoride exposure from drinking water and prevalence of carotid artery atherosclerosis in adults living in fluoride endemic areas. The possible mechanism was the excess fluoride induced the decreasing level of GPx causing the systemic inflammation and endothelial activation by oxidative stress. Copyright © 2013 Elsevier GmbH. All rights reserved.

  9. Hopelessness and 4-year progression of carotid atherosclerosis. The Kuopio Ischemic Heart Disease Risk Factor Study.

    PubMed

    Everson, S A; Kaplan, G A; Goldberg, D E; Salonen, R; Salonen, J T

    1997-08-01

    The importance of hope has long been recognized, whereas a lack of hope, or "giving up," is generally believed to have a negative impact on psychological well-being and physical health. Recently, hopelessness has been identified as a strong, independent predictor of cardiovascular disease morbidity and mortality in both American and Finnish populations. In this study we examined the association between high levels of hopelessness and progression of carotid atherosclerosis in participants (n = 942) in the Kuopio Ischemic Heart Disease Study, a population-based study of middle-aged men from eastern Finland who underwent carotid ultrasonography at baseline and 4 years later. Men reporting high levels of hopelessness at baseline had faster progression of carotid atherosclerosis, assessed by four measures of intima-media thickening (IMT), than men reporting low to moderate levels of hopelessness. Further analyses revealed significant interactions between hopelessness and initial level of atherosclerosis, such that the effects of high hopelessness on progression were greatest among men who had baseline mean IMT values at or above the median. Moreover, progression was greatest among men reporting high levels of hopelessness at both baseline and follow-up. Traditional coronary risk factors and use of cholesterol-lowering and antihypertensive medications did not account for much variance in the observed relationships. These findings indicate that hopelessness contributes to accelerated progression of carotid atherosclerosis, particularly among men with early evidence of atherosclerosis, and that chronically high levels of hopelessness may be especially detrimental. Additional research is needed to identify the contributory pathways and/or mechanisms underlying these relationships.

  10. Polymorphisms of apolipoprotein E and angiotensin-converting enzyme genes and carotid atherosclerosis in heavy drinkers.

    PubMed

    Bednarska-Makaruk, Małgorzata; Rodo, Maria; Markuszewski, Cezary; Rozenfeld, Anna; Swiderska, Malgorzata; Habrat, Bogusław; Wehr, Hanna

    2005-01-01

    To investigate the influence of apolipoprotein E (APOE) and angiotensin-converting enzyme (ACE) gene polymorphisms on carotid artery atherosclerosis in alcoholism. Polymorphism of both genes was identified by DNA analysis in 130 male alcohol-dependent patients. Intima-media thickness (IMT) was measured ultrasonographically. Multivariate regression analysis showed that of all the known risk factors the greatest impact on carotid atherosclerosis in alcoholics was exerted by age, hypertension, LDL cholesterol and fasting plasma glucose levels. Subjects carrying the APO E epsilon4 allele were more liable to develop atherosclerotic changes in carotid arteries compared with subjects with the epsilon3/3 genotype, which showed statistical significance in patients under 50 years of age. No association was shown between ACE I/D polymorphism and carotid atherosclerosis. APO E polymorphism can increase the risk of carotid atherosclerosis development in an alcoholic subject. The association of the APO E epsilon4 allele with carotid atherosclerosis was significant in younger patients. Since the elevated carotid IMT is considered to be a good marker of increased risk of generalized atherosclerosis the consequences could involve both cardiac and cerebrovascular events.

  11. Intranasal immunization with chitosan/pCETP nanoparticles inhibits atherosclerosis in a rabbit model of atherosclerosis.

    PubMed

    Yuan, Xiying; Yang, Xiaorong; Cai, Danning; Mao, Dan; Wu, Jie; Zong, Li; Liu, Jingjing

    2008-07-04

    In search of a convenient and pain-free route of administration of DNA vaccine against atherosclerosis, the plasmid pCR-X8-HBc-CETP (pCETP) encoding B-cell epitope of cholesteryl ester transfer protein C-terminal fragment displayed by Hepatitis B virus core particle was condensed with chitosan to form chitosan/pCETP nanoparticles. Cholesterol-fed rabbits were then intranasally immunized with the chitosan/pCETP nanoparticles to evaluate antiatherogenic effects. The results showed that significant serum antibodies against CETP were detected by enzyme-linked immunosorbent analysis and verified by Western blot analysis. The significant anti-CETP IgG lasted for 21 weeks in the rabbits immunized intranasally. Moreover, the atherogenic index was significantly lower compared with the saline control (5.95 versus 2.39, p<0.05). In addition, the average percentage of aortic lesions in the entire aorta area in the rabbits intranasally vaccinated with nanoparticles was 59.2% less than those treated with saline (29.0+/-10.9% versus 71.0+/-14.4%, p<0.01) and was similar to those intramuscularly injected with pCETP solution (29.0+/-10.9% versus 21.2+/-14.2%, p>0.05). Thus, chitosan/pCETP nanoparticles could significantly attenuate the progression of atherosclerosis by intranasal immunization. The results suggested that intranasal administration could be potentially developed as a vaccination route against atherosclerosis.

  12. Possible roles of platelet-derived microparticles in atherosclerosis.

    PubMed

    Wang, Zhi-Ting; Wang, Zi; Hu, Yan-Wei

    2016-05-01

    Platelets and platelet-derived microparticles (PMPs) play important roles in cardiovascular diseases, especially atherosclerosis. Continued research has revealed that PMPs have numerous functions in atherosclerosis, not only in thrombosis formation, but also by induction of inflammation. PMPs also induce formation of foam cells. Recent evidence strongly indicates a significant role of PMPs in atherosclerosis. Here, current research on the function of PMPs in atherosclerosis is reviewed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Endothelial microparticles-mediated transfer of microRNA-19b promotes atherosclerosis via activating perivascular adipose tissue inflammation in apoE-/- mice.

    PubMed

    Li, Changlong; Li, Sufang; Zhang, Feng; Wu, Manyan; Liang, Huizhu; Song, Junxian; Lee, Chongyou; Chen, Hong

    2018-01-08

    Microparticles(MPs) are the major carriers of circulating microRNAs. Our previous study has shown that microRNA (miR)-19b in endothelial cell-derived microparticles (EMPs) is significantly increased in patients with unstable angina. However, little is known about the relationship between miR-19b in EMPs and the progression of atherosclerosis. The aim of the present study was to define the role and potential mechanism of miR-19b incorporated in EMPs in the development of atherosclerosis. Western-diet-fed apoE -/- mice were injected with phosphate buffered solution(PBS), EMP carrying microRNA control(EMP control ) or miR-19b mimic (EMP miR19b ) intravenously. Systemic treatment with EMP miR19b significantly accelerated carotid artery atherosclerosis progression by increasing lipid, macrophages and smooth muscle cells and decreasing collagen content in atherosclerotic plaque. Fluorescence-labelled EMP miR19b injection proved that miR-19b could be transported into perivascular adipose tissue(PVAT) by EMPs. EMP miR19b treatment also promoted inflammatory cytokines secretion and macrophages infiltration in PVAT. In further experiment, apoE -/- mice were divided into 3 groups: EMP control PVAT(+), EMP miR19b PVAT(+) and EMP miR19b PVAT(-), based on removing or keeping pericarotid adipose tissue and injected with EMP control or EMP miR19b . Loss of PVAT attenuated EMP miR19b -mediated effects on increasing carotid atherosclerosis formation and inflammatory cytokines level in plaque. EMP miR19b inhibited suppressor of cytokine signaling 3 (SOCS3) expression in PVAT. Our findings demonstrate that miR-19b in EMPs exaggerates atherosclerosis progression by augmenting PVAT-specific inflammation proceeded by downregulating SOCS3 expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Osteocalcin expression by circulating endothelial progenitor cells in patients with coronary atherosclerosis.

    PubMed

    Gössl, Mario; Mödder, Ulrike I; Atkinson, Elizabeth J; Lerman, Amir; Khosla, Sundeep

    2008-10-14

    This study was designed to test whether patients with coronary atherosclerosis have increases in circulating endothelial progenitor cells (EPCs) expressing an osteogenic phenotype. Increasing evidence indicates a link between bone and the vasculature, and bone marrow and circulating osteogenic cells have been identified by staining for the osteoblastic marker, osteocalcin (OCN). Endothelial progenitor cells contribute to vascular repair, but repair of vascular injury may result in calcification. Using cell surface markers (CD34, CD133, kinase insert domain receptor [KDR]) to identify EPCs, we examined whether patients with coronary atherosclerosis had increases in the percentage of EPCs expressing OCN. We studied 72 patients undergoing invasive coronary assessment: control patients (normal coronary arteries and no endothelial dysfunction, n = 21) versus 2 groups with coronary atherosclerosis-early coronary atherosclerosis (normal coronary arteries but with endothelial dysfunction, n = 22) and late coronary atherosclerosis (severe, multivessel coronary artery disease, n = 29). Peripheral blood mononuclear cells were analyzed using flow cytometry. Compared with control patients, patients with early or late coronary atherosclerosis had significant increases (approximately 2-fold) in the percentage of CD34+/KDR+ and CD34+/CD133+/KDR+ cells costaining for OCN. Even larger increases were noted in the early and late coronary atherosclerosis patients in the percentage of CD34+/CD133-/KDR+ cells costaining for OCN (5- and 2-fold, p < 0.001 and 0.05, respectively). A higher percentage of EPCs express OCN in patients with coronary atherosclerosis compared with subjects with normal endothelial function and no structural coronary artery disease. These findings have potential implications for the mechanisms of vascular calcification and for the development of novel markers for coronary atherosclerosis.

  15. Evaluation of Chlamydophila psittaci infection and other risk factors for atherosclerosis in pet psittacine birds.

    PubMed

    Pilny, Anthony A; Quesenberry, Katherine E; Bartick-Sedrish, Tracey E; Latimer, Kenneth S; Berghaus, Roy D

    2012-06-15

    To determine whether the presence of Chlamydophila psittaci antigen, plasma cholesterol concentration, diet, sex, species, and age are risk factors for the development of atherosclerosis in pet psittacine birds. Retrospective case-control study. 31 psittacine birds with atherosclerosis (study birds) and 31 psittacine birds without atherosclerosis (control birds). Necropsy reports were reviewed, birds with a histopathologic diagnosis of atherosclerosis were identified, and available medical records were reviewed. Signalment, history, clinicopathologic findings, and other relevant data were recorded and evaluated. Control birds did not have atherosclerosis and were chosen by both convenience sampling and population demographics. Histologic sections of great vessels from all birds (study and control birds) were reviewed and then submitted for immunohistochemical staining for the presence of C psittaci antigen. Result of immunohistochemical staining for C psittaci antigen in blood vessels was significantly associated with atherosclerosis. After adjusting for age, species origin, and type of illness, the odds of atherosclerosis was 7 times as high for birds with positive immunohistochemical staining for C psittaci antigen, compared with that of birds with negative immunohistochemical staining. Study birds and control birds differed significantly only with respect to plasma cholesterol concentrations. The median plasma cholesterol concentration of study birds (421 mg/dL) was significantly higher than that of control birds (223 mg/dL). Infection with C psittaci and a high plasma cholesterol concentration may be risk factors for developing atherosclerosis in pet psittacine birds.

  16. Genetic and Pharmacological Inhibition of TREM-1 Limits the Development of Experimental Atherosclerosis.

    PubMed

    Joffre, Jeremie; Potteaux, Stephane; Zeboudj, Lynda; Loyer, Xavier; Boufenzer, Amir; Laurans, Ludivine; Esposito, Bruno; Vandestienne, Marie; de Jager, Saskia C A; Hénique, Carole; Zlatanova, Ivana; Taleb, Soraya; Bruneval, Patrick; Tedgui, Alain; Mallat, Ziad; Gibot, Sebastien; Ait-Oufella, Hafid

    2016-12-27

    Innate immune responses activated through myeloid cells contribute to the initiation, progression, and complications of atherosclerosis in experimental models. However, the critical upstream pathways that link innate immune activation to foam cell formation are still poorly identified. This study sought to investigate the hypothesis that activation of the triggering receptor expressed on myeloid cells (TREM-1) plays a determinant role in macrophage atherogenic responses. After genetically invalidating Trem-1 in chimeric Ldlr -/- Trem-1 -/- mice and double knockout ApoE -/- Trem-1 -/- mice, we pharmacologically inhibited Trem-1 using LR12 peptide. Ldlr -/- mice reconstituted with bone marrow deficient for Trem-1 (Trem-1 -/- ) showed a strong reduction of atherosclerotic plaque size in both the aortic sinus and the thoracoabdominal aorta, and were less inflammatory compared to plaques of Trem-1 +/+ chimeric mice. Genetic invalidation of Trem-1 led to alteration of monocyte recruitment into atherosclerotic lesions and inhibited toll-like receptor 4 (TLR 4)-initiated proinflammatory macrophage responses. We identified a critical role for Trem-1 in the upregulation of cluster of differentiation 36 (CD36), thereby promoting the formation of inflammatory foam cells. Genetic invalidation of Trem-1 in ApoE -/- /Trem-1 -/- mice or pharmacological blockade of Trem-1 in ApoE -/- mice using LR-12 peptide also significantly reduced the development of atherosclerosis throughout the vascular tree, and lessened plaque inflammation. TREM-1 was expressed in human atherosclerotic lesions, mainly in lipid-rich areas with significantly higher levels of expression in atheromatous than in fibrous plaques. We identified TREM-1 as a major upstream proatherogenic receptor. We propose that TREM-1 activation orchestrates monocyte/macrophage proinflammatory responses and foam cell formation through coordinated and combined activation of CD36 and TLR4. Blockade of TREM-1 signaling may constitute

  17. Macrophage-Specific Expression of IL-37 in Hyperlipidemic Mice Attenuates Atherosclerosis.

    PubMed

    McCurdy, Sara; Baumer, Yvonne; Toulmin, Emma; Lee, Bog-Hieu; Boisvert, William A

    2017-11-15

    Atherosclerosis, the progressive buildup of plaque within arterial blood vessels, can lead to fatal downstream events, such as heart attack or stroke. A key event contributing to the development of atherosclerosis is the infiltration of monocytes and its associated inflammation, as well as the formation of lipid-laden macrophage foam cells within the vessel wall. IL-37 is recognized as an important anti-inflammatory cytokine expressed especially by immune cells. This study was undertaken to elucidate the role of macrophage-expressed IL-37 in reducing the production and effects of proinflammatory cytokines, preventing foam cell formation, and reducing the development of atherosclerosis. Expression of human IL-37 was achieved with a macrophage-specific overexpression system, using the CD68 promoter in mouse primary bone marrow-derived macrophages via retroviral transduction. Macrophage IL-37 expression in vitro resulted in decreased mRNA (e.g., IL-1B, IL-6, and IL-12) and secreted protein production (e.g., IL-6, M-CSF, and ICAM-1) of key inflammatory mediators. IL-37 expression also inhibited macrophage proliferation, apoptosis, and transmigration, as well as reduced lipid uptake, compared with controls in vitro. The in vivo effects of macrophage-expressed IL-37 were investigated through bone marrow transplantation of transduced hematopoietic stem cells into irradiated atherosclerosis-prone Ldlr -/- mice. After 10 wk on a high-fat/high-cholesterol diet, mice with IL-37-expressing macrophages showed reduced disease pathogenesis, which was demonstrated by significantly less arterial plaque development and systemic inflammation compared with control mice. The athero-protective effect of macrophage-expressed IL-37 has implications for development of future therapies to treat atherosclerosis, as well as other chronic inflammatory diseases. Copyright © 2017 by The American Association of Immunologists, Inc.

  18. Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis

    PubMed Central

    Patel, Kevin M.; Strong, Alanna; Tohyama, Junichiro; Jin, Xueting; Morales, Carlos R.; Billheimer, Jeffery; Millar, John; Kruth, Howard; Rader, Daniel J.

    2015-01-01

    Rationale Non-coding gene variants at the SORT1 locus are strongly associated with LDL-C levels as well as with coronary artery disease (CAD). SORT1 encodes a protein called sortilin, and hepatic sortilin modulates LDL metabolism by targeting apoB-containing lipoproteins to the lysosome. Sortilin is also expressed in macrophages, but its role in macrophage uptake of LDL and in atherosclerosis independent of plasma LDL-C levels is unknown. Objective To determine the effect of macrophage sortilin expression on LDL uptake, foam cell formation, and atherosclerosis. Methods and Results We crossed Sort1−/− mice onto a ‘humanized’ Apobec1−/−; hAPOB Tg background and determined that Sort1 deficiency on this background had no effect on plasma LDL-C levels but dramatically reduced atherosclerosis in the aorta and aortic root. In order to test whether this effect was a result of macrophage sortilin deficiency, we transplanted Sort1−/−;LDLR−/− or Sort1+/+;LDLR−/− bone marrow into Ldlr−/− mice and observed a similar reduction in atherosclerosis in mice lacking hematopoetic sortilin without an effect on plasma LDL-C levels. In an effort to determine the mechanism by which hematopoetic sortilin deficiency reduced atherosclerosis, we found no effect of sortilin deficiency on macrophage recruitment or LPS-induced cytokine release in vivo. In contrast, sortilin deficient macrophages had significantly reduced uptake of native LDL ex vivo and reduced foam cell formation in vivo, whereas sortilin overexpression in macrophages resulted in increased LDL uptake and foam cell formation. Conclusions Macrophage sortilin deficiency protects against atherosclerosis by reducing macrophage uptake of LDL. Sortilin-mediated uptake of native LDL into macrophages may be an important mechanism of foam cell formation and contributor to atherosclerosis development. PMID:25593281

  19. The Effect of Low-Dose Proteasome Inhibition on Pre-Existing Atherosclerosis in LDL Receptor-Deficient Mice

    PubMed Central

    Wilck, Nicola; Fechner, Mandy; Dan, Cristian; Stangl, Verena; Stangl, Karl; Ludwig, Antje

    2017-01-01

    Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in atherosclerosis development. However, the nature of UPS dysfunction has been proposed to be specific to certain stages of atherosclerosis development, which has implications for proteasome inhibition as a potential treatment option. Recently, low-dose proteasome inhibition with bortezomib has been shown to attenuate early atherosclerosis in low-density lipoprotein receptor-deficient (LDLR−/−) mice. The present study investigates the effect of low-dose proteasome inhibition with bortezomib on pre-existing advanced atherosclerosis in LDLR−/− mice. We found that bortezomib treatment of LDLR−/− mice with pre-existing atherosclerosis does not alter lesion burden. Additionally, macrophage infiltration of aortic root plaques, total plasma cholesterol levels, and pro-inflammatory serum markers were not influenced by bortezomib. However, plaques of bortezomib-treated mice exhibited larger necrotic core areas and a significant thinning of the fibrous cap, indicating a more unstable plaque phenotype. Taking recent studies on favorable effects of proteasome inhibition in early atherogenesis into consideration, our data support the hypothesis of stage-dependent effects of proteasome inhibition in atherosclerosis. PMID:28387708

  20. Rebamipide ameliorates atherosclerosis by controlling lipid metabolism and inflammation

    PubMed Central

    Jeong, Jeong-Hee; Na, Hyun Sik; Kim, Eun-Kyung; Lee, Seung Hoon; Jung, KyungAh; Min, Jun-Ki; Cho, Mi-La

    2017-01-01

    Atherosclerosis is a chronic inflammatory disease caused by the accumulation of excess lipid in the aorta and the severity is regulated by T lymphocytes subsets. Rebamipide has therapeutic activity in collagen induced arthritis (CIA) by controlling the balance between T helper (Th) 17 and regulatory T (Treg) cells. In this study, we aimed to determine whether rebamipide reduces the development of atherosclerosis. To investigate the therapeutic effect of rebamipide, ApoE-KO mice fed a western diet were administered rebamipide orally for 8 weeks. Mice were sacrificed followed by the evaluation of plaque formation in the aorta or immunohistochemistry for IL-17 and Foxp3. Serum was also prepared to determine the pro-inflammatory cytokine levels. The ability of rebamipide to regulate lipid metabolism or inflammation was confirmed ex vivo. Results The oral administration of rebamipide decreased plaque formation in atherosclerotic lesions as well as the markers of metabolic disorder in ApoE-deficient mice with atherosclerosis. Pro-inflammatory cytokines were also suppressed by rebamapide. In addition, the population of Th17 was decreased, whereas Treg was increased in the spleen of rebamipide-treated ApoE deficient mice. Rebamipide also ameliorated the severity of obese arthritis and has the capability to reduce the development of atherosclerosis by controlling the balance between Th17 and Treg cells. Thus, rebamipide could be a therapeutic agent to improve the progression of inflammation in metabolic diseases. PMID:28241014

  1. Potential therapeutic effects of mTOR inhibition in atherosclerosis

    PubMed Central

    Kurdi, Ammar; De Meyer, Guido R. Y.

    2015-01-01

    Despite significant improvement in the management of atherosclerosis, this slowly progressing disease continues to affect countless patients around the world. Recently, the mechanistic target of rapamycin (mTOR) has been identified as a pre‐eminent factor in the development of atherosclerosis. mTOR is a constitutively active kinase found in two different multiprotein complexes, mTORC1 and mTORC2. Pharmacological interventions with a class of macrolide immunosuppressive drugs, called rapalogs, have shown undeniable evidence of the value of mTORC1 inhibition to prevent the development of atherosclerotic plaques in several animal models. Rapalog‐eluting stents have also shown extraordinary results in humans, even though the exact mechanism for this anti‐atherosclerotic effect remains elusive. Unfortunately, rapalogs are known to trigger diverse undesirable effects owing to mTORC1 resistance or mTORC2 inhibition. These adverse effects include dyslipidaemia and insulin resistance, both known triggers of atherosclerosis. Several strategies, such as combination therapy with statins and metformin, have been suggested to oppose rapalog‐mediated adverse effects. Statins and metformin are known to inhibit mTORC1 indirectly via 5' adenosine monophosphate‐activated protein kinase (AMPK) activation and may hold the key to exploit the full potential of mTORC1 inhibition in the treatment of atherosclerosis. Intermittent regimens and dose reduction have also been proposed to improve rapalog's mTORC1 selectivity, thereby reducing mTORC2‐related side effects. PMID:26551391

  2. Food restriction by intermittent fasting induces diabetes and obesity and aggravates spontaneous atherosclerosis development in hypercholesterolaemic mice.

    PubMed

    Dorighello, Gabriel G; Rovani, Juliana C; Luhman, Christopher J F; Paim, Bruno A; Raposo, Helena F; Vercesi, Anibal E; Oliveira, Helena C F

    2014-03-28

    Different regimens of food restriction have been associated with protection against obesity, diabetes and CVD. In the present study, we hypothesised that food restriction would bring benefits to atherosclerosis- and diabetes-prone hypercholesterolaemic LDL-receptor knockout mice. For this purpose, 2-month-old mice were submitted to an intermittent fasting (IF) regimen (fasting every other day) over a 3-month period, which resulted in an overall 20 % reduction in food intake. Contrary to our expectation, epididymal and carcass fat depots and adipocyte size were significantly enlarged by 15, 72 and 68 %, respectively, in the IF mice compared with the ad libitum-fed mice. Accordingly, plasma levels of leptin were 50 % higher in the IF mice than in the ad libitum-fed mice. In addition, the IF mice showed increased plasma levels of total cholesterol (37 %), VLDL-cholesterol (195 %) and LDL-cholesterol (50 %). As expected, in wild-type mice, the IF regimen decreased plasma cholesterol levels and epididymal fat mass. Glucose homeostasis was also disturbed by the IF regimen in LDL-receptor knockout mice. Elevated levels of glycaemia (40 %), insulinaemia (50 %), glucose intolerance and insulin resistance were observed in the IF mice. Systemic inflammatory markers, TNF-α and C-reactive protein, were significantly increased and spontaneous atherosclerosis development were markedly increased (3-fold) in the IF mice. In conclusion, the IF regimen induced obesity and diabetes and worsened the development of spontaneous atherosclerosis in LDL-receptor knockout mice. Although being efficient in a wild-type background, this type of food restriction is not beneficial in the context of genetic hypercholesterolaemia.

  3. Pediatric Origins of Nephrolithiasis-Associated Atherosclerosis.

    PubMed

    Kusumi, Kirsten; Smith, Sally; Barr-Beare, Evan; Saxena, Vijay; Schober, Megan S; Moore-Clingenpeel, Melissa; Schwaderer, Andrew L

    2015-11-01

    To determine if nephrolithiasis-associated atherosclerosis has pediatric origins and to consider possible association between kidney stones and atherosclerosis-related proteins. We matched children aged 12-17 years with kidney stones and without kidney stones. Carotid artery intima-media thickness (cIMT) was measured by ultrasound. Participants' urine was investigated by enzyme-linked immunosorbent assay for the atherosclerosis-related proteins fibronectin 1, macrophage scavenger receptor 1, osteopontin, and vascular cell adhesion molecule 1 levels, and normalized to urine creatinine levels. Subjects with nephrolithiasis had higher cIMT in the right common carotid artery and overall mean measurement. Urine osteopontin and fibronectin 1 were significant predictors of cIMT. We have provided initial preliminary evidence that nephrolithiasis-associated atherosclerosis has pediatric origins and performed studies that begin to identify potential reasons for the association of nephrolithiasis and vascular disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Why did ancient people have atherosclerosis?: from autopsies to computed tomography to potential causes.

    PubMed

    Thomas, Gregory S; Wann, L Samuel; Allam, Adel H; Thompson, Randall C; Michalik, David E; Sutherland, M Linda; Sutherland, James D; Lombardi, Guido P; Watson, Lucia; Cox, Samantha L; Valladolid, Clide M; Abd El-Maksoud, Gomaa; Al-Tohamy Soliman, Muhammad; Badr, Ibrahem; el-Halim Nur el-Din, Abd; Clarke, Emily M; Thomas, Ian G; Miyamoto, Michael I; Kaplan, Hillard S; Frohlich, Bruno; Narula, Jagat; Stewart, Alexandre F R; Zink, Albert; Finch, Caleb E

    2014-06-01

    Computed tomographic findings of atherosclerosis in the ancient cultures of Egypt, Peru, the American Southwest and the Aleutian Islands challenge our understanding of the fundamental causes of atherosclerosis. Could these findings be true? Is so, what traditional risk factors might be present in these cultures that could explain this apparent paradox? The recent computed tomographic findings are consistent with multiple autopsy studies dating as far back as 1852 that demonstrate calcific atherosclerosis in ancient Egyptians and Peruvians. A nontraditional cause of atherosclerosis that could explain this burden of atherosclerosis is the microbial and parasitic inflammatory burden likely to be present in ancient cultures inherently lacking modern hygiene and antimicrobials. Patients with chronic systemic inflammatory diseases of today, including systemic lupus erythematosus, rheumatoid arthritis, and human immunodeficiency virus infection, experience premature atherosclerosis and coronary events. Might the chronic inflammatory load of ancient times secondary to infection have resulted in atherosclerosis? Smoke inhalation from the use of open fires for daily cooking and illumination represents another potential cause. Undiscovered risk factors could also have been present, potential causes that technologically cannot currently be measured in our serum or other tissue. A synthesis of these findings suggests that a gene-environmental interplay is causal for atherosclerosis. That is, humans have an inherent genetic susceptibility to atherosclerosis, whereas the speed and severity of its development are secondary to known and potentially unknown environmental factors. Copyright © 2014 World Heart Federation (Geneva). Published by Elsevier B.V. All rights reserved.

  5. Biological signatures of asymptomatic extra- and intracranial atherosclerosis: the Barcelona-AsIA (Asymptomatic Intracranial Atherosclerosis) study.

    PubMed

    López-Cancio, Elena; Galán, Amparo; Dorado, Laura; Jiménez, Marta; Hernández, María; Millán, Mónica; Reverté, Silvia; Suñol, Anna; Barallat, Jaume; Massuet, Anna; Alzamora, Maria Teresa; Dávalos, Antonio; Arenillas, Juan Francisco

    2012-10-01

    Intracranial atherosclerotic disease (ICAD) remains a challenge for stroke primary and secondary prevention. Molecular pathways involved in the development of ICAD from its asymptomatic stages are largely unknown. In our population-based study, we aimed to compare the risk factor and biomarker profiles associated with intracranial and extracranial asymptomatic cerebral atherosclerosis. The Asymptomatic Intracranial Atherosclerosis (AsIA) study cohort includes a random sample population of 933 white subjects >50 years with a moderate to high vascular risk (based on REGICOR score) and without a history of stroke (64% males; mean age, 66 years). Carotid and intracranial atherosclerosis were screened by cervical and transcranial color-coded Duplex ultrasound, being moderate to severe stenoses confirmed by MR angiography. We registered clinical and anthropometric data and created a biobank with blood samples at baseline. A panel of biomarkers involved in atherothrombogenesis was determined: C-reactive protein, asymmetric-dimethylarginine, resistin, and plasminogen activator inhibitor-1. Insulin resistance was quantified by Homeostasis Model Assessment index. After multinomial regression analyses, male sex, hypertension, smoking, and alcoholic habits were independent risk factors of isolated extracranial atherosclerotic disease. Diabetes and metabolic syndrome conferred a higher risk for ICAD than for extracranial atherosclerotic disease. Moreover, metabolic syndrome and insulin resistance were independent risk factors of moderate to severe ICAD but were not risk factors of moderate to severe extracranial atherosclerotic disease. Regarding biomarkers, asymmetric-dimethylarginine was independently associated with isolated ICAD and resistin with combined ICAD-extracranial atherosclerotic disease. Our findings show distinct clinical and biological profiles in subclinical ICAD and extracranial atherosclerotic disease. Insulin resistance emerged as an important molecular

  6. Suppressive effects of cacao polyphenols on the development of atherosclerosis in apolipoprotein E-deficient mice.

    PubMed

    Natsume, Midori; Baba, Seigo

    2014-01-01

    Previous studies in humans have shown that the cacao polyphenols, (-)-epicatechin and its oligomers, prevent in vitro and ex vivo low-density lipoprotein oxidation mediated by free radical generators and metal ions and also reduce plasma LDL-cholesterol levels. The aim of this study was to examine the effects of cacao polyphenols on the development of atherosclerosis in apolipoprotein E-deficient (-/-) mice. Mice aged 8 weeks (n = 90) were randomized into three groups, and fed either normal mouse chow (controls) or chow supplemented with 0.25 or 0.40 % cacao polyphenols for 16 weeks. The mean plaque area in cross-sections of the brachiocephalic trunk was measured and found to be lower in the 0.25 % cacao polyphenol group than in the control group (p < 0.05). Pathological observations showed that accumulation of cholesterol crystals in the plaque area was greater in the control group compared with the 0.40 % cacao polyphenol group (p < 0.05). Immunochemical staining in the 0.25 and 0.40 % groups showed that expression of the cell adhesion molecules (VCAM-1 and ICAM-1) and production of oxidative stress markers (4-hydroxynonenal, hexanoyl-lysine, and dityrosine) were reduced in cross-sections of the brachiocephalic trunk. These results suggest that cacao polyphenols inhibit the development of atherosclerosis in apolipoprotein E-deficient (-/-) mice by reducing oxidative stress and inflammatory responses.

  7. MitoNEET in Perivascular Adipose Tissue Blunts Atherosclerosis under Mild Cold Condition in Mice

    PubMed Central

    Xiong, Wenhao; Zhao, Xiangjie; Garcia-Barrio, Minerva T.; Zhang, Jifeng; Lin, Jiandie; Chen, Y. Eugene; Jiang, Zhisheng; Chang, Lin

    2017-01-01

    Background: Perivascular adipose tissue (PVAT), which surrounds most vessels, is de facto a distinct functional vascular layer actively contributing to vascular function and dysfunction. PVAT contributes to aortic remodeling by producing and releasing a large number of undetermined or less characterized factors that could target endothelial cells and vascular smooth muscle cells, and herein contribute to the maintenance of vessel homeostasis. Loss of PVAT in mice enhances atherosclerosis, but a causal relationship between PVAT and atherosclerosis and the possible underlying mechanisms remain to be addressed. The CDGSH iron sulfur domain 1 protein (referred to as mitoNEET), a mitochondrial outer membrane protein, regulates oxidative capacity and adipose tissue browning. The roles of mitoNEET in PVAT, especially in the development of atherosclerosis, are unknown. Methods: The brown adipocyte-specific mitoNEET transgenic mice were subjected to cold environmental stimulus. The metabolic rates and PVAT-dependent thermogenesis were investigated. Additionally, the brown adipocyte-specific mitoNEET transgenic mice were cross-bred with ApoE knockout mice. The ensuing mice were subsequently subjected to cold environmental stimulus and high cholesterol diet challenge for 3 months. The development of atherosclerosis was investigated. Results: Our data show that mitoNEET mRNA was downregulated in PVAT of both peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α)- and beta (Pgc1β)-knockout mice which are sensitive to cold. MitoNEET expression was higher in PVAT of wild type mice and increased upon cold stimulus. Transgenic mice with overexpression of mitoNEET in PVAT were cold resistant, and showed increased expression of thermogenic genes. ApoE knockout mice with mitoNEET overexpression in PVAT showed significant downregulation of inflammatory genes and showed reduced atherosclerosis development upon high fat diet feeding when kept in a 16

  8. Follicular B Cells Promote Atherosclerosis via T Cell-Mediated Differentiation Into Plasma Cells and Secreting Pathogenic Immunoglobulin G.

    PubMed

    Tay, Christopher; Liu, Yu-Han; Kanellakis, Peter; Kallies, Axel; Li, Yi; Cao, Anh; Hosseini, Hamid; Tipping, Peter; Toh, Ban-Hock; Bobik, Alex; Kyaw, Tin

    2018-05-01

    B cells promote or protect development of atherosclerosis. In this study, we examined the role of MHCII (major histocompatibility II), CD40 (cluster of differentiation 40), and Blimp-1 (B-lymphocyte-induced maturation protein) expression by follicular B (FO B) cells in development of atherosclerosis together with the effects of IgG purified from atherosclerotic mice. Using mixed chimeric Ldlr -/- mice whose B cells are deficient in MHCII or CD40, we demonstrate that these molecules are critical for the proatherogenic actions of FO B cells. During development of atherosclerosis, these deficiencies affected T-B cell interactions, germinal center B cells, plasma cells, and IgG. As FO B cells differentiating into plasma cells require Blimp-1, we also assessed its role in the development of atherosclerosis. Blimp-1-deficient B cells greatly attenuated atherosclerosis and immunoglobulin-including IgG production, preventing IgG accumulation in atherosclerotic lesions; Blimp-1 deletion also attenuated lesion proinflammatory cytokines, apoptotic cell numbers, and necrotic core. To determine the importance of IgG for atherosclerosis, we purified IgG from atherosclerotic mice. Their transfer but not IgG from nonatherosclerotic mice into Ldlr -/- mice whose B cells are Blimp-1-deficient increased atherosclerosis; transfer was associated with IgG accumulating in atherosclerotic lesions, increased lesion inflammatory cytokines, apoptotic cell numbers, and necrotic core size. The mechanism by which FO B cells promote atherosclerosis is highly dependent on their expression of MHCII, CD40, and Blimp-1. FO B cell differentiation into IgG-producing plasma cells also is critical for their proatherogenic actions. Targeting B-T cell interactions and pathogenic IgG may provide novel therapeutic strategies to prevent atherosclerosis and its adverse cardiovascular complications. © 2018 American Heart Association, Inc.

  9. Miniature penetrator (MinPen) acceleration recorder development test

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Franco, R.J.; Platzbecker, M.R.

    1998-08-01

    The Telemetry Technology Development Department at Sandia National Laboratories actively develops and tests acceleration recorders for penetrating weapons. This new acceleration recorder (MinPen) utilizes a microprocessor-based architecture for operational flexibility while maintaining electronics and packaging techniques developed over years of penetrator testing. MinPen has been demonstrated to function in shock environments up to 20,000 Gs. The MinPen instrumentation development has resulted in a rugged, versatile, miniature acceleration recorder and is a valuable tool for penetrator testing in a wide range of applications.

  10. Correlation between Mitochondrial Reactive Oxygen and Severity of Atherosclerosis.

    PubMed

    Dorighello, Gabriel G; Paim, Bruno A; Kiihl, Samara F; Ferreira, Mônica S; Catharino, Rodrigo R; Vercesi, Anibal E; Oliveira, Helena C F

    2016-01-01

    Atherosclerosis has been associated with mitochondria dysfunction and damage. Our group demonstrated previously that hypercholesterolemic mice present increased mitochondrial reactive oxygen (mtROS) generation in several tissues and low NADPH/NADP+ ratio. Here, we investigated whether spontaneous atherosclerosis in these mice could be modulated by treatments that replenish or spare mitochondrial NADPH, named citrate supplementation, cholesterol synthesis inhibition, or both treatments simultaneously. Robust statistical analyses in pooled group data were performed in order to explain the variation of atherosclerosis lesion areas as related to the classic atherosclerosis risk factors such as plasma lipids, obesity, and oxidative stress, including liver mtROS. Using three distinct statistical tools (univariate correlation, adjusted correlation, and multiple regression) with increasing levels of stringency, we identified a novel significant association and a model that reliably predicts the extent of atherosclerosis due to variations in mtROS. Thus, results show that atherosclerosis lesion area is positively and independently correlated with liver mtROS production rates. Based on these findings, we propose that modulation of mitochondrial redox state influences the atherosclerosis extent.

  11. Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice.

    PubMed

    Kritikou, Eva; van Puijvelde, Gijs H M; van der Heijden, Thomas; van Santbrink, Peter J; Swart, Maarten; Schaftenaar, Frank H; Kröner, Mara J; Kuiper, Johan; Bot, Ilze

    2016-11-24

    Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA 1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA 1/3 antagonism using the small molecule Ki16425. We show that LPA 1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA 1/3 blockade enhanced the percentage of non-inflammatory, Ly6C low monocytes and CD4 + CD25 + FoxP3 + T-regulatory cells. Finally, we demonstrate that LPA 1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA 1/3 receptors may prove a promising approach to diminish atherosclerosis development.

  12. Endothelium Preserving Microwave Treatment for Atherosclerosis

    NASA Technical Reports Server (NTRS)

    Fink, Patrick; Arndt, G. D.; Ngo, Phong

    2003-01-01

    This slide presentation reviews the use of microwave technology for treating Atherosclerosis while preserving the endothelium. The system uses catheter antennas as part of the system that is intended to treat atherosclerosis. The concept is to use a microwave catheter for heating the atherosclerotic lesions, and reduce constriction in the artery.

  13. Single-Dose and Fractionated Irradiation Promote Initiation and Progression of Atherosclerosis and Induce an Inflammatory Plaque Phenotype in ApoE{sup -/-} Mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hoving, Saske; Heeneman, Sylvia; Gijbels, Marion J.J.

    2008-07-01

    Purpose: Increased risk of atherosclerosis and stroke has been demonstrated in patients receiving radiotherapy for Hodgkin's lymphoma and head-and-neck cancer. We previously showed that 14 Gy to the carotid arteries of hypercholesterolemic ApoE{sup -/-} mice resulted in accelerated development of macrophage-rich, inflammatory atherosclerotic lesions. Here we investigate whether clinically relevant fractionated irradiation schedules and lower single doses also predispose to an inflammatory plaque phenotype. Methods and Materials: ApoE{sup -/-} mice were given 8 or 14 Gy, or 20 x 2.0 Gy in 4 weeks to the neck, and the carotid arteries were subsequently examinated for presence of atherosclerotic lesions, plaquemore » size, and phenotype. Results: At 4 weeks, early atherosclerotic lesions were found in 44% of the mice after single doses of 14 Gy but not in age-matched controls. At 22 to 30 weeks after irradiation there was a twofold increase in the mean number of carotid lesions (8-14 Gy and 20 x 2.0 Gy) and total plaque burden (single doses only), compared with age-matched controls. The majority of lesions seen at 30 to 34 weeks after fractionated irradiation or 14-Gy single doses were granulocyte rich (100% and 63%, respectively), with thrombotic features (90% and 88%), whereas these phenotypes were much less common in age-matched controls or after a single dose of 8 Gy. Conclusions: We showed that fractionated irradiation accelerated the development of atherosclerosis in ApoE{sup -/-} mice and predisposed to the formation of an inflammatory, thrombotic plaque phenotype.« less

  14. Sleep Characteristics and Carotid Atherosclerosis Among Midlife Women.

    PubMed

    Thurston, Rebecca C; Chang, Yuefang; von Känel, Roland; Barinas-Mitchell, Emma; Jennings, J Richard; Hall, Martica H; Santoro, Nanette; Buysse, Daniel J; Matthews, Karen A

    2017-02-01

    Midlife, which encompasses the menopause transition in women, can be a time of disrupted sleep and accelerated atherosclerosis accumulation. Short or poor sleep quality has been associated with cardiovascular disease (CVD) risk; few studies have investigated relations among midlife women. We tested whether shorter actigraphy sleep time or poorer subjective sleep quality was associated with carotid atherosclerosis among midlife women. Two hundred fifty-six peri- and postmenopausal women aged 40-60 years completed 3 days of wrist actigraphy, hot flash monitoring, questionnaires (Pittsburgh Sleep Quality Index [PSQI], Berlin), a blood draw, and carotid ultrasound [intima media thickness (IMT), plaque]. Associations of objective (actigraphy) and subjective (PSQI) sleep with IMT/plaque were tested in regression models (covariates: age, race, education, body mass index, blood pressure, lipids, insulin resistance, medications, snoring, depressive symptoms, sleep hot flashes, and estradiol). Shorter objective sleep time was associated with higher odds of carotid plaque (for each hour shorter sleep, plaque score ≥ 2, odds ratio (OR) [95% confidence interval, CI] = 1.58 [1.11-2.27], p = .01; plaque score = 1, OR [95% CI] = 0.95 [0.68-1.32], p = .75, vs. no plaque, multivariable). Poorer subjective sleep quality was associated with higher mean IMT [β, b (standard error, SE) = 0.004 (0.002), p = .03], maximal IMT [b (SE) = 0.009 (0.003), p = .005], and plaque [plaque score ≥ 2, OR (95% CI) = 1.23 (1.09-1.40), p = .001; score = 1, OR (95% CI) = 1.06 (0.93-1.21), p = .37, vs. no plaque] in multivariable models. Findings persisted additionally adjusting for sleep hot flashes and estradiol. Shorter actigraphy-assessed sleep time and poorer subjective sleep quality were associated with increased carotid atherosclerosis among midlife women. Associations persisted adjusting for CVD risk factors, hot flashes, and estradiol. © Sleep Research Society 2016. Published by Oxford

  15. Regressing Atherosclerosis by Resolving Plaque Inflammation

    DTIC Science & Technology

    2017-07-01

    Atherosclerosis is a chronic inflammatory disease that develops in the setting of hyperlipidemia, with progression a consequence of the failure to...measured in distilled water because of the increased ionic strength on the surface of NPs in PBS solution [29]. In contrast, NPs(550) with a lipid-PEG...J.A. is a recipient of a Scientist Development Grant from the American Heart Association (16SDG27550012). A.M. was supported by an NYU training

  16. Early Onset Intrauterine Growth Restriction in a Mouse Model of Gestational Hypercholesterolemia and Atherosclerosis

    PubMed Central

    Busso, Dolores; Mascareño, Lilian; Salas, Francisca; Berkowitz, Loni; Santander, Nicolás; Quiroz, Alonso; Amigo, Ludwig; Valdés, Gloria; Rigotti, Attilio

    2014-01-01

    The susceptibility to develop atherosclerosis is increased by intrauterine growth restriction and prenatal exposure to maternal hypercholesterolemia. Here, we studied whether mouse gestational hypercholesterolemia and atherosclerosis affected fetal development and growth at different stages of gestation. Female LDLR KO mice fed a proatherogenic, high cholesterol (HC) diet for 3 weeks before conception and during pregnancy exhibited a significant increase in non-HDL cholesterol and developed atherosclerosis. At embryonic days 12.5 (E12.5), E15.5, and E18.5, maternal gestational hypercholesterolemia and atherosclerosis were associated to a 22–24% reduction in male and female fetal weight without alterations in fetal number/litter or morphology nor placental weight or structure. Feeding the HC diet exclusively at the periconceptional period did not alter fetal growth, suggesting that maternal hypercholesterolemia affected fetal weight only after implantation. Vitamin E supplementation (1,000 UI of α-tocopherol/kg) of HC-fed females did not change the mean weight of E18.5 fetuses but reduced the percentage of fetuses exhibiting body weights below the 10th percentile of weight (HC: 90% vs. HC/VitE: 68%). In conclusion, our results showed that maternal gestational hypercholesterolemia and atherosclerosis in mice were associated to early onset fetal growth restriction and that dietary vitamin E supplementation had a beneficial impact on this condition. PMID:25295255

  17. Rebamipide ameliorates atherosclerosis by controlling lipid metabolism and inflammation.

    PubMed

    Jhun, JooYeon; Kwon, Jeong-Eun; Kim, Se-Young; Jeong, Jeong-Hee; Na, Hyun Sik; Kim, Eun-Kyung; Lee, Seung Hoon; Jung, KyungAh; Min, Jun-Ki; Cho, Mi-La

    2017-01-01

    The oral administration of rebamipide decreased plaque formation in atherosclerotic lesions as well as the markers of metabolic disorder in ApoE-deficient mice with atherosclerosis. Pro-inflammatory cytokines were also suppressed by rebamapide. In addition, the population of Th17 was decreased, whereas Treg was increased in the spleen of rebamipide-treated ApoE deficient mice. Rebamipide also ameliorated the severity of obese arthritis and has the capability to reduce the development of atherosclerosis by controlling the balance between Th17 and Treg cells. Thus, rebamipide could be a therapeutic agent to improve the progression of inflammation in metabolic diseases.

  18. Is atherosclerosis fundamental to human aging? Lessons from ancient mummies.

    PubMed

    Clarke, Emily M; Thompson, Randall C; Allam, Adel H; Wann, L Samuel; Lombardi, Guido P; Sutherland, M Linda; Sutherland, James D; Cox, Samantha L; Soliman, Muhammad Al-Tohamy; Abd el-Maksoud, Gomaa; Badr, Ibrahem; Miyamoto, Michael I; Frohlich, Bruno; Nur el-din, Abdel-Halim; Stewart, Alexandre F R; Narula, Jagat; Zink, Albert R; Finch, Caleb E; Michalik, David E; Thomas, Gregory S

    2014-05-01

    Case reports from Johan Czermak, Marc Ruffer, and others a century or more ago demonstrated ancient Egyptians had atherosclerosis three millennia ago. The Horus study team extended their findings, demonstrating that atherosclerosis was prevalent among 76 ancient Egyptian mummies and among 61 mummies from each of the ancient cultures of Peru, the American Southwest, and the Aleutian Islands. These findings challenge the assumption that atherosclerosis is a modern disease caused by present day risk factors. An extensive autopsy of an ancient Egyptian teenage male weaver named Nakht found that he was infected with four parasites: Schistosoma haematobium, Taenia species, Trichinella spiralis, and Plasmodium falciparum. Modern day patients with chronic inflammatory disease such as rheumatoid arthritis, systemic lupus erythematosus, and human immunodeficiency virus experience premature atherosclerosis. Could the burden of chronic inflammatory disease have been a risk factor for atherosclerosis in these ancient cultures? The prevalence of atherosclerosis in four diverse ancient cultures is consistent with atherosclerosis being fundamental to aging. The impact of risk factors in modern times, and potentially in ancient times, suggests a strong gene-environmental interplay: human genes provide a vulnerability to atherosclerosis, the environment determines when and if atherosclerosis becomes manifest clinically. Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  19. Molecular intravascular imaging approaches for atherosclerosis.

    PubMed

    Press, Marcella Calfon; Jaffer, Farouc A

    2014-10-01

    Coronary artery disease (CAD) is an inflammatory process that results in buildup of atherosclerosis, typically lipid-rich plaque in the arterial wall. Progressive narrowing of the vessel wall and subsequent plaque rupture can lead to myocardial infarction and death. Recent advances in intravascular fluorescence imaging techniques have provided exciting coronary artery-targeted platforms to further characterize the molecular changes that occur within the vascular wall as a result of atherosclerosis and following coronary stent-induced vascular injury. This review will summarize exciting recent developments in catheter-based imaging of coronary arterial-sized vessels; focusing on two-dimensional near-infrared fluorescence imaging (NIRF) molecular imaging technology as an approach to specifically identify inflammation and fibrin directly within coronary artery-sized vessels. Intravascular NIRF is anticipated to provide new insights into the in vivo biology underlying high-risk plaques, as well as high-risks stents prone to stent restenosis or stent thrombosis.

  20. Vinpocetine attenuates lipid accumulation and atherosclerosis formation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cai, Yujun; Li, Jian-Dong; Yan, Chen, E-mail: Chen_Yan@urmc.rochester.edu

    Highlights: •Vinpocetine attenuates hyperlipidemia-induced atherosclerosis in a mouse model. •Vinpocetine antagonizes ox-LDL uptake and accumulation in macrophages. •Vinpocetine blocks the induction of ox-LDL receptor LOX-1 in vitro and in vivo. -- Abstract: Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent anti-inflammatorymore » agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partially through suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis.« less

  1. Vinpocetine Attenuates Lipid Accumulation and Atherosclerosis Formation

    PubMed Central

    Cai, Yujun; Li, Jian-Dong; Yan, Chen

    2013-01-01

    Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent inflammatory agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partially through suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis PMID:23583194

  2. Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming

    PubMed Central

    Zimmer, Sebastian; Grebe, Alena; Bakke, Siril S.; Bode, Niklas; Halvorsen, Bente; Ulas, Thomas; Skjelland, Mona; De Nardo, Dominic; Labzin, Larisa I.; Kerksiek, Anja; Hempel, Chris; Heneka, Michael T.; Hawxhurst, Victoria; Fitzgerald, Michael L; Trebicka, Jonel; Gustafsson, Jan-Åke; Westerterp, Marit; Tall, Alan R.; Wright, Samuel D.; Espevik, Terje; Schultze, Joachim L.; Nickenig, Georg; Lütjohann, Dieter; Latz, Eicke

    2016-01-01

    Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Since cholesterol accumulation and deposition of cholesterol crystals (CCs) triggers a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility, in preventing and reversing atherosclerosis. Here we show that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load, and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques, and promoted liver X receptor (LXR)-mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the anti-atherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Since CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis. PMID:27053774

  3. [Technical Gap of Chinese Medical Accelerator and Its Development Path].

    PubMed

    Tian, Xinzhi

    2017-11-30

    With the reform and opening up the tide through nearly four decades of development, our medical accelerator business isfacing new era demands now, in this new historical opportunity in front of the younger generation of medical accelerator staff must assume the older generation of scientific research personnel are different of the historical responsibility. Based on the development of the predecessors, we try to analyze the current situation of the domestic accelerator, establish the new development ideas of the domestic medical accelerator, and directly face and solve the dilemma facing the development of the domestic accelerator.

  4. G Protein-coupled Estrogen Receptor Protects from Atherosclerosis

    PubMed Central

    Meyer, Matthias R.; Fredette, Natalie C.; Howard, Tamara A.; Hu, Chelin; Ramesh, Chinnasamy; Daniel, Christoph; Amann, Kerstin; Arterburn, Jeffrey B.; Barton, Matthias; Prossnitz, Eric R.

    2014-01-01

    Coronary atherosclerosis and myocardial infarction in postmenopausal women have been linked to inflammation and reduced nitric oxide (NO) formation. Natural estrogen exerts protective effects on both processes, yet also displays uterotrophic activity. Here, we used genetic and pharmacologic approaches to investigate the role of the G protein-coupled estrogen receptor (GPER) in atherosclerosis. In ovary-intact mice, deletion of gper increased atherosclerosis progression, total and LDL cholesterol levels and inflammation while reducing vascular NO bioactivity, effects that were in some cases aggravated by surgical menopause. In human endothelial cells, GPER was expressed on intracellular membranes and mediated eNOS activation and NO formation, partially accounting for estrogen-mediated effects. Chronic treatment with G-1, a synthetic, highly selective small molecule agonist of GPER, reduced postmenopausal atherosclerosis and inflammation without uterotrophic effects. In summary, this study reveals an atheroprotective function of GPER and introduces selective GPER activation as a novel therapeutic approach to inhibit postmenopausal atherosclerosis and inflammation in the absence of uterotrophic activity. PMID:25532911

  5. [The receptor theory of atherosclerosis].

    PubMed

    Likhoded, V G; Bondarenko, V M; Gintsburg, A L

    2010-01-01

    Lipopolysaccharides of Gram-negative bacteria can interact with Toll-like receptor 4 (TLR4) and induce atheroma formation. The risk of atherosclerosis is decreased in case of TLR4 mutation. Other bacterial ligands and endogenous ligands of TLRs can also be involved in induction of atherogenesis. The general concept of atherosclerosis pathogentsis is presented. According to this concept atherogenesis can be initiated by some reactions resulting from interaction of exogenous and endogenous microbial ligands with Toll-like receptors.

  6. Hepatocyte growth factor is associated with progression of atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA).

    PubMed

    Bell, Elizabeth J; Decker, Paul A; Tsai, Michael Y; Pankow, James S; Hanson, Naomi Q; Wassel, Christina L; Larson, Nicholas B; Cohoon, Kevin P; Budoff, Matthew J; Polak, Joseph F; Stein, James H; Bielinski, Suzette J

    2018-05-01

    Hepatocyte growth factor (HGF) has previously been associated with risk of stroke, coronary heart disease, and atherosclerosis. We hypothesized that higher circulating HGF is associated with greater progression of measures of atherosclerosis: coronary artery calcium (CAC) and carotid plaque. Participants aged 45-84 years from the prospective cohort study Multi-Ethnic Study of Atherosclerosis had HGF measured at baseline (between 2000 and 2002) and were followed for progression of atherosclerosis for up to 12 years. CAC was measured at all five exams using the Agatston method. Mixed-effects models were used to examine the association of HGF and CAC progression among 6695 participants with available data. Relative risk regression was used to assess the association between HGF and new or additional carotid plaque between exams 1 and 5 in 3400 participants with available data. All point estimates were adjusted for potential confounding variables. Each standard deviation higher HGF at baseline was associated with 2.9 Agatston units/year greater CAC progression (95% CI: 1.6-4.2, p < 0.0001), and the magnitude of this association differed by race/ethnicity (p value for interaction by race = 0.003). Each standard deviation higher HGF at baseline was associated with a 4% higher risk of new or additional carotid plaque (95% CI: 1.01-1.08, p = 0.005). Higher levels of HGF were significantly associated with greater progression of atherosclerosis in this large and diverse population. Circulating HGF continues to show promise as a potential clinical biomarker for cardiovascular disease. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Expansion of CD25+ Innate Lymphoid Cells Reduces Atherosclerosis

    PubMed Central

    Engelbertsen, Daniel; Foks, Amanda C.; Alberts-Grill, Noah; Kuperwaser, Felicia; Chen, Tao; Lederer, James A.; Jarolim, Petr; Grabie, Nir; Lichtman, Andrew H.

    2015-01-01

    Objective Innate lymphoid cells (ILCs) are a newly discovered subset of immune cells that promote tissue homeostasis and protect against pathogens. ILCs produce cytokines also produced by T lymphocytes that have been shown to affect atherosclerosis, but the influence of ILCs on atherosclerosis has not been explored. Approach and Results We demonstrate that CD25+ ILCs that produce type 2 cytokines (ILC2s) are present in the aorta of atherosclerotic immunodeficient ldlr−/−rag1−/− mice. To investigate the role of ILCs in atherosclerosis, ldlr−/−rag1−/− mice were concurrently fed an atherogenic diet and treated with either ILC-depleting anti-CD90.2 antibodies or with IL-2/anti-IL-2 complexes that expand CD25+ ILCs. Lesion development was not affected by anti-CD90.2 treatment, but was reduced in IL-2/anti-IL-2 -treated mice. These IL-2 treated mice had reduced VLDL cholesterol and increased triglycerides compared to controls and reduced apolipoprotein B100 gene expression in the liver. IL-2/anti-IL-2 treatment caused expansion of ILC2s in aorta and other tissues, elevated levels of IL-5, systemic eosinophila and hepatic eosinophilic inflammation. Blockade of IL-5 reversed the IL-2-complex-induced eosinophilia but did not change lesion size. Conclusions This study demonstrates that expansion of CD25-expressing ILCs by IL-2/anti-IL-2 complexes leads to a reduction in VLDL cholesterol and atherosclerosis. Global depletion of ILCs by anti-CD90.2 did not significantly affect lesion size indicating that different ILC subsets may have divergent effects on atherosclerosis. PMID:26494229

  8. [Age-related macular degeneration as a local manifestation of atherosclerosis - a novel insight into pathogenesis].

    PubMed

    Machalińska, Anna

    2013-01-01

    Age-related macular degeneration is the leading cause of irreversible visual impairment and disability among the elderly in developed countries. There is compelling evidence that atherosclerosis and age-related macular degeneration share a similar pathogenic process. The association between atherosclerosis and age-related macular degeneration has been inferred from histological, biochemical and epidemiological studies. Many published data indicate that drusen are similar in molecular composition to plaques in atherosclerosis. Furthermore, a great body of evidence has emerged over the past decade that implicates the chronic inflammatory processes in the pathogenesis and progression of both disorders. We speculate that vascular atherosclerosis and age-related macular degeneration may represent different manifestations of the same disease induced by a pathologic tissue response to the damage caused by oxidative stress and local ischemia. In this review, we characterise in detail a strong association between age-related macular degeneration and atherosclerosis development, and we postulate the hypothesis that age-related macular degeneration is a local manifestation of a systemic disease. This provides a new approach for understanding the aspects of pathogenesis and might improve the prevention and treatment of both diseases which both result from ageing of the human body.

  9. Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis

    PubMed Central

    Chistiakov, Dimitry A.; Nikiforov, Nikita G.

    2016-01-01

    Atherosclerosis can be regarded as a chronic inflammatory state, in which macrophages play different and important roles. Phagocytic proinflammatory cells populate growing atherosclerotic lesions, where they actively participate in cholesterol accumulation. Moreover, macrophages promote formation of complicated and unstable plaques by maintaining proinflammatory microenvironment. At the same time, anti-inflammatory macrophages contribute to tissue repair and remodelling and plaque stabilization. Macrophages therefore represent attractive targets for development of antiatherosclerotic therapy, which can aim to reduce monocyte recruitment to the lesion site, inhibit proinflammatory macrophages, or stimulate anti-inflammatory responses and cholesterol efflux. More studies are needed, however, to create a comprehensive classification of different macrophage phenotypes and to define their roles in the pathogenesis of atherosclerosis. In this review, we provide an overview of the current knowledge on macrophage diversity, activation, and plasticity in atherosclerosis and describe macrophage-based cellular tests for evaluation of potential antiatherosclerotic substances. PMID:27493969

  10. The Multifaceted Uses and Therapeutic Advantages of Nanoparticles for Atherosclerosis Research.

    PubMed

    DiStasio, Nicholas; Lehoux, Stephanie; Khademhosseini, Ali; Tabrizian, Maryam

    2018-05-08

    Nanoparticles are uniquely suited for the study and development of potential therapies against atherosclerosis by virtue of their size, fine-tunable properties, and ability to incorporate therapies and/or imaging modalities. Furthermore, nanoparticles can be specifically targeted to the atherosclerotic plaque, evading off-target effects and/or associated cytotoxicity. There has been a wealth of knowledge available concerning the use of nanotechnologies in cardiovascular disease and atherosclerosis, in particular in animal models, but with a major focus on imaging agents. In fact, roughly 60% of articles from an initial search for this review included examples of imaging applications of nanoparticles. Thus, this review focuses on experimental therapy interventions applied to and observed in animal models. Particular emphasis is placed on how nanoparticle materials and properties allow researchers to learn a great deal about atherosclerosis. The objective of this review was to provide an update for nanoparticle use in imaging and drug delivery studies and to illustrate how nanoparticles can be used for sensing and modelling, for studying fundamental biological mechanisms, and for the delivery of biotherapeutics such as proteins, peptides, nucleic acids, and even cells all with the goal of attenuating atherosclerosis. Furthermore, the various atherosclerosis processes targeted mainly for imaging studies have been summarized in the hopes of inspiring new and exciting targeted therapeutic and/or imaging strategies.

  11. Development of bipolar-pulse accelerator for intense pulsed ion beam acceleration

    NASA Astrophysics Data System (ADS)

    Masugata, Katsumi; Shimizu, Yuichro; Fujioka, Yuhki; Kitamura, Iwao; Tanoue, Hisao; Arai, Kazuo

    2004-12-01

    To improve the purity of intense pulsed ion beams, a new type of pulsed ion beam accelerator named "bipolar pulse accelerator" was proposed. To confirm the principle of the accelerator a prototype of the experimental system was developed. The system utilizes By type magnetically insulated acceleration gap and operated with single polar negative pulse. A coaxial gas puff plasma gun was used as an ion source, which was placed inside the grounded anode. Source plasma (nitrogen) of current density ≈25 A/cm2, duration ≈1.5 μs was injected into the acceleration gap by the plasma gun. The ions were successfully accelerated from the grounded anode to the drift tube by applying negative pulse of voltage 240 kV, duration 100 ns to the drift tube. Pulsed ion beam of current density ≈40 A/cm2, duration ≈50 ns was obtained at 41 mm downstream from the anode surface. To evaluate the irradiation effect of the ion beam to solid material, an amorphous silicon thin film of thickness ≈500 nm was used as the target, which was deposited on the glass substrate. The film was found to be poly-crystallized after 4-shots of the pulsed nitrogen ion beam irradiation.

  12. High Consumption of Iron Exacerbates Hyperlipidemia, Atherosclerosis, and Female Sterility in Zebrafish via Acceleration of Glycation and Degradation of Serum Lipoproteins.

    PubMed

    Kim, So-Hee; Yadav, Dhananjay; Kim, Suk-Jeong; Kim, Jae-Ryong; Cho, Kyung-Hyun

    2017-07-02

    Elevated serum iron level is linked with an increased risk of diabetes and atherosclerosis. However, the pathological mechanism by which iron affects serum lipoprotein levels is unknown. To elucidate the mechanism, a high dose of ferrous ion was applied (final 60 µM, 120 µM) to human serum lipoproteins, macrophages, and human dermal fibroblast (HDF) cells. Iron-treated lipoproteins showed loss of antioxidant ability along with protein degradation and multimerization, especially co-treatment with fructose (final 10 mM). In the presence of fructose, HDF cells showed 3.5-fold more severe cellular senescence, as compared to the control, dependent on the dosage of fructose. In macrophages, phagocytosis of acetylated low-density lipoprotein (acLDL) was more accelerated by ferrous ion, occurring at a rate that was up to 1.8-fold higher, than acLDL alone. After 24 weeks supplementation with 0.05% and 0.1% ferrous ion in the diet (wt/wt), serum total cholesterol (TC) level was elevated 3.7- and 2.1-fold, respectively, under normal diet (ND). Serum triglyceride (TG) was elevated 1.4- and 1.7-fold, respectively, under ND upon 0.05% and 0.1% ferrous ion supplementation. Serum glucose level was elevated 2.4- and 1.2-fold under ND and high cholesterol diet (HCD), respectively. However, body weight was decreased by the Fe 2+ consumption. Iron consumption caused severe reduction of embryo laying and reproduction ability, especially in female zebrafish via impairment of follicular development. In conclusion, ferrous ion treatment caused more pro-atherogenic, and pro-senescence processes in human macrophages and dermal cells. High consumption of iron exacerbated hyperlipidemia and hyperglycemia as well as induced fatty liver changes and sterility along with reduction of female fertility.

  13. Genetic Basis of Atherosclerosis: Insights from Mice and Humans

    PubMed Central

    Stylianou, Ioannis M.; Bauer, Robert C.; Reilly, Muredach P.; Rader, Daniel J.

    2012-01-01

    Atherosclerosis is a complex and heritable disease involving multiple cell types and the interactions of many different molecular pathways. The genetic and molecular mechanisms of atherosclerosis have in part been elucidated by mouse models; at least 100 different genes have been shown to influence atherosclerosis in mice. Importantly, unbiased genome-wide association studies have recently identified a number of novel loci robustly associated with atherosclerotic coronary artery disease (CAD). Here we review the genetic data elucidated from mouse models of atherosclerosis, as well as significant associations for human CAD. Furthermore, we discuss in greater detail some of these novel human CAD loci. The combination of mouse and human genetics has the potential to identify and validate novel genes that influence atherosclerosis, some of which may be candidates for new therapeutic approaches. PMID:22267839

  14. Atherosclerosis profile and incidence of cardiovascular events: a population-based survey.

    PubMed

    Robinson, Jennifer G; Fox, Kathleen M; Bullano, Michael F; Grandy, Susan

    2009-09-15

    Atherosclerosis is a chronic progressive disease often presenting as clinical cardiovascular disease (CVD) events. This study evaluated the characteristics of individuals with a diagnosis of atherosclerosis and estimated the incidence of CVD events to assist in the early identification of high-risk individuals. Respondents to the US SHIELD baseline survey were followed for 2 years to observe incident self-reported CVD. Respondents had subclinical atherosclerosis if they reported a diagnosis of narrow or blocked arteries/carotid artery disease without a past clinical CVD event (heart attack, stroke or revascularization). Characteristics of those with atherosclerosis and incident CVD were compared with those who did not report atherosclerosis at baseline but had CVD in the following 2 years using chi-square tests. Logistic regression model identified characteristics associated with atherosclerosis and incident events. Of 17,640 respondents, 488 (2.8%) reported having subclinical atherosclerosis at baseline. Subclinical atherosclerosis was associated with age, male gender, dyslipidemia, circulation problems, hypertension, past smoker, and a cholesterol test in past year (OR = 2.2) [all p < 0.05]. Incident CVD was twice as high in respondents with subclinical atherosclerosis (25.8%) as in those without atherosclerosis or clinical CVD (12.2%). In individuals with subclinical atherosclerosis, men (RR = 1.77, p = 0.050) and individuals with circulation problems (RR = 2.36, p = 0.003) were at greatest risk of experiencing CVD events in the next 2 years. Self-report of subclinical atherosclerosis identified an extremely high-risk group with a >25% risk of a CVD event in the next 2 years. These characteristics may be useful for identifying individuals for more aggressive diagnostic and therapeutic efforts.

  15. Vinpocetine attenuates lipid accumulation and atherosclerosis formation.

    PubMed

    Cai, Yujun; Li, Jian-Dong; Yan, Chen

    2013-05-10

    Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent anti-inflammatory agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partially through suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Hawthorn (Crataegus pinnatifida Bunge) leave flavonoids attenuate atherosclerosis development in apoE knock-out mice.

    PubMed

    Dong, Pengzhi; Pan, Lanlan; Zhang, Xiting; Zhang, Wenwen; Wang, Xue; Jiang, Meixiu; Chen, Yuanli; Duan, Yajun; Wu, Honghua; Xu, Yantong; Zhang, Peng; Zhu, Yan

    2017-02-23

    Hawthorn (Crataegus pinnatifida Bunge) leave have been used to treat cardiovascular diseases in China and Europe. Hawthorn leave flavonoids (HLF) are the main part of extraction. Whether hawthorn leave flavonoids could attenuate the development of atherosclerosis and the possible mechanism remain unknown. High-fat diet (HFD) mixed with HLF at concentrations of 5mg/kg and 20mg/kg were administered to apolipoprotein E (apoE) knock out mice. 16 weeks later, mouse serum was collected to determine the lipid profile while the mouse aorta dissected was prepared to measure the lesion area. Hepatic mRNA of genes involved in lipid metabolism were determined. Peritoneal macrophages were collected to study the impact of HLF on cholesterol efflux, formation of foam cell and the expression of ATP binding cassette transporter A1 (ABCA1). Besides, in vivo reverse cholesterol transport (RCT) was conducted. HLF attenuated the development of atherosclerosis that the mean atherosclerotic lesion area in en face aortas was reduced by 23.1% (P<0.05). In mice fed with 20mg/kg HLF, Total cholesterol (TC) level was decreased by 18.6% and very low density lipoprotein cholesterol plus low density lipoprotein cholesterol (VLDLc+LDLc) level were decreased by 23.1% whereas high density lipoprotein cholesterol (HDLc) and triglyceride (TG) levels were similar compared to that of the control group. Peroxisome proliferator activated receptor alpha (PPARα) mRNA was increased by 31.2% (P<0.05) and 60.9% (P<0.05) in mice fed with 5mg/kg and 20mg/kg HLF respectively. Sterol regulatory element binding protein-1c (SREBP-1c) was decreased by 59.3% in the group of 20mg/kg. Carnitine palmitoyl transferase 1 (CPT-1) mRNA level of 20mg/kg group was induced 66.7% (P<0.05). Superoxide dismutase 1 and 2 (SOD1 and SOD2) mRNA were induced 25.4% (P<0.05) and 71.4% (P<0.05) while induced by 36.3% (P<0.05) and 73.2% (P<0.05) in group of 20mg/kg. Glutathione peroxidase 3 (Gpx3) mRNA in the group of 20mg/kg was induced

  17. Atherosclerosis and Stroke

    MedlinePlus

    ... Stroke and atherosclerosis There are two types of ischemic stroke caused by blood clots, narrowing of blood vessels ... 2 What Is an Arteriovenous Malformation (AVM)? 3 Ischemic Strokes (Clots) 4 Hemorrhagic Strokes (Bleeds) 5 What You ...

  18. Function of CD147 in atherosclerosis and atherothrombosis

    PubMed Central

    Wang, Cuiping; Jin, Rong; Zhu, Xiaolei; Yan, Jinchuan; Guohong, Li

    2015-01-01

    CD147, a member of the immunoglobulin super family, is a well-known potent inducer of extracellular matrix metalloproteinases. Studies show that CD147 is upregulated in inflammatory diseases. Atherosclerosis is a chronic inflammatory disease of the artery wall. Further understanding of the functions of CD147 in atherosclerosis and atherothrombosis may provide a new strategy for preventing and treating cardiovascular disease. In this review, we discuss how CD147 contributes to atherosclerosis and atherothrombosis. PMID:25604960

  19. Association between diabetes mellitus, hypothyroidism or hyperadrenocorticism, and atherosclerosis in dogs.

    PubMed

    Hess, Rebecka S; Kass, Philip H; Van Winkle, Thomas J

    2003-01-01

    The objective of this study was to determine whether dogs with atherosclerosis are more likely to have concurrent diabetes mellitus, hypothyroidism, or hyperadrenocorticism than dogs that do not have atherosclerosis. A retrospective mortality prevalence case-control study was performed. The study group included 30 dogs with histopathological evidence of atherosclerosis. The control group included 142 dogs with results of a complete postmortem examination, a final postmortem examination diagnosis of neoplasia, and no histopathological evidence of atherosclerosis. Control dogs were frequency matched for age and year in which the postmortem examination was performed. Proportionate changes in the prevalence of diabetes mellitus, hypothyroidism, and hyperadrenocorticism were calculated by exact prevalence odds ratios (POR), 95% confidence intervals (95% CI), and P values. Multiple logistic regression analysis was used to examine the combined effects of prevalence determinants while controlling for age and year of postmortem examination. Dogs with atherosclerosis were over 53 times more likely to have concurrent diabetes mellitus than dogs without atherosclerosis (POR = 53.6; 95% CI, 4.6-627.5; P = .002) and over 51 times more likely to have concurrent hypothyroidism than dogs without atherosclerosis (POR = 51.1; 95% CI, 14.5-180.1; P < .001). Dogs with atherosclerosis were not found to be more likely to have concurrent hyperadrenocorticism than dogs that did not have atherosclerosis (POR = 1.8; 95% CI, 0.2-17.6; P = .59). Diabetes mellitus and hypothyroidism, but not hyperadrenocorticism, are more prevalent in dogs with atherosclerosis compared to dogs without atherosclerosis on postmortem examination.

  20. Impact of Gut Microbiota and Diet on the Development of Atherosclerosis in Apoe-/- Mice.

    PubMed

    Lindskog Jonsson, Annika; Caesar, Robert; Akrami, Rozita; Reinhardt, Christoph; Fåk Hållenius, Frida; Borén, Jan; Bäckhed, Fredrik

    2018-06-14

    To investigate the effect of gut microbiota and diet on atherogenesis. Here, we investigated the interaction between the gut microbiota and diet on atherosclerosis by feeding germ-free or conventionally raised Apoe -/- mice chow or Western diet alone or supplemented with choline (which is metabolized by the gut microbiota and host enzymes to trimethylamine N-oxide) for 12 weeks. We observed smaller aortic lesions and lower plasma cholesterol levels in conventionally raised mice compared with germ-free mice on a chow diet; these differences were not observed in mice on a Western diet. Choline supplementation increased plasma trimethylamine N-oxide levels in conventionally raised mice but not in germ-free mice. However, this treatment did not affect the size of aortic lesions or plasma cholesterol levels. Gut microbiota composition was analyzed by sequencing of 16S rRNA genes. As expected, the global community structure and relative abundance of many taxa differed between mice fed chow or a Western diet. Choline supplementation had minor effects on the community structure although the relative abundance of some taxa belonging to Clostridiales was altered. In conclusion, the impact of the gut microbiota on atherosclerosis is dietary dependent and is associated with plasma cholesterol levels. Furthermore, the microbiota was required for trimethylamine N-oxide production from dietary choline, but this process could not be linked to increased atherosclerosis in this model. © 2018 The Authors.

  1. RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Meng, Lingjun, E-mail: menglingjun@nibs.ac.cn; National Institute of Biological Sciences, Beijing 102206; Jin, Wei

    Atherothrombotic vascular disease is already the leading cause of mortality worldwide. Atherosclerosis shares features with diseases caused by chronic inflammation. More attention should concentrates on the innate immunity effect atherosclerosis progress. RIP3 (receptor-interacting protein kinase 3) act through the transcription factor named Nr4a3 (Nuclear orphan receptors) to regulate cytokine production. Deletion RIP3 decreases IL-1α production. Injection of anti-IL-1α antibody protects against the progress of atherosclerosis in ApoE −/− mice. RIP3 as a molecular switch in necrosis, controls macrophage necrotic death caused inflammation. Inhibiting necrosis will certainly reduce atherosclerosis through limit inflammation. Necrotic cell death caused systemic inflammation exacerbated cardiovascular disease. Inhibitionmore » of necrosis may yield novel therapeutic targets for treatment in years to come. - Highlights: • RIP3 regulate the Nr4a3 to control cytokine production. • Deletion RIP3 decreases IL-1a production. • Injection anti-IL-1a antibody protects against the progress of atherosclerosis. • RIP3 controls macrophage necrotic dead caused inflammation.« less

  2. Endothelial dysfunction: the early predictor of atherosclerosis.

    PubMed

    Mudau, Mashudu; Genis, Amanda; Lochner, Amanda; Strijdom, Hans

    2012-05-01

    Since the discovery in the 1980s that nitric oxide (NO) is in fact the elusive endothelium-derived relaxing factor, it has become evident that NO is not only a major cardiovascular signalling molecule, but that changes in its bioavailability are crucial in determining whether atherosclerosis will develop or not. Sustained high levels of harmful circulating stimuli associated with cardiovascular risk factors such as diabetes mellitus elicit responses in endothelial cells that appear sequentially, namely endothelial cell activation and endothelial dysfunction (ED). ED, characterised by reduced NO bioavailability, is now recognised by many as an early, reversible precursor of atherosclerosis. The pathogenesis of ED is multifactorial; however, oxidative stress appears to be the common underlying cellular mechanism in the ensuing loss of vaso-active, inflammatory, haemostatic and redox homeostasis in the body's vascular system. The role of ED as a pathophysiological link between early endothelial cell changes associated with cardiovascular risk factors and the development of ischaemic heart disease is of importance to basic scientists and clinicians alike.

  3. Site-Specific Antioxidative Therapy for Prevention of Atherosclerosis and Cardiovascular Disease

    PubMed Central

    Otani, Hajime

    2013-01-01

    Oxidative stress has been implicated in pathophysiology of aging and age-associated disease. Antioxidative medicine has become a practice for prevention of atherosclerosis. However, limited success in preventing cardiovascular disease (CVD) in individuals with atherosclerosis using general antioxidants has prompted us to develop a novel antioxidative strategy to prevent atherosclerosis. Reducing visceral adipose tissue by calorie restriction (CR) and regular endurance exercise represents a causative therapy for ameliorating oxidative stress. Some of the recently emerging drugs used for the treatment of CVD may be assigned as site-specific antioxidants. CR and exercise mimetic agents are the choice for individuals who are difficult to continue CR and exercise. Better understanding of molecular and cellular biology of redox signaling will pave the way for more effective antioxidative medicine for prevention of CVD and prolongation of healthy life span. PMID:23738041

  4. The population-based Barcelona-Asymptomatic Intracranial Atherosclerosis Study (ASIA): rationale and design

    PubMed Central

    2011-01-01

    Background Large-artery intracranial atherosclerosis may be the most frequent cause of ischemic stroke worldwide. Traditional approaches have attempted to target the disease when it is already symptomatic. However, early detection of intracranial atherosclerosis may allow therapeutic intervention while the disease is still asymptomatic. The prevalence and natural history of asymptomatic intracranial atherosclerosis in Caucasians remain unclear. The aims of the Barcelona-ASymptomatic Intracranial Atherosclerosis (ASIA) study are (1) to determine the prevalence of ASIA in a moderate-high vascular risk population, (2) to study its prognostic impact on the risk of suffering future major ischemic events, and (3) to identify predictors of the development, progression and clinical expression of this condition. Methods/Design Cross-over and cohort, population-based study. A randomly selected representative sample of 1,503 subjects with a mild-moderate-high vascular risk (as defined by a REGICOR score ≥ 5%) and with neither a history of cerebrovascular nor ischemic heart disease will be studied. At baseline, all individuals will undergo extracranial and transcranial Color-Coded Duplex (TCCD) ultrasound examinations to detect presence and severity of extra and intracranial atherosclerosis. Intracranial stenoses will be assessed by magnetic resonance angiography (MRA). Clinical and demographic variables will be recorded and blood samples will be drawn to investigate clinical, biological and genetic factors associated with the presence of ASIA. A long-term clinical and sonographic follow-up will be conducted thereafter to identify predictors of disease progression and of incident vascular events. Discussion The Barcelona-ASIA is a population-based study aiming to evaluate the prevalence and clinical importance of asymptomatic intracranial large-artery atherosclerosis in Caucasians. The ASIA project may provide a unique scientific resource to better understand the dynamics of

  5. The population-based Barcelona-Asymptomatic Intracranial Atherosclerosis Study (ASIA): rationale and design.

    PubMed

    López-Cancio, Elena; Dorado, Laura; Millán, Mónica; Reverté, Silvia; Suñol, Anna; Massuet, Anna; Mataró, María; Galán, Amparo; Alzamora, Maite; Pera, Guillem; Torán, Pere; Dávalos, Antoni; Arenillas, Juan F

    2011-02-17

    Large-artery intracranial atherosclerosis may be the most frequent cause of ischemic stroke worldwide. Traditional approaches have attempted to target the disease when it is already symptomatic. However, early detection of intracranial atherosclerosis may allow therapeutic intervention while the disease is still asymptomatic. The prevalence and natural history of asymptomatic intracranial atherosclerosis in Caucasians remain unclear. The aims of the Barcelona-ASymptomatic Intracranial Atherosclerosis (ASIA) study are (1) to determine the prevalence of ASIA in a moderate-high vascular risk population, (2) to study its prognostic impact on the risk of suffering future major ischemic events, and (3) to identify predictors of the development, progression and clinical expression of this condition. Cross-over and cohort, population-based study. A randomly selected representative sample of 1,503 subjects with a mild-moderate-high vascular risk (as defined by a REGICOR score ≥ 5%) and with neither a history of cerebrovascular nor ischemic heart disease will be studied. At baseline, all individuals will undergo extracranial and transcranial Color-Coded Duplex (TCCD) ultrasound examinations to detect presence and severity of extra and intracranial atherosclerosis. Intracranial stenoses will be assessed by magnetic resonance angiography (MRA). Clinical and demographic variables will be recorded and blood samples will be drawn to investigate clinical, biological and genetic factors associated with the presence of ASIA. A long-term clinical and sonographic follow-up will be conducted thereafter to identify predictors of disease progression and of incident vascular events. The Barcelona-ASIA is a population-based study aiming to evaluate the prevalence and clinical importance of asymptomatic intracranial large-artery atherosclerosis in Caucasians. The ASIA project may provide a unique scientific resource to better understand the dynamics of intracranial atherosclerosis from

  6. Melanocortin 1 Receptor Deficiency Promotes Atherosclerosis in Apolipoprotein E-/- Mice.

    PubMed

    Rinne, Petteri; Kadiri, James J; Velasco-Delgado, Mauricio; Nuutinen, Salla; Viitala, Miro; Hollmén, Maija; Rami, Martina; Savontaus, Eriika; Steffens, Sabine

    2018-02-01

    The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transporter subfamily G member 1). In this study, we aimed to investigate whether global deficiency in MC1-R signaling affects the development of atherosclerosis. Apoe -/- (apolipoprotein E deficient) mice were crossed with recessive yellow (Mc1r e/e ) mice carrying dysfunctional MC1-R and fed a high-fat diet to induce atherosclerosis. Apoe -/- Mc1r e/e mice developed significantly larger atherosclerotic lesions in the aortic sinus and in the whole aorta compared with Apoe -/- controls. In terms of plaque composition, MC1-R deficiency was associated with less collagen and smooth muscle cells and increased necrotic core, indicative of more vulnerable lesions. These changes were accompanied by reduced Abca1 and Abcg1 expression in the aorta. Furthermore, Apoe -/- Mc1r e/e mice showed a defect in bile acid metabolism that aggravated high-fat diet-induced hypercholesterolemia and hepatic lipid accumulation. Flow cytometric analysis of leukocyte profile revealed that dysfunctional MC1-R enhanced arterial accumulation of classical Ly6C high monocytes and macrophages, effects that were evident in mice fed a normal chow diet but not under high-fat diet conditions. In support of enhanced arterial recruitment of Ly6C high monocytes, these cells had increased expression of L-selectin and P-selectin glycoprotein ligand 1. The present study highlights the importance of MC1-R in the development of atherosclerosis. Deficiency in MC1-R signaling exacerbates atherosclerosis by disturbing cholesterol handling and by increasing arterial monocyte accumulation. © 2017 The Authors.

  7. Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE-/- mouse model of atherosclerosis with alterations in IL10/AMPKα pathway.

    PubMed

    Thompson, D; Morrice, N; Grant, L; Le Sommer, S; Ziegler, K; Whitfield, P; Mody, N; Wilson, H M; Delibegović, M

    2017-08-01

    Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD. We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE -/- /LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed. Myeloid-PTP1B knockout mice on atherogenic background (ApoE -/- /LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKα and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE 2 ), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting. Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE -/- mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk.

  8. Life stress and atherosclerosis: a pathway through unhealthy lifestyle.

    PubMed

    Mainous, Arch G; Everett, Charles J; Diaz, Vanessa A; Player, Marty S; Gebregziabher, Mulugeta; Smith, Daniel W

    2010-01-01

    To examine the relationship between a general measure of chronic life stress and atherosclerosis among middle aged adults without clinical cardiovascular disease via pathways through unhealthy lifestyle characteristics. We conducted an analysis of The Multi-Ethnic Study of Atherosclerosis (MESA). The MESA collected in 2000 includes 5,773 participants, aged 45-84. We computed standard regression techniques to examine the relationship between life stress and atherosclerosis as well as path analysis with hypothesized paths from stress to atherosclerosis through unhealthy lifestyle. Our outcome was sub-clinical atherosclerosis measured as presence of coronary artery calcification (CAC). A logistic regression adjusted for potential confounding variables along with the unhealthy lifestyle characteristics of smoking, excessive alcohol use, high caloric intake, sedentary lifestyle, and obesity yielded no significant relationship between chronic life stress (OR 0.93, 95% CI 0.80-1.08) and CAC. However, significant indirect pathways between chronic life stress and CAC through smoking (p = .007), and sedentary lifestyle (p = .03) and caloric intake (.002) through obesity were found. These results suggest that life stress is related to atherosclerosis once paths of unhealthy coping behaviors are considered.

  9. Periodontal disease and carotid atherosclerosis: A meta-analysis of 17,330 participants.

    PubMed

    Zeng, Xian-Tao; Leng, Wei-Dong; Lam, Yat-Yin; Yan, Bryan P; Wei, Xue-Mei; Weng, Hong; Kwong, Joey S W

    2016-01-15

    The association between periodontal disease and carotid atherosclerosis has been evaluated primarily in single-center studies, and whether periodontal disease is an independent risk factor of carotid atherosclerosis remains uncertain. This meta-analysis aimed to evaluate the association between periodontal disease and carotid atherosclerosis. We searched PubMed and Embase for relevant observational studies up to February 20, 2015. Two authors independently extracted data from included studies, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for overall and subgroup meta-analyses. Statistical heterogeneity was assessed by the chi-squared test (P<0.1 for statistical significance) and quantified by the I(2) statistic. Data analysis was conducted using the Comprehensive Meta-Analysis (CMA) software. Fifteen observational studies involving 17,330 participants were included in the meta-analysis. The overall pooled result showed that periodontal disease was associated with carotid atherosclerosis (OR: 1.27, 95% CI: 1.14-1.41; P<0.001) but statistical heterogeneity was substantial (I(2)=78.90%). Subgroup analysis of adjusted smoking and diabetes mellitus showed borderline significance (OR: 1.08; 95% CI: 1.00-1.18; P=0.05). Sensitivity and cumulative analyses both indicated that our results were robust. Findings of our meta-analysis indicated that the presence of periodontal disease was associated with carotid atherosclerosis; however, further large-scale, well-conducted clinical studies are needed to explore the precise risk of developing carotid atherosclerosis in patients with periodontal disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Combination therapy for treatment or prevention of atherosclerosis: Focus on the lipid-RAAS interaction☆

    PubMed Central

    Koh, Kwang Kon; Han, Seung Hwan; Oh, Pyung Chun; Shin, Eak Kyun; Quon, Michael J.

    2010-01-01

    Large clinical trials demonstrate that control of blood pressure or hyperlipidemia reduces risk for cardiovascular events by ~30%. Factors that may further reduce remaining risk are not definitively established. One potential target is atherosclerosis, a crucial feature in the pathogenesis of cardiovascular diseases whose development is determined by multiple mechanism including complex interactions between endothelial dysfunction and insulin resistance. Reciprocal relationships between endothelial dysfunction and insulin resistance as well as cross-talk between hyperlipidemia and the rennin–angiotensin–aldosterone system may contribute to development of atherosclerosis. Therefore, one appealing strategy for prevention or treatment of atherosclerosis may be to simultaneously address several risk factors with combination therapies that target multiple pathogenic mechanisms. Combination therapy with statins, peroxisome proliferators-activated receptor agonists, and rennin–angiotensin–aldosterone system blockers demonstrate additive beneficial effects on endothelial dysfunction and insulin resistance when compared with monotherapies in patients with cardiovascular risk factors. Additive beneficial effects of combined therapy are mediated by both distinct and interrelated mechanisms, consistent with both pre-clinical and clinical investigations. Thus, combination therapy may be an important concept in developing more effective strategies to treat and prevent atherosclerosis, coronary heart disease, and co-morbid metabolic disorders characterized by endothelial dysfunction and insulin resistance. PMID:19800624

  11. Amide-adducts in atherosclerosis.

    PubMed

    Naito, Michitaka

    2014-01-01

    Too many hypotheses in the etiology of atherosclerosis have been proposed. Classically, lipid insudation hypothesis by Virchow and thrombogenic hypothesis by Rokitansky are famous. However, in the recent progress in the area of atherosclerosis, the response-to-injury hypothesis by Ross (Ross R Glomset JA, N Engl J Med 295:369-377, 420-425, 1976; Ross R, Arteriosclerosis 1:293-311, 1981; Ross R, N Engl J Med 314:488-500, 1986; Ross R, Nature 362:801-809, 1993; Ross R, N Engl J Med 340:115-126, 1999) has been the leading one. In this review, however, the author focuses to the recent debate on the role of oxidative modification of atherogenic lipoproteins.

  12. Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hsieh, Yi-Chen; Lien, Li-Ming; School of Medicine, Taipei Medical University, Taipei, Taiwan

    2011-08-15

    Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study.more » Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose-response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50 {mu}g/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50 {mu}g/l in drinking water and those who carried the PNP A-T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79-23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50 {mu}g/l). - Highlights: {yields}Arsenic metabolic genes might be associated with carotid atherosclerosis

  13. Myeloid interferon-γ receptor deficiency does not affect atherosclerosis in LDLR(-/-) mice.

    PubMed

    Boshuizen, Marieke C S; Neele, Annette E; Gijbels, Marion J J; van der Velden, Saskia; Hoeksema, Marten A; Forman, Ruth A; Muller, Werner; Van den Bossche, Jan; de Winther, Menno P J

    2016-03-01

    Atherosclerosis is a chronic lipid-driven inflammatory disease of the arterial wall. Interferon gamma (IFNγ) is an important immunomodulatory cytokine and a known pro-atherosclerotic mediator. However, cell-specific targeting of IFNγ or its signaling in atherosclerosis development has not been studied yet. As macrophages are important IFNγ targets, we here addressed the involvement of myeloid IFNγ signaling in murine atherosclerosis. Bone marrow was isolated from interferon gamma receptor 2 chain (IFNγR2) wildtype and myeloid IFNγR2 deficient mice and injected into lethally irradiated LDLR(-/-) mice. After recovery mice were put on a high fat diet for 10 weeks after which atherosclerotic lesion analysis was performed. In addition, the accompanying liver inflammation was assessed. Even though absence of myeloid IFNγ signaling attenuated the myeloid IFNγ response, no significant differences in atherosclerotic lesion size or phenotype were found. Also, when examining the liver inflammatory state no effects of IFNγR2 deficiency could be observed. Overall, our data argue against a role for myeloid IFNγR2 in atherosclerosis development. Since myeloid IFNγ signaling seems to be nonessential throughout atherogenesis, it is important to understand the mechanisms by which IFNγ acts in atherogenesis. In the future new studies should be performed considering other cell-specific targets. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Telomerase Activation in Atherosclerosis and Induction of Telomerase Reverse Transcriptase Expression by Inflammatory Stimuli in Macrophages

    PubMed Central

    Gizard, Florence; Heywood, Elizabeth B.; Findeisen, Hannes M.; Zhao, Yue; Jones, Karrie L.; Cudejko, Cèline; Post, Ginell R.; Staels, Bart; Bruemmer, Dennis

    2010-01-01

    Objective Telomerase serves as a critical regulator of tissue renewal. Although telomerase activity is inducible in response to various environmental cues, it remains unknown whether telomerase is activated during the inflammatory remodeling underlying atherosclerosis formation. To address this question, we investigated in the present study the regulation of telomerase in macrophages and during atherosclerosis development in LDL-receptor-deficient mice. Methods and Results We demonstrate that inflammatory stimuli activate telomerase in macrophages by inducing the expression of the catalytic subunit telomerase reverse transcriptase (TERT). Reporter and chromatin immunoprecipitation assays identified a previously unrecognized NF-κB response element in the TERT promoter, to which NF-κB is recruited during inflammation. Inhibition of NF-κB signaling completely abolished the induction of TERT expression, characterizing TERT as a bona fide NF-κB target gene. Furthermore, functional experiments revealed that TERT-deficiency results in a senescent cell phenotype. Finally, we demonstrate high levels of TERT expression in macrophages of human atherosclerotic lesions and establish that telomerase is activated during atherosclerosis development in LDL-receptor-deficient mice. Conclusion These results characterize TERT as a previously unrecognized NF-κB target gene in macrophages and demonstrate that telomerase is activated during atherosclerosis. This induction of TERT expression prevents macrophage senescence and may have important implications for the development of atherosclerosis. PMID:21106948

  15. FoxO4 inhibits atherosclerosis through its function in bone marrow derived cells

    PubMed Central

    Zhu, Min; Zhang, Qing-Jun; Wang, Lin; Li, Hao; Liu, Zhi-Ping

    2011-01-01

    Objectives FoxO proteins are transcription factors involved in varieties of cellular processes, including immune cell homeostasis, cytokine production, anti-oxidative stress, and cell proliferation and differentiation. Although these processes are implicated in the development of atherosclerosis, very little is known about the role of FoxO proteins in the context of atherosclerosis. Our objectives were to determine whether and how inactivation of Foxo4, a member of the FoxO family, in vivo promotes atherosclerosis. Methods and Results Apolipoprotein E-deficient (apoE−/−) mice were crossbred with animals lacking Foxo4 (Foxo4−/−). After 10 weeks on a high fat diet (HFD), Foxo4−/−apoE−/− mice showed elevated atherosclerosis and increased amount of macrophages and T cells in the plaque compared to apoE−/− mice. Bone marrow transplantations of chimeric C57B/6 mice reconstituted with either wild-type or Foxo4−/− bone marrows indicate that Foxo4-deficiency in bone marrow derived cells sufficiently promoted atherosclerosis. Foxo4-null macrophages produced elevated inflammatory cytokine IL-6 and levels of reactive oxygen species (ROS) in response to lipopolysaccharides in vitro. Serum levels of IL-6 were upregulated in HFD-fed Foxo4−/−apoE−/− mice compared to those of apoE−/− mice. Conclusions FoxO4 inhibits atherosclerosis through bone marrow derived cells, possibly by inhibition of ROS and inflammatory cytokines that promote monocyte recruitment and/or retention. PMID:22005198

  16. Diffusion reflection technique for diagnosis of atherosclerosis in mice using gold nanorods

    NASA Astrophysics Data System (ADS)

    Chakraborty, Ruchira; Ankri, Rinat; Leshem-Lev, Dorit; Lev, Eli I.; Hochhauser, Edith; Motiei, Menachem; Fixler, Dror

    2018-02-01

    Atherosclerosis, the leading cause of morbidity and mortality of cardiovascular disease, occur due to hardening and narrowing of arteries for development of vulnerable plaques made of cholesterols, tissue macrophages, foam cells and smooth muscle cells. Early detection of atherosclerosis is essential for proper treatment. Our group has already reported about the potential application of the non-invasive diffusion reflection (DR) technique in the detection of atherosclerosis using gold nanorods (GNRs) as contrast agent in carotid artery injured mice model. The basics of the study lie on the uptake GNRs by macrophages that located at the vulnerable plaques, which act as a good absorption contrast for DR measurement. Accumulations of GNRs cause changes in the optical property of the tissues and in turn cause changes in DR profile. In this study, we report the potential application of DR measurement in the detection of atherosclerosis in high-fat diet mice. Here, we have used PEG-coated GNRs with absorption maxima around 660nm. The time kinetics showed that after 24h of GNR injection the DR can find the atherosclerotic plaques and with time (up to 72h) the GNR accumulation in plaques were faded out, but still can be detectable by DR. Our result strongly suggests that in future DR can be used for early detection of atherosclerosis.

  17. [Potential protective role of nitric oxide and Hsp70 linked to functional foods in the atherosclerosis].

    PubMed

    Camargo, Alejandra B; Manucha, Walter

    Atherosclerosis, one of the main pathologic entities considered epidemic and a worldwide public health problem, is currently under constant review as regards its basic determining mechanisms and therapeutic possibilities. In this regard, all patients afflicted with the disease exhibit mitochondrial dysfunction, oxidative stress and inflammation. Interestingly, nitric oxide - a known vasoactive messenger gas - has been closely related to the inflammatory, oxidative and mitochondrial dysfunctional process that characterizes atherosclerosis. In addition, it has recently been demonstrated that alterations in the bioavailability of nitric oxide would induce the expression of heat shock proteins. This agrees with the use of functional foods as a strategy to prevent both vascular aging and the development of atherosclerosis. Finally, a greater knowledge regarding the mechanisms implied in the development of atherosclerosis will enable proposing new and possible hygiene, health and therapeutic interventions. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  18. Prevalence and Correlates of Subclinical Atherosclerosis in Alaskan Eskimos

    PubMed Central

    Cutchins, Alexis; Roman, Mary J.; Devereux, Richard B.; Ebbesson, Sven O.E.; Umans, Jason G.; Zhu, Jianhui; Weissman, Neil J.; Howard, Barbara V.

    2009-01-01

    Background and Purpose The recent increase in clinical cardiovascular disease in Alaska Eskimos suggests that changes in traditional lifestyle may have adverse public health consequences. This study examines the prevalence of subclinical vascular disease and its relation to risk factors in Alaska Eskimos. Methods Participants in the population-based Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study underwent evaluation of cardiovascular disease risk factors and carotid ultrasound. Outcome variables were carotid intimal-medial thickness and presence and extent of atherosclerosis. Results In multivariate analyses, intimal-medial thickness and presence and extent of atherosclerosis were all associated with traditional cardiovascular disease risk factors but not dietary intake of omega-3 fatty acids. Rates of carotid atherosclerosis were higher than those reported in 2 large population-based US studies. Conclusions Alaska Eskimos have similar traditional risk factors for carotid atherosclerosis as other ethnic and racial populations but have higher prevalences of atherosclerosis, possibly attributable to higher rates of smoking. PMID:18617652

  19. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis

    PubMed Central

    Koeth, Robert A.; Wang, Zeneng; Levison, Bruce S.; Buffa, Jennifer A.; Org, Elin; Sheehy, Brendan T.; Britt, Earl B.; Fu, Xiaoming; Wu, Yuping; Li, Lin; Smith, Jonathan D.; DiDonato, Joseph A.; Chen, Jun; Li, Hongzhe; Wu, Gary D.; Lewis, James D.; Warrier, Manya; Brown, J. Mark; Krauss, Ronald M.; Tang, W. H. Wilson; Bushman, Frederic D.; Lusis, Aldons J.; Hazen, Stanley L.

    2013-01-01

    Intestinal microbiota metabolism of choline/phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). Herein we demonstrate that intestinal microbiota metabolism of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis. Omnivorous subjects are shown to produce significantly more TMAO than vegans/vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. Specific bacterial taxa in human feces are shown to associate with both plasma TMAO and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predict increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (MI, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice significantly altered cecal microbial composition, markedly enhanced synthesis of TMA/TMAO, and increased atherosclerosis, but not following suppression of intestinal microbiota. Dietary supplementation of TMAO, or either carnitine or choline in mice with intact intestinal microbiota, significantly reduced reverse cholesterol transport in vivo. Intestinal microbiota may thus participate in the well-established link between increased red meat consumption and CVD risk. PMID:23563705

  20. Potential Mechanisms Linking Atherosclerosis and Increased Cardiovascular Risk in COPD: Focus On Sirtuins

    PubMed Central

    Corbi, Graziamaria; Bianco, Andrea; Turchiarelli, Viviana; Cellurale, Michele; Fatica, Federica; Daniele, Aurora; Mazzarella, Gennaro; Ferrara, Nicola

    2013-01-01

    The development of atherosclerosis is a multi-step process, at least in part controlled by the vascular endothelium function. Observations in humans and experimental models of atherosclerosis have identified monocyte recruitment as an early event in atherogenesis. Chronic inflammation is associated with ageing and its related diseases (e.g., atherosclerosis and chronic obstructive pulmonary disease). Recently it has been discovered that Sirtuins (NAD+-dependent deacetylases) represent a pivotal regulator of longevity and health. They appear to have a prominent role in vascular biology and regulate aspects of age-dependent atherosclerosis. Many studies demonstrate that SIRT1 exhibits anti-inflammatory properties in vitro (e.g., fatty acid-induced inflammation), in vivo (e.g., atherosclerosis, sustainment of normal immune function in knock-out mice) and in clinical studies (e.g., patients with chronic obstructive pulmonary disease). Because of a significant reduction of SIRT1 in rodent lungs exposed to cigarette smoke and in lungs of patients with chronic obstructive pulmonary disease (COPD), activation of SIRT1 may be a potential target for chronic obstructive pulmonary disease therapy. We review the inflammatory mechanisms involved in COPD-CVD coexistence and the potential role of SIRT1 in the regulation of these systems. PMID:23774840

  1. Advanced Accelerator Development Strategy Report: DOE Advanced Accelerator Concepts Research Roadmap Workshop

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    None, None

    Over a full two day period, February 2–3, 2016, the Office of High Energy Physics convened a workshop in Gaithersburg, MD to seek community input on development of an Advanced Accelerator Concepts (AAC) research roadmap. The workshop was in response to a recommendation by the HEPAP Accelerator R&D Subpanel [1] [2] to “convene the university and laboratory proponents of advanced acceleration concepts to develop R&D roadmaps with a series of milestones and common down selection criteria towards the goal for constructing a multi-TeV e+e– collider” (the charge to the workshop can be found in Appendix A). During the workshop, proponentsmore » of laser-driven plasma wakefield acceleration (LWFA), particle-beam-driven plasma wakefield acceleration (PWFA), and dielectric wakefield acceleration (DWFA), along with a limited number of invited university and laboratory experts, presented and critically discussed individual concept roadmaps. The roadmap workshop was preceded by several preparatory workshops. The first day of the workshop featured presentation of three initial individual roadmaps with ample time for discussion. The individual roadmaps covered a time period extending until roughly 2040, with the end date assumed to be roughly appropriate for initial operation of a multi-TeV e+e– collider. The second day of the workshop comprised talks on synergies between the roadmaps and with global efforts, potential early applications, diagnostics needs, simulation needs, and beam issues and challenges related to a collider. During the last half of the day the roadmaps were revisited but with emphasis on the next five to ten years (as specifically requested in the charge) and on common challenges. The workshop concluded with critical and unanimous endorsement of the individual roadmaps and an extended discussion on the characteristics of the common challenges. (For the agenda and list of participants see Appendix B.)« less

  2. PAR2 (Protease-Activated Receptor 2) Deficiency Attenuates Atherosclerosis in Mice.

    PubMed

    Jones, Shannon M; Mann, Adrien; Conrad, Kelsey; Saum, Keith; Hall, David E; McKinney, Lisa M; Robbins, Nathan; Thompson, Joel; Peairs, Abigail D; Camerer, Eric; Rayner, Katey J; Tranter, Michael; Mackman, Nigel; Owens, A Phillip

    2018-06-01

    PAR2 (protease-activated receptor 2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. The objective of this study was to determine the effect of PAR2 deficiency on the development of atherosclerosis. PAR2 mRNA and protein expression is increased in human carotid artery and mouse aortic arch atheroma versus control carotid and aortic arch arteries, respectively. To determine the effect of PAR2 deficiency on atherosclerosis, male and female low-density lipoprotein receptor-deficient ( Ldlr -/- ) mice (8-12 weeks old) that were Par2 +/+ or Par2 -/- were fed a fat- and cholesterol-enriched diet for 12 or 24 weeks. PAR2 deficiency attenuated atherosclerosis in the aortic sinus and aortic root after 12 and 24 weeks. PAR2 deficiency did not alter total plasma cholesterol concentrations or lipoprotein distributions. Bone marrow transplantation showed that PAR2 on nonhematopoietic cells contributed to atherosclerosis. PAR2 deficiency significantly attenuated levels of the chemokines Ccl2 and Cxcl1 in the circulation and macrophage content in atherosclerotic lesions. Mechanistic studies using isolated primary vascular smooth muscle cells showed that PAR2 deficiency is associated with reduced Ccl2 and Cxcl1 mRNA expression and protein release into the supernatant resulting in less monocyte migration. Our results indicate that PAR2 deficiency is associated with attenuation of atherosclerosis and may reduce lesion progression by blunting Ccl2 - and Cxcl1 -induced monocyte infiltration. © 2018 American Heart Association, Inc.

  3. Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis

    PubMed Central

    Mortensen, Martin B.; Kjolby, Mads; Gunnersen, Stine; Larsen, Jakob V.; Palmfeldt, Johan; Falk, Erling; Nykjaer, Anders; Bentzon, Jacob F.

    2014-01-01

    Genome-wide association studies have identified a link between genetic variation at the human chromosomal locus 1p13.3 and coronary artery disease. The gene encoding sortilin (SORT1) has been implicated as the causative gene within the locus, as sortilin regulates hepatic lipoprotein metabolism. Here we demonstrated that sortilin also directly affects atherogenesis, independent of its regulatory role in lipoprotein metabolism. In a mouse model of atherosclerosis, deletion of Sort1 did not alter plasma cholesterol levels, but reduced the development of both early and late atherosclerotic lesions. We determined that sortilin is a high-affinity receptor for the proinflammatory cytokines IL-6 and IFN-γ. Moreover, macrophages and Th1 cells (both of which mediate atherosclerotic plaque formation) lacking sortilin had reduced secretion of IL-6 and IFN-γ, but not of other measured cytokines. Transfer of sortilin-deficient BM into irradiated atherosclerotic mice reduced atherosclerosis and systemic markers of inflammation. Together, these data demonstrate that sortilin influences cytokine secretion and that targeting sortilin in immune cells attenuates inflammation and reduces atherosclerosis. PMID:25401472

  4. Iron and Atherosclerosis: Nailing Down a Novel Target with Magnetic Resonance

    PubMed Central

    Sharkey-Toppen, Travis P.; Tewari, Arun K.; Raman, Subha V.

    2014-01-01

    Iron is an essential mineral in many proteins and enzymes in human physiology, with limited means of iron elimination to maintain iron balance. Iron accrual incurs various pathological mechanisms linked to cardiovascular disease. In atherosclerosis, iron catalyzes the creation of reactive oxygen free radicals that contribute to lipid modification, which is essential to atheroma formation. Inflammation further fuels iron-related pathologic processes associated with plaque progression. Given iron’s role in atherosclerosis development, in vivo detection techniques sensitive iron are needed for translational studies targeting iron for earlier diagnosis and treatment. Magnetic resonance imaging (MRI) is uniquely able to quantify iron in human tissues noninvasively and without ionizing radiation, offering appealing for longitudinal and interventional studies. Particularly intriguing is iron’s complementary biology vs. calcium, which is readily detectable by computed tomography (CT). This review summarizes the role of iron in atherosclerosis with considerable implications for novel diagnostic and therapeutic approaches. PMID:24590608

  5. What Is Atherosclerosis?

    MedlinePlus

    ... builds up in the renal arteries. These arteries supply oxygen-rich blood to your kidneys. Over time, chronic kidney disease causes a slow loss of kidney function. The main function of the kidneys is to remove waste and extra water from the body. Overview The cause of atherosclerosis ...

  6. Bisphenol A Exposure Enhances Atherosclerosis in WHHL Rabbits

    PubMed Central

    Fang, Chao; Ning, Bo; Waqar, Ahmed Bilal; Niimi, Manabu; Li, Shen; Satoh, Kaneo; Shiomi, Masashi; Ye, Ting; Dong, Sijun; Fan, Jianglin

    2014-01-01

    Bisphenol A (BPA) is an environmental endocrine disrupter. Excess exposure to BPA may increase susceptibility to many metabolic disorders, but it is unclear whether BPA exposure has any adverse effects on the development of atherosclerosis. To determine whether there are such effects, we investigated the response of Watanabe heritable hyperlipidemic (WHHL) rabbits to 400-µg/kg BPA per day, administered orally by gavage, over the course of 12 weeks and compared aortic and coronary atherosclerosis in these rabbits to the vehicle group using histological and morphometric methods. In addition, serum BPA, cytokines levels and plasma lipids as well as pathologic changes in liver, adipose and heart were analyzed. Moreover, we treated human umbilical cord vein endothelial cells (HUVECs) and rabbit aortic smooth muscle cells (SMCs) with different doses of BPA to investigate the underlying molecular mechanisms involved in BPA action(s). BPA treatment did not change the plasma lipids and body weights of the WHHL rabbits; however, the gross atherosclerotic lesion area in the aortic arch was increased by 57% compared to the vehicle group. Histological and immunohistochemical analyses revealed marked increases in advanced lesions (37%) accompanied by smooth muscle cells (60%) but no significant changes in the numbers of macrophages. With regard to coronary atherosclerosis, incidents of coronary stenosis increased by 11% and smooth muscle cells increased by 73% compared to the vehicle group. Furthermore, BPA-treated WHHL rabbits showed increased adipose accumulation and hepatic and myocardial injuries accompanied by up-regulation of endoplasmic reticulum (ER) stress and inflammatory and lipid metabolism markers in livers. Treatment with BPA also induced the expression of ER stress and inflammation related genes in cultured HUVECs. These results demonstrate for the first time that BPA exposure may increase susceptibility to atherosclerosis in WHHL rabbits. PMID:25333893

  7. Framework for Development and Distribution of Hardware Acceleration

    NASA Astrophysics Data System (ADS)

    Thomas, David B.; Luk, Wayne W.

    2002-07-01

    This paper describes IGOL, a framework for developing reconfigurable data processing applications. While IGOL was originally designed to target imaging and graphics systems, its structure is sufficiently general to support a broad range of applications. IGOL adopts a four-layer architecture: application layer, operation layer, appliance layer and configuration layer. This architecture is intended to separate and co-ordinate both the development and execution of hardware and software components. Hardware developers can use IGOL as an instance testbed for verification and benchmarking, as well as for distribution. Software application developers can use IGOL to discover hardware accelerated data processors, and to access them in a transparent, non-hardware specific manner. IGOL provides extensive support for the RC1000-PP board via the Handel-C language, and a wide selection of image processing filters have been developed. IGOL also supplies plug-ins to enable such filters to be incorporated in popular applications such as Premiere, Winamp, VirtualDub and DirectShow. Moreover, IGOL allows the automatic use of multiple cards to accelerate an application, demonstrated using DirectShow. To enable transparent acceleration without sacrificing performance, a three-tiered COM (Component Object Model) API has been designed and implemented. This API provides a well-defined and extensible interface which facilitates the development of hardware data processors that can accelerate multiple applications.

  8. Gradient Echo MRI Characterization of Development of Atherosclerosis in the Abdominal Aorta in Watanabe Heritable Hyperlipidemic Rabbits

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Yi-Xiang J., E-mail: yi-xiang.wang@astrazeneca.com; Kuribayashi, Hideto; Wagberg, Maria

    Purpose. The Watanabe Heritable Hyperlipidemic (WHHL) rabbit provides an important model of spontaneous atherosclerosis. With a strain of WHHL rabbits which do not develop abdominal aorta lumen stenosis even with advanced atherosclerosis, we studied the MRI-histology correlation, and the natural progression of atherosclerosis in the abdominal aorta. In addition, intra-reader segmentation repeatability and scan-rescan reproducibility were assessed. Methods. Two batches of female WHHL rabbits were used. The first batch of 6 rabbits was scanned at 20 weeks old. A second batch of 17 rabbits was scanned at 50 weeks old and then randomly divided into two subgroups: 8 were killedmore » for histologic investigation; 9 were kept alive for follow-up, with repeat scanning a week later to assess scan-rescan reproducibility, and again at 73 weeks old to assess disease progression. MR images were acquired at 4.7 T using a chemical shift selective fat suppression gradient echo with a saturation band suppressing blood signal within the aortic lumen. Five slices per animal were acquired, centered around the renal artery region of the abdominal aorta, with in-plane resolution of 0.195 mm and slice thickness of 3 mm. Results. The coefficient of variation for intra-reader reproducibility for aortic wall thickness measurements was 2.5% for repeat segmentations of the same scans on the same day, but segmentations of these same scans made 8 months later showed a systematic change, suggesting that intra-reader bias as well as increased variability could compromise assessments made over time. Comparative analyses were therefore performed in one postprocessing session. The coefficient of variation for scan-rescan reproducibility for aortic wall thickness was 5.5% for nine pairs of scans acquired a week apart and segmented on the same day. Good MRI-histology correlation was obtained. The MRI-measured mean aortic wall thickness of animals at 20 weeks of age was 76% that of animals at 50

  9. Chronic oral infection with major periodontal bacteria Tannerella forsythia modulates systemic atherosclerosis risk factors and inflammatory markers.

    PubMed

    Chukkapalli, Sasanka S; Rivera-Kweh, Mercedes F; Velsko, Irina M; Chen, Hao; Zheng, Donghang; Bhattacharyya, Indraneel; Gangula, Pandu R; Lucas, Alexandra R; Kesavalu, Lakshmyya

    2015-04-01

    Tannerella forsythia is a Gram-negative anaerobic organism that inhabits the subgingival cavity and initiates connective tissue destruction and alveolar bone resorption in periodontal disease (PD). PD is a chronic immunoinflammatory disease and has been linked to several systemic diseases including atherosclerosis. This study evaluated the effects of a chronic oral infection with T. forsythia ATCC 43037 on the induction of PD, inflammatory markers and atherosclerosis risk factors in hyperlipidemic ApoE(null) mice. Mice were orally infected for 12 and 24 weeks prior to euthanasia. Bacterial colonization of the oral cavity and bacteremia was confirmed via isolation of genomic DNA from oral plaque and tissues. Oral infection elicited significantly elevated levels of serum IgG and IgM antibodies and alveolar bone resorption compared to control mice. Tannerella forsythia-infected mice had increased serum amyloid A, and significantly reduced serum nitric oxide when compared to controls. Tannerella forsythia chronic infection also significantly increased serum lipoproteins suggesting altered cholesterol metabolism and potential for aortic inflammation. Despite enhanced acute phase reactants and altered lipid profiles, T. forsythia infection was associated with decreased aortic plaque. This study investigates the potential of a known periodontal bacterial pathogen found in atherosclerotic plaque in humans to accelerate atherosclerosis in hyperlipdemic mice. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  10. Ezetimibe reduces plaque inflammation in a rabbit model of atherosclerosis and inhibits monocyte migration in addition to its lipid-lowering effect

    PubMed Central

    Gómez-Garre, D; Muñoz-Pacheco, P; González-Rubio, ML; Aragoncillo, P; Granados, R; Fernández-Cruz, A

    2009-01-01

    Background and purpose: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, might also suppress inflammatory components of atherogenesis. We have studied the effects of ezetimibe on two characteristics of atherosclerotic plaques (infiltrate and fibrosis) and on expression of inflammatory genes in a rabbit model of accelerated atherosclerosis. Experimental approach: Femoral atherosclerosis was induced by a combination of endothelial desiccation and atherogenic diet. Animals were randomized to ezetimibe (0.6 mg·kg−1·day−1), simvastatin (5 mg·kg−1·day−1), ezetimibe plus simvastatin or no treatment, still on atherogenic diet. A control group of rabbits received normolipidemic diet. Key results: Rabbits fed the normolipidemic diet showed normal plasma lipid levels. Either the normolipidemic diet or drug treatment reduced the intima/media ratio (normolipidemic diet: 22%, ezetimibe: 13%, simvastatin: 27%, ezetimibe + simvastatin: 28%), compared with rabbits with atherosclerosis. Ezetimibe also decreased macrophage content and monocyte chemoattractant protein-1 expression in atherosclerotic lesions. Furthermore, ezetimibe reduced the increased activity of nuclear factor κB in peripheral blood leucocytes and plasma C-reactive protein levels in rabbits with atherosclerosis. In THP-1 cells, ezetimibe decreased monocyte chemoattractant protein-1-induced monocyte migration. Importantly, the combination of ezetimibe with simvastatin was associated with a more significant reduction in plaque monocyte/macrophage content and some proinflammatory markers than observed with each drug alone. Conclusions and implications: Ezetimibe had beneficial effects both on atherosclerosis progression and plaque stabilization and showed additional anti-atherogenic benefits when combined with simvastatin. Its effect on monocyte migration provides a potentially beneficial action, in addition to its effects on lipids. PMID:19222481

  11. Sex differences in the combined effect of chronic stress with impaired vascular endothelium functioning and the development of early atherosclerosis: The Cardiovascular Risk in Young Finns study

    PubMed Central

    2010-01-01

    Background The syndrome of vital exhaustion (VE), characterized by fatigue and irritability, may contribute to an increased risk of atherosclerosis. The aim of the study was to explore sex differences in the interactions of VE with endothelial dysfunction and VE with reduced carotid elasticity, the important contributors to the development of early atherosclerosis, on preclinical atherosclerosis. Methods The participants were 1002 women and 719 men aged 24-39 examined in the Cardiovascular Risk in Young Finns study. Vital exhaustion was measured using the Maastricht Questionnaire. Preclinical atherosclerosis was assessed by carotid intima-media thickness (IMT), endothelial function was measured by brachial flow-mediated dilatation (FMD), and arterial elasticity by carotid artery compliance (CAC) using ultrasound techniques. Results We found a significant CAC x VE interaction for IMT only for the men. Our results imply that high VE level significantly related to high IMT levels among the men with low CAC, but not among the women with low CAC or among the women or men with high CAC. No significant FMD x VE interactions for IMT for the women or men were found. Conclusions High VE may exert an effect on IMT for men with impaired arterial elasticity. The results suggest that high vitally exhausted men with reduced arterial elasticity are at increased risk of atherosclerosis in early life and imply men's decreased stress coping in relation to stressful psychological coronary risk factors. PMID:20624297

  12. [Cyclooxygenase-2: a new therapeutic target in atherosclerosis?].

    PubMed

    Páramo, José A; Beloqui, Oscar; Orbe, Josune

    2006-05-27

    It is now widely accepted that atherosclerosis is a complex chronic inflammatory disorder of the arterial tree associated with several risk factors. From the initial phases to eventual rupture of vulnerable atherosclerotic plaques, a low-grade inflammation, also termed microinflammation, appears to play a key pathogenetic role. Systemic inflammatory markers (C reactive protein, cytokines adhesion molecules) also play a role in this process. Experimental and clinical evidence suggests that cyclooxygenase-2 (COX-2), an enzyme which catalyzes the generation of prostaglandins from arachidonic acid, also contributes to lesion formation. Recent reports by our group have demonstrated increased monocyte COX-2 activity and the production of prostaglandin E2 in relation to cardiovascular risk factors and subclinical atherosclerosis in asymptomatic subjects. Our findings support the notion that the COX-2/prostaglandin E2 axis may have a role, raising the question as to whether its selective inhibition might be an attractive therapeutic target in atherosclerosis. COX-2 inhibitors, collectively called "coxibs" (celecoxib, rofecoxib, valdecoxib, lumiracoxib, etc), held a promise as anti-inflammatory drugs without the some of the side effects of aspirin or non steroidal antiinflammatory agents. However, clinical studies raise several clinically relevant questions as to their beneficial role in atherosclerosis prevention, because of increased thrombogenicity and cardiovascular risk, and therefore coxibs should be restricted in atherosclerosis-prone patients.

  13. EuCARD2: enhanced accelerator research and development in Europe

    NASA Astrophysics Data System (ADS)

    Romaniuk, Ryszard S.

    2013-10-01

    Accelerator science and technology is one of a key enablers of the developments in the particle physic, photon physics and also applications in medicine and industry. EuCARD2 is an European research project which will be realized during 2013-2017 inside the EC FP7 framework. The project concerns the development and coordination of European Accelerator Research and Development. The project is particularly important, to a number of domestic laboratories, due to some plans to build large accelerator infrastructure in Poland. Large accelerator infrastructure of fundamental and applied research character stimulates around it the development and industrial applications as well as biomedical of advanced accelerators, material research and engineering, cryo-technology, mechatronics, robotics, and in particular electronics - like networked measurement and control systems, sensors, computer systems, automation and control systems. The paper presents a digest of the European project EuCARD2 which is Enhanced European Coordination for Accelerator Research and Development. The paper presents a digest of the research results and assumptions in the domain of accelerator science and technology in Europe, shown during the final fourth annual meeting of the EuCARD - European Coordination of Accelerator R&D, and the kick-off meeting of the EuCARD2. There are debated a few basic groups of accelerator systems components like: measurement - control networks of large geometrical extent, multichannel systems for large amounts of metrological data acquisition, precision photonic networks of reference time, frequency and phase distribution, high field magnets, superconducting cavities, novel beam collimators, etc. The paper bases on the following materials: Internet and Intranet documents combined with EuCARD2, Description of Work FP7 EuCARD-2 DoW-312453, 2013-02-13, and discussions and preparatory materials worked on by Eucard-2 initiators.

  14. FAD286, an aldosterone synthase inhibitor, reduced atherosclerosis and inflammation in apolipoprotein E-deficient mice.

    PubMed

    Gamliel-Lazarovich, Aviva; Gantman, Anna; Coleman, Raymond; Jeng, Arco Y; Kaplan, Marielle; Keidar, Shlomo

    2010-09-01

    Aldosterone is known to be involved in atherosclerosis and cardiovascular disease and blockade of its receptor was shown to improve cardiovascular function. It was, therefore, hypothesized that inhibition of aldosterone synthesis would also reduce atherosclerosis development. To test this hypothesis, we examined the effect of FAD286 (FAD), an aldosterone synthase inhibitor, on the development of atherosclerosis in spontaneous atherosclerotic apolipoprotein E-deficient mice. Mice were divided into three treatment groups: normal diet, low-salt diet (LSD) and LSD treated with FAD at 30 mg/kg per day (LSD + FAD) for 10 weeks. Histomorphometry of the aortas obtained from these mice showed that atherosclerotic lesion area increased by three-fold under LSD compared with normal diet and FAD significantly reduced lesion area to values similar to normal diet. Changes in atherosclerosis were paralleled by changes in the expression of the inflammation markers (C-reactive protein, monocyte chemotactic protein-1, interleukin-6, nuclear factor kappa B and intercellular adhesion molecule-1) in peritoneal macrophages obtained from these mice. Surprisingly, whereas LSD increased serum or urine aldosterone levels, FAD did not alter these levels when evaluated at the end of the study. In J774A.1 macrophage-like cell line stimulated with lipopolysaccharide, FAD was shown to have a direct dose-dependent anti-inflammatory effect. In apolipoprotein E-deficient mice, FAD reduces atherosclerosis and inflammation. However, these actions appeared to be dissociated from its effect on inhibition of aldosterone synthesis.

  15. Subclinical atherosclerosis and subsequent cognitive function

    PubMed Central

    Rossetti, Heidi C.; Weiner, Myron; Hynan, Linda S.; Cullum, C. Munro; Khera, Amit; Lacritz, Laura H.

    2016-01-01

    Objective To examine the relationship between measures of subclinical atherosclerosis and subsequent cognitive function. Method Participants from the Dallas Heart Study (DHS), a population-based multiethnic study of cardiovascular disease pathogenesis, were re-examined 8 years later (DHS-2) with the Montreal Cognitive Assessment (MoCA); N = 1904, mean age = 42.9, range 8–65. Associations of baseline measures of subclinical atherosclerosis (coronary artery calcium, abdominal aortic plaque, and abdominal aortic wall thickness) with MoCA scores measured at follow-up were examined in the group as a whole and in relation to age and ApoE4 status. Results A significant linear trend of successively lower MoCA scores with increasing numbers of atherosclerotic indicators was observed (F(3, 1150) = 5.918, p = .001). CAC was weakly correlated with MoCA scores (p = .047) and MoCA scores were significantly different between participants with and without CAC (M = 22.35 vs 23.69, p = 0.038). With the exception of a small association between abdominal AWT and MoCA in subjects over age 50, abdominal AWT and abdominal aortic plaque did not correlate with MoCA total score (p ≥.052). Cognitive scores and atherosclerosis measures were not impacted by ApoE4 status (p ≥.455). Conclusion In this ethnically diverse population-based sample, subclinical atherosclerosis was minimally associated with later cognitive function in middle-aged adults. PMID:25957568

  16. Testing the iron hypothesis in a mouse model of atherosclerosis

    PubMed Central

    Kautz, Léon; Gabayan, Victoria; Wang, Xuping; Wu, Judy; Onwuzurike, James; Jung, Grace; Qiao, Bo; Lusis, Aldons J.; Ganz, Tomas; Nemeth, Elizabeta

    2013-01-01

    SUMMARY Hepcidin, the iron-regulatory hormone and acute phase reactant, is proposed to contribute to the pathogenesis of atherosclerosis by promoting iron accumulation in plaque macrophages, leading to increased oxidative stress and inflammation in the plaque (the “iron hypothesis”). Hepcidin and iron may thus represent modifiable risk factors in atherosclerosis. We measured hepcidin expression in Apoe−/− mice with varying diets and ages. To assess the role of macrophage iron in atherosclerosis, we generated Apoe−/− mice with macrophage-specific iron accumulation by introducing the ferroportin ffe mutation. Macrophage iron loading was also enhanced by intravenous iron injection. Contrary to the iron hypothesis, we found that hepatic hepcidin expression was not increased at any stage of the atherosclerosis progression in Apoe−/− or Apoe/ffe mice and the atherosclerotic plaque size was not increased in mice with elevated macrophage iron. Our results strongly argue against any significant role of macrophage iron in atherosclerosis progression in mice. PMID:24316081

  17. The walking dead: macrophage inflammation and death in atherosclerosis.

    PubMed

    Kavurma, Mary M; Rayner, Katey J; Karunakaran, Denuja

    2017-04-01

    To highlight recent studies that describe novel inflammatory and signaling mechanisms that regulate macrophage death in atherosclerosis. Macrophages contribute to all stages of atherosclerosis. The traditional dogma states that in homeostatic conditions, macrophages undergo apoptosis and are efficiently phagocytosed to be cleared by a process called efferocytosis. In advanced atherosclerosis, however, defective efferocytosis results in secondary necrosis of these uncleared apoptotic cells, which ultimately contributes to the formation of the characteristic necrotic core and the vulnerable plaque. Here, we outline the different types of lesional macrophage death: apoptosis, autophagic and the newly defined necroptosis (i.e. a type of programmed necrosis). Recent discoveries demonstrate that macrophage necroptosis directly contributes to necrotic core formation and plaque instability. Further, promoting the resolution of inflammation using preresolving mediators has been shown to enhance efferocytosis and decrease plaque vulnerability. Finally, the canonical 'don't eat me' signal CD47 has recently been described as playing an important role in atherosclerotic lesion progression by impairing efficient efferocytosis. Although we have made significant strides in improving our understanding of cell death and clearance mechanisms in atherosclerosis, there still remains unanswered questions as to how these pathways can be harnessed using therapeutics to promote lesion regression and disease stability. Improving our understanding of the mechanisms that regulate macrophage death in atherosclerosis, in particular apoptosis, necroptosis and efferocytosis, will provide novel therapeutic opportunities to resolve atherosclerosis and promote plaque stability.

  18. [The impact of electronic cigarettes usage on the endothelial function and the progression of atherosclerosis].

    PubMed

    Knura, Miłosz; Dragon, Jonasz; Łabuzek, Krzysztof; Okopień, Bogusław

    2018-01-23

    The exponetial growth in popularity of electronic cigarettes in the world markets intensifies the debate about their health effects. The smoking of traditional tabacoo products is a factor associated with the endothelium damage and progression of atherosclerosis. The elimination of the combustion process in electronic cigarettes allows to conclude that they are less harmful to a vascular endothelium than traditional tobacco products. E-cigarette aerosol contains many compounds that have an influence on initiation and progression of atherosclerosis. Nicotine protherogenic action is not fully explained. On one hand, nicotine modifies metabolic pathways leading to atherosclerosis, whereas epidemiological studies do not show an increased risk of cardiovascular disease in the population using nicotine replacement therapy or snuff. Acrolein, formaldehyde and the ultrafine particles generated during e-liquid heating have an impact on initiation and progression of atherosclerosis, but their level is lower than that of tobacco smoke. In order to assess accurately the longterm effects of e-cigarettes, it is necessary to conduct epidemiological studies measuring the effects of using e-cigarettes. It is claimed that the use of electronic cigarettes has a potential impact on the development of atherosclerosis, but is significantly lower than that of traditional cigarettes.

  19. 10-Year Study Links Faster Progression of Atherosclerosis to Air Pollution

    EPA Pesticide Factsheets

    The Multi-Ethnic Study of Atherosclerosis Air Pollution Study (MESA Air) was the first U.S. research study to measure directly how long-term exposure to air pollution contributes to the development of heart disease.

  20. Development of a 20 MeV Dielectric-Loaded Test Accelerator

    NASA Astrophysics Data System (ADS)

    Gold, Steven H.; Kinkead, Allen K.; Gai, Wei; Power, John G.; Konecny, Richard; Jing, Chunguang; Long, Jidong; Tantawi, Sami G.; Nantista, Christopher D.; Bruce, Ralph W.; Fliflet, Arne W.; Lombardi, Marcie; Lewis, David

    2006-11-01

    This paper presents a progress report on a joint project by the Naval Research Laboratory (NRL) and Argonne National Laboratory (ANL), in collaboration with the Stanford Linear Accelerator Center (SLAC), to develop a dielectric-loaded test accelerator in the magnicon facility at NRL. The accelerator will be powered by an experimental 11.424-GHz magnicon amplifier that presently produces 25 MW of output power in a ˜250-ns pulse at up to 10 Hz. The accelerator will include a 5-MeV electron injector originally developed at the Tsinghua University in Beijing, China, and can incorporate DLA structures up to 0.5 m in length. The DLA structures are being developed by ANL, and shorter test structures fabricated from a variety of dielectric materials have undergone testing at NRL at gradients up to ˜8 MV/m. SLAC has developed components to distribute the power from the two magnicon output arms to the injector and to the DLA accelerating structure with separate control of the power ratio and relative phase. RWBruce Associates, Inc., working with NRL, has investigated means to join short ceramic sections into a continuous accelerator tube by a brazing process using an intense 83-GHz beam. The installation and testing of the first dielectric-loaded test accelerator, including injector, DLA test structure, and spectrometer, should take place within the next year.

  1. B-cell-specific depletion of tumour necrosis factor alpha inhibits atherosclerosis development and plaque vulnerability to rupture by reducing cell death and inflammation.

    PubMed

    Tay, Christopher; Liu, Yu-Han; Hosseini, Hamid; Kanellakis, Peter; Cao, Anh; Peter, Karlheinz; Tipping, Peter; Bobik, Alex; Toh, Ban-Hock; Kyaw, Tin

    2016-09-01

    B2 lymphocytes promote atherosclerosis development but their mechanisms of action are unknown. Here, we investigated the role of tumour necrosis factor alpha (TNF-α) produced by B2 cells in atherogenesis. We found that 50% of TNF-α-producing spleen lymphocytes were B2 cells and ∼20% of spleen and aortic B cells produced TNF-α in hyperlipidemic ApoE(-/-) mice. We generated mixed bone marrow (80% μMT/20% TNF-α(-/-)) chimeric LDLR(-/-) mice where only B cells did not express TNF-α. Atherosclerosis was reduced in chimeric LDLR(-/-) mice with TNF-α-deficient B cells. TNF-α expression in atherosclerotic lesions and in macrophages were also reduced accompanied by fewer apoptotic cells, reduced necrotic cores, and reduced lesion Fas, interleukin-1β and MCP-1 in mice with TNF-α-deficient B cells compared to mice with TNF-α-sufficient B cells. To confirm that the reduced atherosclerosis is attributable to B2 cells, we transferred wild-type and TNF-α-deficient B2 cells into ApoE(-/-) mice deficient in B cells or in lymphocytes. After 8 weeks of high fat diet, we found that atherosclerosis was increased by wild-type but not TNF-α-deficient B2 cells. Lesions of mice with wild-type B2 cells but not TNF-α-deficient B2 cells also had increased apoptotic cells and necrotic cores. Transferred B2 cells were found in lesions of recipient mice, suggesting that TNF-α-producing B2 cells promote atherosclerosis within lesions. We conclude that TNF-α produced by B2 cells is a key mechanism by which B2 cells promote atherogenesis through augmenting macrophage TNF-α production to induce cell death and inflammation that promote plaque vulnerability. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

  2. Second International Conference on Accelerating Biopharmaceutical Development

    PubMed Central

    2009-01-01

    The Second International Conference on Accelerating Biopharmaceutical Development was held in Coronado, California. The meeting was organized by the Society for Biological Engineering (SBE) and the American Institute of Chemical Engineers (AIChE); SBE is a technological community of the AIChE. Bob Adamson (Wyeth) and Chuck Goochee (Centocor) were co-chairs of the event, which had the theme “Delivering cost-effective, robust processes and methods quickly and efficiently.” The first day focused on emerging disruptive technologies and cutting-edge analytical techniques. Day two featured presentations on accelerated cell culture process development, critical quality attributes, specifications and comparability, and high throughput protein formulation development. The final day was dedicated to discussion of technology options and new analysis methods provided by emerging disruptive technologies; functional interaction, integration and synergy in platform development; and rapid and economic purification process development. PMID:20065637

  3. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.

    PubMed

    Koeth, Robert A; Wang, Zeneng; Levison, Bruce S; Buffa, Jennifer A; Org, Elin; Sheehy, Brendan T; Britt, Earl B; Fu, Xiaoming; Wu, Yuping; Li, Lin; Smith, Jonathan D; DiDonato, Joseph A; Chen, Jun; Li, Hongzhe; Wu, Gary D; Lewis, James D; Warrier, Manya; Brown, J Mark; Krauss, Ronald M; Tang, W H Wilson; Bushman, Frederic D; Lusis, Aldons J; Hazen, Stanley L

    2013-05-01

    Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.

  4. Increased activity of vascular adenosine deaminase in atherosclerosis and therapeutic potential of its inhibition.

    PubMed

    Kutryb-Zajac, Barbara; Mateuszuk, Lukasz; Zukowska, Paulina; Jasztal, Agnieszka; Zabielska, Magdalena A; Toczek, Marta; Jablonska, Patrycja; Zakrzewska, Agnieszka; Sitek, Barbara; Rogowski, Jan; Lango, Romuald; Slominska, Ewa M; Chlopicki, Stefan; Smolenski, Ryszard T

    2016-11-01

    Extracellular nucleotides and adenosine that are formed or degraded by membrane-bound ecto-enzymes could affect atherosclerosis by regulating the inflammation and thrombosis. This study aimed to evaluate a relation between ecto-enzymes that convert extracellular adenosine triphosphate to adenine dinucleotide phosphate, adenosine monophosphate, adenosine, and inosine on the surface of the vessel wall with the severity or progression of experimental and clinical atherosclerosis. Furthermore, we tested whether the inhibition of adenosine deaminase will block the development of experimental atherosclerosis. Vascular activities of ecto-nucleoside triphosphate diphosphohydrolase 1, ecto-5'-nucleotidase, and ecto-adenosine deaminase (eADA) were measured in aortas of apolipoprotein E-/- low density lipoprotein receptor (ApoE-/-LDLR-/-) and wild-type mice as well as in human aortas. Plaques were analysed in the entire aorta, aortic root, and brachiocephalic artery by Oil-Red O and Orcein Martius Scarlet Blue staining and vascular accumulation of macrophages. The cellular location of ecto-enzymes was analysed by immunofluorescence. The effect of eADA inhibition on atherosclerosis progression was studied by a 2-month deoxycoformycin treatment of ApoE-/-LDLR-/- mice. The vascular eADA activity prominently increased in ApoE-/-LDLR-/- mice when compared with wild type already at the age of 1 month and progressed along atherosclerosis development, reaching a 10-fold difference at 10 months. The activity of eADA correlated with atherosclerotic changes in human aortas. High abundance of eADA in atherosclerotic vessels originated from activated endothelial cells and macrophages. There were no changes in ecto-nucleoside triphosphate diphosphohydrolase 1 activity, whereas ecto-5'-nucleotidase was moderately decreased in ApoE-/-LDLR-/- mice. Deoxycoformycin treatment attenuated plaque development in aortic root and brachiocephalic artery of ApoE-/-LDLR-/- mice, suppressed vascular

  5. Effect of ascorbic acid on prevention of hypercholesterolemia induced atherosclerosis.

    PubMed

    Das, S; Ray, R; Snehlata; Das, N; Srivastava, L M

    2006-04-01

    The notion that oxidation of lipids and propagation of free radicals may contribute to the pathogenesis of atherosclerosis is supported by a large body of evidence. To circumvent the damage caused by oxygen free radicals, antioxidants are needed which provide the much needed neutralization of free radical by allowing the pairing of electrons. In this study we have investigated the effect of ascorbic acid, a water soluble antioxidant on the development of hypercholesterolemia induced atherosclerosis in rabbits. Rabbits were made hypercholesterolemic and atherosclerotic by feeding 100 mg cholesterol/day. Different doses of ascorbic acid were administered to these rabbits. Low dose of ascorbic acid (0.5 mg/100 g body weight/day) did not have any significant effect on the percent of total area covered by atherosclerotic plaque. However, ascorbic acid when fed at a higher dose (15 mg/100 g body weight/day) was highly effective in reducing the atherogenecity. With this dose the percent of total surface area covered by atherosclerotic plaque was significantly less (p < 0.001). This suggests that use of ascorbic acid may have great promise in the prevention of hypercholesterolemia induced atherosclerosis.

  6. Risk of carotid atherosclerosis associated with genetic polymorphisms of apolipoprotein E and inflammatory genes among arsenic exposed residents in Taiwan

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hsieh, Y.-C.; Hsieh, F.-I; Lien, L.-M.

    2008-02-15

    Arsenic had been reported to be associated with carotid atherosclerosis. However, there were few studies to evaluate the association between the susceptible gene of lipid metabolism and inflammation and carotid atherosclerosis among arsenic exposure residents. The aim of the study was to investigate the associations between the genetic polymorphisms of APOE and MCP-1 and the risk of carotid atherosclerosis among residents of Lanyang Basin in Taiwan which was a newly confirmed arsenic-endemic area. In total, 479 residents who had been genotyped of these two genes and examined the severity of carotid atherosclerosis were included in this study. The study subjectsmore » with carotid intima media thickness (IMT) {>=} 1.0 mm or with the observable plaque in the extracranial carotid artery were diagnosed as carotid atherosclerosis. A significantly age- and gender-adjusted odds ratio of 2.0 for the development of carotid atherosclerosis was observed in study subjects with {epsilon}4 allele of APOE than those without {epsilon}4 allele. Compared with study subjects who carried wild genotypes of APOE and MCP-1, those with both risk genotypes of APOE and MCP-1 had 2.5-fold risk of carotid atherosclerosis after adjustment for age and gender, revealing a significant dose-response relationship between number of risk genotypes of these genes and risk of carotid atherosclerosis. Additionally, study subjects with two risk genotypes of APOE and MCP-1 and either had ingested well water contained arsenic level > 10 {mu}g/L or had arsenic exposure > 0.22 mg/L-year would have strikingly highest risk of 10.3-fold and 15.7-fold, respectively, for the development carotid atherosclerosis, showing significant joint effect of arsenic exposure and risk genotypes of APOE and MCP-1.« less

  7. Loss of TIMP3 exacerbates atherosclerosis in ApoE null mice.

    PubMed

    Stöhr, Robert; Cavalera, Michele; Menini, Stefano; Mavilio, Maria; Casagrande, Viviana; Rossi, Claudia; Urbani, Andrea; Cardellini, Marina; Pugliese, Giuseppe; Menghini, Rossella; Federici, Massimo

    2014-08-01

    Tissue inhibitor of metalloproteinase 3 (TIMP3) is a stromal protein that inhibits the activity of various proteases and receptors. We have previously shown TIMP3 to be downregulated in metabolic and inflammatory disorders, such as type 2 diabetes mellitus. We have now generated an ApoE(-/-)Timp3(-/-) mouse model in which, through the use of genetics, metabolomics and in-vivo phenotypical analysis we investigated the role of TIMP3 in the development of atherosclerosis. En face aorta analysis and aortic root examination showed that ApoE(-/-)Timp3(-/-) mice show increased atherosclerosis with increased infiltration of macrophages into the plaque. Serum concentration of MCP-1 were elevated in the serum of ApoE(-/-)Timp3(-/-) mice coupled with an expansion of the inflammatory (M1) Gr1+ macrophages, both in the circulation and within the aortic tissue. Targeted analysis of metabolites revealed a trend to reduced short chain acylcarnitines. Our study shows that lack of TIMP3 increases inflammation and polarizes macrophages towards a more inflammatory phenotype resulting in increased atherosclerosis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. Combined Vitamin C and Vitamin E Deficiency Worsens Early Atherosclerosis in ApoE-Deficient Mice

    PubMed Central

    Babaev, Vladimir R.; Li, Liying; Shah, Sanket; Fazio, Sergio; Linton, MacRae F.; May, James M.

    2010-01-01

    Objective Atherosclerosis is an inflammatory condition associated with oxidative stress, but controversy persists regarding whether antioxidants such as vitamins C and E are preventative. To assess the role of combined deficiencies of vitamins C and E on the earliest stages of atherosclerosis, four combinations of vitamin supplementation (Low C/Low E, Low C/High E, High C/Low E, High C/High E) were studied in atherosclerosis-prone apolipoprotein E (apoE)-deficient mice also unable to synthesize their own vitamin C (gulo−/−). The effect of a more severe depletion of vitamin C alone was evaluated in a second experiment using gulo−/− mice carrying the hemizygous deletion of SVCT2, the vitamin C transporter. Methods and Results After 8 weeks on a high-fat diet (16% lard, 0.2% cholesterol), atherosclerosis developed in the aortic sinus areas of mice in all diet groups. Each vitamin-deficient diet significantly decreased liver and brain contents of the corresponding vitamin. Combined deficiency of both vitamins increased lipid peroxidation, doubled plaque size, and increased plaque macrophage content by 2-3-fold in males, although only plaque macrophage content was increased in females. A more severe deficiency of vitamin C in gulo−/− mice with defective cellular uptake of vitamin C increased both oxidative stress and atherosclerosis in apoE−/− mice compared to littermates on a diet replete in vitamin C, again most clearly in males. Conclusion Combined vitamin E and C deficiencies are required to worsen early atherosclerosis in an apoE-deficient mouse model. However, a more severe cellular deficiency of vitamin C alone promotes atherosclerosis when vitamin E is replete. PMID:20558818

  9. Macrophage Phenotype and Function in Different Stages of Atherosclerosis

    PubMed Central

    Tabas, Ira; Bornfeldt, Karin E.

    2016-01-01

    The remarkable plasticity and plethora of biological functions performed by macrophages have enticed scientists to study these cells in relation to atherosclerosis for more than 50 years, and major discoveries continue to be made today. It is now understood that macrophages play important roles in all stages of atherosclerosis, from initiation of lesions and lesion expansion, to necrosis leading to rupture and the clinical manifestations of atherosclerosis, to resolution and regression of atherosclerotic lesions. Lesional macrophages are derived primarily from blood monocytes, although recent research has shown that lesional macrophage-like cells can also be derived from smooth muscle cells. Lesional macrophages take on different phenotypes depending on their environment and which intracellular signaling pathways are activated. Rather than a few distinct populations of macrophages, the phenotype of the lesional macrophage is more complex and likely changes during the different phases of atherosclerosis and with the extent of lipid and cholesterol loading, activation by a plethora of receptors, and metabolic state of the cells. These different phenotypes allow the macrophage to engulf lipids, dead cells, and other substances perceived as danger signals; efflux cholesterol to HDL; proliferate and migrate; undergo apoptosis and death; and secrete a large number of inflammatory and pro-resolving molecules. This review article, part of the Compendium on Atherosclerosis, discusses recent advances in our understanding of lesional macrophage phenotype and function in different stages of atherosclerosis. With the increasing understanding of the roles of lesional macrophages, new research areas and treatment strategies are beginning to emerge. PMID:26892964

  10. CXCR6 promotes atherosclerosis by supporting T-cell homing, interferon-gamma production, and macrophage accumulation in the aortic wall.

    PubMed

    Galkina, Elena; Harry, Brian L; Ludwig, Andreas; Liehn, Elisa A; Sanders, John M; Bruce, Anthony; Weber, Christian; Ley, Klaus

    2007-10-16

    T lymphocytes are thought to be important in atherosclerosis, but very little is known about the mechanisms of lymphocyte recruitment into atherosclerosis-prone aortas. In this study we tested the hypothesis that CXCR6, a chemokine receptor that is expressed on a subset of CD4+ T helper 1 cells and natural killer T cells, is involved in lymphocyte homing into the aortic wall and modulates the development and progression of atherosclerosis. To investigate the role of CXCR6 in the development and progression of atherosclerosis, we bred CXCR6-deficient (CXCR6(GFP/GFP)) mice with apolipoprotein E-deficient (ApoE(-/-)) mice. We found that CXCR6(GFP/GFP)/ApoE(-/-) mice fed a Western diet for 17 weeks or a chow diet for 56 weeks had decreased atherosclerosis compared with ApoE(-/-) controls. Flow cytometry analysis of the aortas from CXCR6(GFP/GFP)/ApoE(-/-) mice showed that the reduction of atherosclerosis was accompanied by a decreased percentage of CXCR6+ T cells within the aortas. Short-term homing experiments demonstrated that CXCR6 is involved in the recruitment of CXCR6+ leukocytes into the atherosclerosis-prone aortic wall. The reduced percentage of CXCR6+ T cells within the aortas resulted in significantly diminished production of interferon-gamma and reduction of CD11b+/CD68+ macrophages in the aorta. These data provide evidence for a proatherosclerotic role of CXCR6. Absence of CXCR6 alters the recruitment of CXCR6+ leukocytes and modulates the local immune response within the aortic wall.

  11. Subclinical atherosclerosis and subsequent cognitive function.

    PubMed

    Rossetti, Heidi C; Weiner, Myron; Hynan, Linda S; Cullum, C Munro; Khera, Amit; Lacritz, Laura H

    2015-07-01

    To examine the relationship between measures of subclinical atherosclerosis and subsequent cognitive function. Participants from the Dallas Heart Study (DHS), a population-based multiethnic study of cardiovascular disease pathogenesis, were re-examined 8 years later (DHS-2) with the Montreal Cognitive Assessment (MoCA); N = 1904, mean age = 42.9, range 8-65. Associations of baseline measures of subclinical atherosclerosis (coronary artery calcium, abdominal aortic plaque, and abdominal aortic wall thickness) with MoCA scores measured at follow-up were examined in the group as a whole and in relation to age and ApoE4 status. A significant linear trend of successively lower MoCA scores with increasing numbers of atherosclerotic indicators was observed (F(3, 1150) = 5.918, p = .001). CAC was weakly correlated with MoCA scores (p = .047) and MoCA scores were significantly different between participants with and without CAC (M = 22.35 vs 23.69, p = 0.038). With the exception of a small association between abdominal AWT and MoCA in subjects over age 50, abdominal AWT and abdominal aortic plaque did not correlate with MoCA total score (p ≥ .052). Cognitive scores and atherosclerosis measures were not impacted by ApoE4 status (p ≥ .455). In this ethnically diverse population-based sample, subclinical atherosclerosis was minimally associated with later cognitive function in middle-aged adults. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. C-reactive protein in relation to early atherosclerosis and periodontitis.

    PubMed

    Yakob, Maha; Meurman, Jukka H; Jogestrand, Tomas; Nowak, Jacek; Söder, Per-Östen; Söder, Birgitta

    2012-02-01

    Periodontitis may affect atherosclerosis via the chronic inflammation. We investigated high-sensitivity C-reactive protein (hsCRP) in relation to early vascular atherosclerotic changes in non-symptomatic subjects with and without long-term periodontitis. Carotid ultrasonography with calculation of common carotid artery intima-media area (cIMA) was performed, and hsCRP and atherosclerosis risk factors were analysed in randomly chosen 93 patients with periodontitis and 41 controls. The relationship between hsCRP, cIMA and atherosclerosis risk factors was evaluated with multiple logistic regression analysis. Women displayed lower hsCRP (p < 0.05) and higher serum HDL (p < 0.001) than men. In all patients with periodontitis, cIMA values were higher than in controls. Periodontitis appeared to be a major predictor for increased cIMA (odds ratio, 3.82; 95% confidence interval, 1.19-12.26). Neither of these factors was significantly associated with hsCRP which thus appeared not sensitive enough to be a marker for periodontitis or atherosclerosis. Hence, irrespective of low hsCRP levels, periodontitis appeared to increase the risk for atherosclerosis.

  13. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies.

    PubMed

    Reilly, Muredach P; Li, Mingyao; He, Jing; Ferguson, Jane F; Stylianou, Ioannis M; Mehta, Nehal N; Burnett, Mary Susan; Devaney, Joseph M; Knouff, Christopher W; Thompson, John R; Horne, Benjamin D; Stewart, Alexandre F R; Assimes, Themistocles L; Wild, Philipp S; Allayee, Hooman; Nitschke, Patrick Linsel; Patel, Riyaz S; Martinelli, Nicola; Girelli, Domenico; Quyyumi, Arshed A; Anderson, Jeffrey L; Erdmann, Jeanette; Hall, Alistair S; Schunkert, Heribert; Quertermous, Thomas; Blankenberg, Stefan; Hazen, Stanley L; Roberts, Robert; Kathiresan, Sekar; Samani, Nilesh J; Epstein, Stephen E; Rader, Daniel J

    2011-01-29

    We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. MicroRNA-142-3p Induces Atherosclerosis-Associated Endothelial Cell Apoptosis by Directly Targeting Rictor.

    PubMed

    Qin, Bing; Shu, Yaqing; Long, Ling; Li, Haiyan; Men, Xuejiao; Feng, Li; Yang, Huan; Lu, Zhengqi

    2018-06-27

    Atherosclerosis, a multifactorial chronic disease, is the main cause of death and impairment in the world. Endothelial cells (ECs) apoptosis plays a crucial role in the onset and development of atherosclerosis, whereas the underlying molecular mechanisms are unclear. MicroRNA-142-3p (miR-142-3p) is a well-defined tumor suppressor in several types of cancer, while the role of miR-142-3p in ECs apoptosis and the development of atherosclerosis has yet to be elucidated. Therefore, the present study aimed to investigate the role of miR-142-3p in ECs apoptosis during atherosclerosis and the underlying mechanism. Human aortic endothelial cells (HAECs) were treated with oxidized low-density lipoprotein (ox-LDL). The expression level of miR-142-3p was detected using qRT-PCR. Apoptosis was determined via flow cytometry and Caspase-3 activity assay. Prediction of the binding between miR-142-3p and 3'-UTR of Rictor mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. The effects of miR-142-3p on endothelial apoptosis and atherosclerosis were further analyzed in an in vivo model using ApoE-/- mice fed with high-fat diet (HFD). MiR-142-3p expression was substantially up-regulated during the ox-LDL-elicited apoptosis in HAECs. Forced expression of miR-142-3p exacerbated apoptosis in ECs whereas inhibition of miR-142-3p could partly alleviate apoptotic cell death mediated by ox-LDL. Further analysis identified Rictor as a direct target of miR-142-3p, and Rictor knockdown abolished the anti-apoptotic effect of miR-142-3p inhibitor. Moreover, the Akt/endothelial nitric oxide synthase (eNOS) signaling pathway was found to mediate the beneficial effect of miR-142-3p inhibitor on endothelial apoptosis. Finally, systemic treatment with miR-142-3p antagomir attenuated endothelial apoptosis and retarded the progression of atherosclerosis in the aorta of ApoE-/- mice. Down-regulation of miR-142-3p inhibited ECs apoptosis and atherosclerotic

  15. Curcumin Protects against Atherosclerosis in Apolipoprotein E-Knockout Mice by Inhibiting Toll-like Receptor 4 Expression.

    PubMed

    Zhang, Shanshan; Zou, Jun; Li, Peiyang; Zheng, Xiumei; Feng, Dan

    2018-01-17

    Toll-like receptor 4 (TLR4) has been reported to play a critical role in the pathogenesis of atherosclerosis, the current study aimed to investigate whether curcumin suppresses atherosclerosis development in ApoE-knockout (ApoE -/- ) mice by inhibiting TLR4 expression. ApoE -/- mice were fed a high-fat diet supplemented with or without curcumin (0.1% w/w) for 16 weeks. Curcumin supplementation significantly reduced TLR4 expression and macrophage infiltration in atherosclerotic plaques. Curcumin also reduced aortic interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression, nuclear factor-κB (NF-κB) activity, and plasma IL-1β, TNF-α, soluble VCAM-1 and ICAM-1 levels. In addition, aortic sinus sections revealed that curcumin treatment reduced the extent of atherosclerotic lesions and inhibited atherosclerosis development. In vitro, curcumin inhibited NF-κB activation in macrophages and reduced TLR4 expression induced by lipopolysaccharide. Our results indicate that curcumin protects against atherosclerosis at least partially by inhibiting TLR4 expression and its related inflammatory reaction.

  16. Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in Yucatan miniature pigs.

    PubMed

    Davis, Bryan T; Wang, Xiao-Jun; Rohret, Judy A; Struzynski, Jason T; Merricks, Elizabeth P; Bellinger, Dwight A; Rohret, Frank A; Nichols, Timothy C; Rogers, Christopher S

    2014-01-01

    Recent progress in engineering the genomes of large animals has spurred increased interest in developing better animal models for diseases where current options are inadequate. Here, we report the creation of Yucatan miniature pigs with targeted disruptions of the low-density lipoprotein receptor (LDLR) gene in an effort to provide an improved large animal model of familial hypercholesterolemia and atherosclerosis. Yucatan miniature pigs are well established as translational research models because of similarities to humans in physiology, anatomy, genetics, and size. Using recombinant adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer, male and female LDLR+/- pigs were generated. Subsequent breeding of heterozygotes produced LDLR-/- pigs. When fed a standard swine diet (low fat, no cholesterol), LDLR+/- pigs exhibited a moderate, but consistent increase in total and LDL cholesterol, while LDLR-/- pigs had considerably elevated levels. This severe hypercholesterolemia in homozygote animals resulted in atherosclerotic lesions in the coronary arteries and abdominal aorta that resemble human atherosclerosis. These phenotypes were more severe and developed over a shorter time when fed a diet containing natural sources of fat and cholesterol. LDLR-targeted Yucatan miniature pigs offer several advantages over existing large animal models including size, consistency, availability, and versatility. This new model of cardiovascular disease could be an important resource for developing and testing novel detection and treatment strategies for coronary and aortic atherosclerosis and its complications.

  17. Advanced atherosclerosis is associated with increased medial degeneration in sporadic ascending aortic aneurysms.

    PubMed

    Albini, Paul T; Segura, Ana Maria; Liu, Guanghui; Minard, Charles G; Coselli, Joseph S; Milewicz, Dianna M; Shen, Ying H; LeMaire, Scott A

    2014-02-01

    The pathogenesis of non-familial, sporadic ascending aortic aneurysms (SAAA) is poorly understood, and the relationship between ascending aortic atherosclerosis and medial degeneration is unclear. We evaluated the prevalence and severity of aortic atherosclerosis and its association with medial degeneration in SAAA. Atherosclerosis was characterized in ascending aortic tissues collected from 68 SAAA patients (mean age, 62.9 ± 12.0 years) and 15 controls (mean age, 56.6 ± 11.4 years [P = 0.07]) by using a modified American Heart Association classification system. Upon histologic examination, 97% of SAAA patients and 73% of controls showed atherosclerotic changes. Most SAAA samples had intermediate (types 2 and 3, 35%) or advanced atherosclerosis (types ≥ 4; 40%), whereas most control samples showed minimal atherosclerosis (none or type 1, 80%; P < 0.001 after adjusting for age). In a separate analysis, we examined the total incidence and grade distribution of medial degenerative changes among SAAA samples according to atherosclerosis grade. Advanced atherosclerosis was associated with higher grades of smooth muscle cell depletion (P < 0.001), elastic fiber depletion (P = 0.02), elastic fiber fragmentation (P < 0.001), and mucopolysaccharide accumulation (P = 0.04). Aortic diameter was larger in SAAA patients with advanced atherosclerosis than in patients with minimal (P = 0.04) or intermediate atherosclerosis (P = 0.04). Immunostaining showed marked CD3+ T-cell and CD68+ macrophage infiltration, MMP-2 and MMP-9 production, and cryopyrin expression in the medial layer adjacent to atherosclerotic plaque. SAAA tissues exhibited advanced atherosclerosis that was associated with severe medial degeneration and increased aortic diameter. Our findings suggest a role for atherosclerosis in the progression of sporadic ascending aortic aneurysms. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  18. Is systemic lupus erithematosus a new risk factor for atherosclerosis?

    PubMed

    Freire, Beatriz Funayama Alvarenga; da Silva, Rogério Cardoso; Fabro, Alexandre Todorovic; dos Santos, Daniela Cristina

    2006-09-01

    To evaluate the prevalence of cardiovascular events (CVE) secondary to atherosclerosis in lupus patients and correlate them to the traditional risk factors, disease duration and drug therapy used. A retrospective study was carried out based on data obtained from patients charts. Patients included were those who had a lupus diagnosis confirmed at least two years before inclusion in the study and had been followed since 1992. CVE were characterized as MI, angina pectoris and stroke non-related to lupus activity. Risk factors and drugs used for treatment were recorded. Seventy-one charts were analyzed. Patients mean age was 34.2+/-12.7 years; 68 were women and three were men; 58 were Caucasian (81.6%). Ten (14.08%) presented CVE. Patients in whom CVE were observed were older (42.7 vs. 32.8 years p=0.0021) and presented longer disease duration (10.8 vs. 7.2 years p=0.011). The traditional risk factors, daily and cumulative doses of steroids, immunosuppressive drugs and antimalarial drugs were not significant when patients with and without CVE were compared. The prevalence of CVE secondary to atherosclerosis in systemic lupus erythematosus (SLE) was 14.08%. The traditional risk factors were not associated with the development of CVE in lupus patients. Patients that presented cardiovascular events were older and presented longer disease duration. It is a premature conclusion to establish SLE as an independent risk factor for atherosclerosis development.

  19. Dietary cholesterol worsens adipose tissue macrophage accumulation and atherosclerosis in obese LDL receptor-deficient mice

    PubMed Central

    Subramanian, Savitha; Han, Chang Yeop; Chiba, Tsuyoshi; McMillen, Timothy S.; Wang, Shari A.; Haw, Antonio; Kirk, Elizabeth A.; O’Brien, Kevin D.; Chait, Alan

    2009-01-01

    Objective Chronic systemic inflammation accompanies obesity and predicts development of cardiovascular disease. Dietary cholesterol has been shown to increase inflammation and atherosclerosis in LDL receptor-deficient (LDLR-/-) mice. This study was undertaken to determine whether dietary cholesterol and obesity have additive effects on inflammation and atherosclerosis. Methods and Results LDLR-/- mice were fed chow, high fat, high carbohydrate (diabetogenic) diet without (DD) or with added cholesterol (DDC) for 24 weeks. Effects on adipose tissue, inflammatory markers and atherosclerosis were studied. Despite similar weight gain between DD and DDC groups, addition of dietary cholesterol increased insulin resistance relative to DD. Adipocyte hypertrophy, macrophage accumulation and local inflammation were observed in intra-abdominal adipose tissue in DD and DDC, but were significantly higher in the DDC group. Circulating levels of the inflammatory protein serum amyloid A (SAA) were 4.4-fold higher in DD animals and 15-fold higher in DDC animals than controls, suggesting chronic systemic inflammation. Hepatic SAA mRNA levels were similarly elevated. Atherosclerosis was increased in the DD-fed animals and further increased in the DDC group. Conclusions Obesity-induced macrophage accumulation in adipose tissue is exacerbated by dietary cholesterol. These local inflammatory changes in adipose tissue are associated with insulin resistance, systemic inflammation and increased atherosclerosis in this mouse model. PMID:18239153

  20. MicroRNAs and atherosclerosis: new actors for an old movie.

    PubMed

    Santovito, D; Mezzetti, A; Cipollone, F

    2012-11-01

    To date, cardiovascular diseases (CVDs) are the leading causes of morbidity and mortality worldwide. MicroRNAs (miRNAs) are endogenous, short, non-coding RNA sequences able to regulate gene expression principally at the post-transcriptional level. Initially, they were thought to be involved only in developmental timing of worms. Their involvement in human biology was recently discovered and many studies have been performed to demonstrate the role of miRNA in human cancer. Since the first observation in 2005 of their implication in cardiac biology, many studies have demonstrated their role in the genetic modulation of cardiovascular development and in cardiovascular diseases such as cardial remodeling and heart failure, cardiac arrhythmias, cardiac ischaemia, cardiac fibrosis, atherosclerosis and stroke. Thus, the aim of this review is to describe the role of miRNA in atherosclerosis development and evolution and to individuate their role as potential therapeutic target. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Endothelial dysfunction in patients with coronary atherosclerosis.

    PubMed

    Chapidze, L; Kapanadze, S; Dolidze, N; Bakhutashvili, Z; Latsabidze, N

    2007-01-01

    It is well known that endothelial dysfunction as a nontraditional risk factor is an important early event in the pathogenesis of coronary atherosclerosis, contributing to plaque initiation and progression. In order to assess endothelial function plasma nitric oxide (NO) concentrations were determined. A total of 157 patients (119 men and 38 women, mean age 57+/-5,4 years) with coronary atherosclerosis were enrolled in the research. The study was cross-sectional in design. Most of the patients (n=127) had undergone myocardial revascularization procedures. There was statistically significant difference in mean values of plasma nitric oxide levels between patients with coronary atherosclerosis and healthy subjects (11,1+/-2,52 mkmol/L and 22,3+/-3,27 mkmol/L, respectively. p<0,01). Among all 157 patients only 17% had normal NO concentrations. In 59% cases low and in 24% cases high nitric oxide levels were found. Extent of coronary artery disease was associated with severity of endothelial dysfunction. The patients with three-vessel disease had the lowest mean plasma NO concentration. There was statistically significant negative correlation between mean plasma NO level and extent of coronary artery disease. Measurement of plasma nitric oxide concentration will give useful information for cardiologists, modification of abnormal levels of this parameter may delay progression of aggressive atherosclerotic process and thus, may prevent recurrent coronary events in patients with coronary atherosclerosis.

  2. Agent Based Modeling of Atherosclerosis: A Concrete Help in Personalized Treatments

    NASA Astrophysics Data System (ADS)

    Pappalardo, Francesco; Cincotti, Alessandro; Motta, Alfredo; Pennisi, Marzio

    Atherosclerosis, a pathology affecting arterial blood vessels, is one of most common diseases of the developed countries. We present studies on the increased atherosclerosis risk using an agent based model of atherogenesis that has been previously validated using clinical data. It is well known that the major risk in atherosclerosis is the persistent high level of low density lipoprotein (LDL) concentration. However, it is not known if short period of high LDL concentration can cause irreversible damage and if reduction of the LDL concentration (either by life style or drug) can drastically or partially reduce the already acquired risk. We simulated four different clinical situations in a large set of virtual patients (200 per clinical scenario). In the first one the patients lifestyle maintains the concentration of LDL in a no risk range. This is the control case simulation. The second case is represented by patients having high level of LDL with a delay to apply appropriate treatments; The third scenario is characterized by patients with high LDL levels treated with specific drugs like statins. Finally we simulated patients that are characterized by several oxidative events (smoke, sedentary life style, assumption of alcoholic drinks and so on so forth) that effective increase the risk of LDL oxidation. Those preliminary results obviously need to be clinically investigated. It is clear, however, that SimAthero has the power to concretely help medical doctors and clinicians in choosing personalized treatments for the prevention of the atherosclerosis damages.

  3. Effects of Restoration of Blood Flow on the Development of Aortic Atherosclerosis in ApoE-/- Mice With Unilateral Renal Artery Stenosis.

    PubMed

    Pathak, Alokkumar S; Huang, Jianhua; Rojas, Mauricio; Bazemore, Taylor C; Zhou, Ruihai; Stouffer, George A

    2016-04-03

    Chronic unilateral renal artery stenosis (RAS) causes accelerated atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice, but effects of restoration of renal blood flow on aortic atherosclerosis are unknown. Male ApoE(-/-) mice underwent sham surgery (n=16) or had partial ligation of the right renal artery (n=41) with the ligature being removed 4 days later (D4LR; n=6), 8 days later (D8LR; n=11), or left in place for 90 days (chronic RAS; n=24). Ligature removal at 4 or 8 days resulted in improved renal blood flow, decreased plasma angiotensin II levels, a return of systolic blood pressure to baseline, and increased plasma levels of neutrophil gelatinase associated lipocalin. Chronic RAS resulted in increased lipid staining in the aortic arch (33.2% [24.4, 47.5] vs 11.6% [6.1, 14.2]; P<0.05) and descending thoracic aorta (10.2% [6.4, 25.9] vs 4.9% [2.8, 7.8]; P<0.05), compared to sham surgery. There was an increased amount of aortic arch lipid staining in the D8LR group (22.7% [22.1, 32.7]), compared to sham-surgery, but less than observed with chronic RAS. Lipid staining in the aortic arch was not increased in the D4LR group, and lipid staining in the descending aorta was not increased in either the D8LR or D4LR groups. There was less macrophage expression in infrarenal aortic atheroma in the D4LR and D8LR groups compared to the chronic RAS group. Restoration of renal blood flow at either 4 or 8 days after unilateral RAS had a beneficial effect on systolic blood pressure, aortic lipid deposition, and atheroma inflammation. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  4. Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis.

    PubMed

    Jones, Gareth W; McLeod, Louise; Kennedy, Catherine L; Bozinovski, Steven; Najdovska, Meri; Jenkins, Brendan J

    2015-02-01

    Interleukin (IL)-6 is a key modulator of the acute phase response (APR), and while both are implicated in atherosclerosis, the pathological role of specific IL-6 signalling cascades is ill-defined. Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 pathway, here we evaluate whether gp130-dependent STAT3 activation modulates atherosclerosis. High-fat diet-induced atherosclerosis was established in ApoE(-/-) mice crossed with gp130(F/F) knock-in mice displaying elevated gp130-dependent STAT3 activation and production of the APR protein, serum amyloid A (SAA). Also generated were gp130(F/F):Stat3(-/+):ApoE(-/-) mice displaying genetically-normalised STAT3 activation and SAA levels, and bone marrow chimeras involving ApoE(-/-) and gp130(F/F):ApoE(-/-) mice. At 10 weeks post high-fat diet, aortic atherosclerotic lesions, including the presence of CD68(+) macrophages, and plasma lipid and SAA profiles, were assessed. Aortic plaque development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) mice were significantly reduced (3-fold, P < 0.001) compared to ApoE(-/-) littermates. By contrast, in gp130(F/F):ApoE(-/-) mice, atherosclerotic plaques contained augmented CD68(+) macrophage infiltrates, and plasma SAA levels were elevated, compared to ApoE(-/-) mice. Atherosclerotic lesion development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) and gp130(F/F):Stat3(-/+):ApoE(-/-) mice were comparable, despite a significant (P < 0.05) reduction in macrophage numbers in lesions, and also plasma SAA levels, in gp130(F/F):Stat3(-/+):ApoE(-/-) mice. Aortic plaque development and plasma triglyceride levels were comparable in ApoE(-/-) mice reconstituted with gp130(F/F):ApoE(-/-) (ApoE(F/F:ApoE)) or ApoE(-/-) (ApoE(ApoE)) bone marrow cells. Deregulation of gp130/STAT3 signalling augments the APR and macrophage infiltration during atherosclerosis without impacting on the development of aortic plaques. Copyright © 2014 Elsevier Ireland Ltd

  5. Resistant Atherosclerosis: The Need for Monitoring of Plaque Burden.

    PubMed

    Spence, J David; Solo, Karla

    2017-06-01

    Recent studies indicate that patients with lower levels of low-density lipoprotein cholesterol (LDL-C) have greater regression of coronary plaque. In 2002, we found that carotid plaque progression doubled cardiovascular risk. In 2003, we therefore implemented a new approach, treating arteries instead of risk factors. Since then, we have seen many patients with carotid plaque progression despite very low levels of LDL-C, suggesting other causes of atherosclerosis. We studied the relationship of achieved LDL-C and change in LDL-C to progression/regression of atherosclerosis, before and after 2003. All 4512 patients in our clinic database with at least 2 measurements of LDL-C and carotid total plaque area approximately a year apart and complete data for analyses (n=2025 before and 2487 after December 31, 2003) were included in the study. Baseline total plaque area was significantly higher after 2003 (129.56±134.32 versus 113.33±121.52 mm 2 ; P <0.0001), and plaque progression was significantly less after 2003 (2.94±37.11 versus 12.62±43.24 mm 2 ; P <0.0001). Many patients with LDL-C <1.8 mm had plaque progression (47.5%), and change in LDL-C was not correlated with plaque progression/regression. Increasing age and serum creatinine contributed to resistant atherosclerosis. Many patients have Resistant Atherosclerosis, failing to achieve regression of atherosclerosis despite low levels of LDL-C. Instead of relying on LDL-C, measuring plaque burden may be a more useful way of assessing individual response to therapy, particularly in resistant atherosclerosis. © 2017 American Heart Association, Inc.

  6. Lipoprotein-associated phospholipase A(2) and atherosclerosis.

    PubMed

    Wilensky, Robert L; Macphee, Colin H

    2009-10-01

    There is substantial data from over 50 000 patients that increased lipoprotein-associated phospholipase A2 (Lp-PLA2) mass or activity is associated with an increased risk of cardiac death, myocardial infarction, acute coronary syndromes and ischemic stroke. However, only recently have data emerged demonstrating a role of Lp-PLA2 in development of advanced coronary artery disease. Indeed, Lp-PLA2 may be an important link between lipid homeostasis and the vascular inflammatory response. Lp-PLA2, also known as platelet-activating factor acetylhydrolase, rapidly cleaves oxidized phosphatidylcholine molecules produced during the oxidation of LDL and atherogenic lipoprotein Lp(a), generating the soluble proinflammatory and proapoptotic lipid mediators, lyso-phosphatidylcholine and oxidized nonesterified fatty acids. These proinflammatory lipids play an important role in the development of atherosclerotic necrotic cores, the substrate for acute unstable coronary disease by recruiting and activating leukocytes/macrophages, inducing apoptosis and impairing the subsequent removal of dead cells. Selective inhibition of Lp-PLA2 reduces development of necrotic cores and may result in stabilization of atherosclerotic plaques. Recent data have shown that immune pathways play a major role in the development and progression of high-risk atherosclerosis, which leads to ischemic sudden death, myocardial infarction, acute coronary syndromes and ischemic strokes. Persistent and sustained macrophage apoptosis appears to play a major role in the resulting local inflammatory response in part by effects elicited by Lp-PLA2. Selective inhibition of Lp-PLA2 has been postulated to reduce necrotic core progression and the clinical sequelae of advanced, unstable atherosclerosis.

  7. Monocytic cell junction proteins serve important roles in atherosclerosis via the endoglin pathway

    PubMed Central

    Chen, Lina; Chen, Zhongliang; Ge, Menghua; Tang, Oushan; Cheng, Yinhong; Zhou, Haoliang; Shen, Yu; Qin, Fengming

    2017-01-01

    The formation of atherosclerosis is recognized to be caused by multiple factors including pathogenesis in monocytes during inflammation. The current study provided evidence that monocytic junctions were significantly altered in patients with atherosclerosis, which suggested an association between cell junctions and atherosclerosis. Claudin-1, occludin-1 and ZO-1 were significantly enhanced in atherosclerosis, indicating that the tight junction pathway was activated during the pathogenesis of atherosclerosis. In addition, the gene expression of 5 connexin members involved in the gap junction pathway were quantified, indicating that connexin 43 and 46 were significantly up-regulated in atherosclerosis. Furthermore, inflammatory factors including endoglin and SMAD were observed, suggesting that immune regulative factors were down-regulated in this pathway. Silicon-based analysis additionally identified that connexins and tight junctions were altered in association with monocytic inflammation regulations, endoglin pathway. The results imply that reduced expression of the immune regulation pathway in monocytes is correlated with the generation of gap junctions and tight junctions which serve important roles in atherosclerosis. PMID:28901429

  8. Targeted Interleukin-10 Nanotherapeutics Developed with a Microfluidic Chip Enhance Resolution of Inflammation in Advanced Atherosclerosis.

    PubMed

    Kamaly, Nazila; Fredman, Gabrielle; Fojas, Jhalique Jane R; Subramanian, Manikandan; Choi, Won Ii; Zepeda, Katherine; Vilos, Cristian; Yu, Mikyung; Gadde, Suresh; Wu, Jun; Milton, Jaclyn; Carvalho Leitao, Renata; Rosa Fernandes, Livia; Hasan, Moaraj; Gao, Huayi; Nguyen, Vance; Harris, Jordan; Tabas, Ira; Farokhzad, Omid C

    2016-05-24

    Inflammation is an essential protective biological response involving a coordinated cascade of signals between cytokines and immune signaling molecules that facilitate return to tissue homeostasis after acute injury or infection. However, inflammation is not effectively resolved in chronic inflammatory diseases such as atherosclerosis and can lead to tissue damage and exacerbation of the underlying condition. Therapeutics that dampen inflammation and enhance resolution are currently of considerable interest, in particular those that temper inflammation with minimal host collateral damage. Here we present the development and efficacy investigations of controlled-release polymeric nanoparticles incorporating the anti-inflammatory cytokine interleukin 10 (IL-10) for targeted delivery to atherosclerotic plaques. Nanoparticles were nanoengineered via self-assembly of biodegradable polyester polymers by nanoprecipitation using a rapid micromixer chip capable of producing nanoparticles with retained IL-10 bioactivity post-exposure to organic solvent. A systematic combinatorial approach was taken to screen nanoparticles, resulting in an optimal bioactive formulation from in vitro and ex vivo studies. The most potent nanoparticle termed Col-IV IL-10 NP22 significantly tempered acute inflammation in a self-limited peritonitis model and was shown to be more potent than native IL-10. Furthermore, the Col-IV IL-10 nanoparticles prevented vulnerable plaque formation by increasing fibrous cap thickness and decreasing necrotic cores in advanced lesions of high fat-fed LDLr(-/-) mice. These results demonstrate the efficacy and pro-resolving potential of this engineered nanoparticle for controlled delivery of the potent IL-10 cytokine for the treatment of atherosclerosis.

  9. Status of high temperature superconductor development for accelerator magnets

    NASA Technical Reports Server (NTRS)

    Hirabayashi, H.

    1995-01-01

    High temperature superconductors are still under development for various applications. As far as conductors for magnets are concerned, the development has just been started. Small coils wound by silver sheathed Bi-2212 and Bi-2223 oxide conductors have been reported by a few authors. Essential properties of high T(sub c) superconductors like pinning force, coherent length, intergrain coupling, weak link, thermal property, AC loss and mechanical strength are still not sufficiently understandable. In this talk, a review is given with comparison between the present achievement and the final requirement for high T(sub c) superconductors, which could be particularly used in accelerator magnets. Discussions on how to develop high T(sub c) superconductors for accelerator magnets are included with key parameters of essential properties. A proposal of how to make a prototype accelerator magnet with high T(sub c) superconductors with prospect for future development is also given.

  10. Vascular wall shear stress in zebrafish model of early atherosclerosis

    NASA Astrophysics Data System (ADS)

    Choi, Woorak; Seo, Eunseok; Yeom, Eunseop; Lee, Sang Joon

    2016-11-01

    Although atherosclerosis is a multifactorial disease, the role of hemodynamic force has strong influence on the outbreak of the disease. Low and oscillating wall shear stress (WSS) is associated with the incidence of atherosclerosis. Many researchers have investigated relationships between WSS and the occurrence of atherosclerosis using in vitro and in vivo models. However, these models possess technological limitations in mimicking real biophysiological conditions and monitoring the temporal progression of atherosclerosis. In this study, a hypercholesterolaemic zebrafish model was established as a novel model to resolve these technical limitations. WSS in blood vessels of 15 days post-fertilisation zebrafish was measured using a micro PIV technique, and the spatial distribution of lipids inside blood vessels was quantitatively visualized using a confocal microscopy. As a result, lipids are mainly deposited in the regions of low WSS. The oscillating WSS is not induced by blood flows in the zebrafish disease model. The present hypercholesterolaemic zebrafish model would be useful for understanding the effect of WSS on the early stage of atherosclerosis. This work was supported by the National Research Foundation of Korea (NRF) under a Grant funded by the Korean government (MSIP) (No. 2008-0061991).

  11. Development of High Power Vacuum Tubes for Accelerators and Plasma Heating

    NASA Astrophysics Data System (ADS)

    Srivastava, Vishnu

    2012-11-01

    High pulsed power magnetrons and klystrons for medical and industrial accelerators, and high CW power klystrons and gyrotrons for plasma heating in tokamak, are being developed at CEERI. S-band 2.0MW pulsed tunable magnetrons of centre frequency 2856MHz and 2998 MHz were developed, and S-band 2.6MW pulsed tunable magnetron is being developed for medical LINAC, and 3MW pulsed tunable magnetron is being developed for industrial accelerator. S-band (2856MHz), 5MW pulsed klystron was developed for particle accelerator, and S-band 6MW pulsed klystron is under development for 10MeV industrial accelerator. 350MHz, 100kW (CW) klystron is being developed for proton accelerator, and C-band 250kW (CW) klystron is being developed for plasma heating. 42GHz, 200kW (CW/Long pulse) gyrotron is under development for plasma heating. Plasma filled tubes are also being developed for switching. 25kV/1kA and 40kV/3kA thyratrons were developed for high voltage high current switching in pulse modulators for magnetrons and klystrons. 25kV/3kA Pseudospark switch of current rise time of 1kA/|a-sec and pulse repetition rate of 500Hz is being developed. Plasma assisted high power microwave device is also being investigated.

  12. Multi-Ethnic Study of Atherosclerosis (MESA)

    ClinicalTrials.gov

    2016-07-28

    Atherosclerosis; Cardiovascular Diseases; Heart Diseases; Coronary Artery Disease; Coronary Disease; Stroke; Myocardial Infarction; Heart Failure; Diabetes Mellitus, Type 2; Hypertension; Diabetes Mellitus

  13. Basic mechanisms in intracranial large-artery atherosclerosis: advances and challenges.

    PubMed

    Arenillas, Juan F; Alvarez-Sabín, José

    2005-01-01

    Intracranial large-artery atherosclerosis is a major cause of ischemic stroke worldwide. Patients affected by this disease are at a high risk of suffering recurrent ischemic events despite antithrombotic therapy. Progression and a greater extent of intracranial atherosclerosis imply a higher risk for recurrence. Studies performed by our group in patients with symptomatic intracranial large-artery atherosclerosis have shown that: (1) C-reactive protein predicts its progression and recurrence, suggesting that inflammation may play a deleterious role in this condition; (2) a high level of the anti-angiogenic endostatin is also associated with a progressive and recurrent intracranial atherosclerosis, which might support a beneficial role for angiogenesis in this group of patients; and (3) elevated lipoprotein(a) concentration and diabetes mellitus characterize those patients with a higher number of intracranial stenoses. 2005 S. Karger AG, Basel

  14. Combined vitamin C and vitamin E deficiency worsens early atherosclerosis in apolipoprotein E-deficient mice.

    PubMed

    Babaev, Vladimir R; Li, Liying; Shah, Sanket; Fazio, Sergio; Linton, MacRae F; May, James M

    2010-09-01

    To assess the role of combined deficiencies of vitamins C and E on the earliest stages of atherosclerosis (an inflammatory condition associated with oxidative stress), 4 combinations of vitamin supplementation (low C/low E, low C/high E, high C/low E, and high C/high E) were studied in atherosclerosis-prone apolipoprotein E-deficient mice also unable to synthesize their own vitamin C (gulonolactone oxidase(-/-)); and to evaluate the effect of a more severe depletion of vitamin C alone in a second experiment using gulonolactone oxidase(-/-) mice carrying the hemizygous deletion of SVCT2 (the vitamin C transporter). After 8 weeks of a high-fat diet (16% lard and 0.2% cholesterol), atherosclerosis developed in the aortic sinus areas of mice in all diet groups. Each vitamin-deficient diet significantly decreased liver and brain contents of the corresponding vitamin. Combined deficiency of both vitamins increased lipid peroxidation, doubled plaque size, and increased plaque macrophage content by 2- to 3-fold in male mice, although only plaque macrophage content was increased in female mice. A more severe deficiency of vitamin C in gulonolactone oxidase(-/-) mice with defective cellular uptake of vitamin C increased both oxidative stress and atherosclerosis in apolipoprotein E(-/-) mice compared with littermates receiving a diet replete in vitamin C, again most clearly in males. Combined deficiencies of vitamins E and C are required to worsen early atherosclerosis in an apolipoprotein E-deficient mouse model. However, a more severe cellular deficiency of vitamin C alone promotes atherosclerosis when vitamin E is replete.

  15. EuCARD 2010: European coordination of accelerator research and development

    NASA Astrophysics Data System (ADS)

    Romaniuk, Ryszard S.

    2010-09-01

    Accelerators are basic tools of the experimental physics of elementary particles, nuclear physics, light sources of the fourth generation. They are also used in myriad other applications in research, industry and medicine. For example, there are intensely developed transmutation techniques for nuclear waste from nuclear power and atomic industries. The European Union invests in the development of accelerator infrastructures inside the framework programs to build the European Research Area. The aim is to build new accelerator research infrastructures, develop the existing ones, and generally make the infrastructures more available to competent users. The paper summarizes the first year of activities of the EU FP7 Project Capacities EuCARD -European Coordination of Accelerator R&D. EuCARD is a common venture of 37 European Accelerator Laboratories, Institutes, Universities and Industrial Partners involved in accelerator sciences and technologies. The project, initiated by ESGARD, is an Integrating Activity co-funded by the European Commission under Framework Program 7 - Capacities for a duration of four years, starting April 1st, 2009. Several teams from this country participate actively in this project. The contribution from Polish research teams concerns: photonic and electronic measurement - control systems, RF-gun co-design, thin-film superconducting technology, superconducting transport infrastructures, photon and particle beam measurements and control.

  16. Accelerating Drug Development: Antiviral Therapies for Emerging Viruses as a Model.

    PubMed

    Everts, Maaike; Cihlar, Tomas; Bostwick, J Robert; Whitley, Richard J

    2017-01-06

    Drug discovery and development is a lengthy and expensive process. Although no one, simple, single solution can significantly accelerate this process, steps can be taken to avoid unnecessary delays. Using the development of antiviral therapies as a model, we describe options for acceleration that cover target selection, assay development and high-throughput screening, hit confirmation, lead identification and development, animal model evaluations, toxicity studies, regulatory issues, and the general drug discovery and development infrastructure. Together, these steps could result in accelerated timelines for bringing antiviral therapies to market so they can treat emerging infections and reduce human suffering.

  17. Coronary atherosclerosis: Significance of autophagic armour.

    PubMed

    Arora, Mansi; Kaul, Deepak

    2012-09-26

    Autophagy is a lysosomal degradation pathway of cellular components such as organelles and long-lived proteins. Though a protective role for autophagy has been established in various patho-physiologic conditions such as cancer, neurodegeneration, aging and heart failure, a growing body of evidence now reveals a protective role for autophagy in atherosclerosis, mainly by removing oxidatively damaged organelles and proteins and also by promoting cholesterol egress from the lipid-laden cells. Recent studies by Razani et al and Liao et al unravel novel pathways that might be involved in autophagic protection and in this commentary we highlight the importance of autophagy in atherosclerosis in the light of these two recent papers.

  18. Prevention of oxLDL uptake leads to decreased atherosclerosis in hematopoietic NPC1-deficient Ldlr-/- mice.

    PubMed

    Jeurissen, Mike L J; Walenbergh, Sofie M A; Houben, Tom; Gijbels, Marion J J; Li, Jieyi; Hendrikx, Tim; Oligschlaeger, Yvonne; van Gorp, Patrick J; Binder, Christoph J; Donners, Marjo M P C; Shiri-Sverdlov, Ronit

    2016-12-01

    Atherosclerosis is a chronic inflammatory disease of medium and large vessels and is typically characterized by the predominant accumulation of low-density lipoprotein (LDL)-cholesterol inside macrophages that reside in the vessel walls. Previous studies clearly demonstrated an association specifically between the oxidized type of LDL (oxLDL) and atherosclerotic lesion formation. Further observations revealed that these atherosclerotic lesions displayed enlarged, lipid-loaded lysosomes. By increasing natural antibodies against oxLDL, pneumococcal vaccination has been shown to reduce atherosclerosis in LDL receptor knockout (Ldlr -/- ) mice. Relevantly, loss of the lysosomal membrane protein Niemann-Pick Type C1 (NPC1) led to lysosomal accumulation of various lipids and promoted atherosclerosis. Yet, the importance of lysosomal oxLDL accumulation inside macrophages, compared to non-modified LDL, in atherosclerosis has never been established. By transplanting NPC1 bone marrow into lethally irradiated Ldlr -/- mice, a hematopoietic mouse model for lysosomal cholesterol accumulation was created. Through injections with heat-inactivated pneumococci, we aimed to demonstrate the specific contribution of lysosomal oxLDL accumulation inside macrophages in atherosclerosis development. While there were no differences in plaque morphology, a reduction in plaque size and plaque inflammation was found in immunized NPC1 mut -transplanted mice, compared to non-immunized NPC1 mut -transplanted mice. Lysosomal oxLDL accumulation within macrophages contributes to murine atherosclerosis. Future intervention strategies should focus specifically on preventing oxLDL, unlike non-modified LDL, from being internalized into lysosomes. Such an intervention can have an additive effect to current existing treatments against atherosclerosis. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  19. Corkscrew collaterals in atherosclerosis obliterans.

    PubMed

    Fujii, Yuichi; Ueda, Tomohiro; Uchimura, Yuko; Teragawa, Hiroki

    2017-12-01

    Marked calcifications in the femoral artery obscured imaging of the artery in computed tomography (CT) and duplex ultrasonography. The presence of corkscrew collateral arteries in patients with Atherosclerosis obliterans (ASO) indicates total artery occlusion.

  20. Development of Bipolar Pulse Accelerator for Pulsed Ion Beam Implantation to Semiconductor

    NASA Astrophysics Data System (ADS)

    Masugata, Katsumi; Kawahara, Yoshihiro; Mitsui, Chihiro; Kitamura, Iwao; Takahashi, Takakazu; Tanaka, Yasunori; Tanoue, Hisao; Arai, Kazuo

    2002-12-01

    To improve the purity of the ion beams new type of pulsed power ion accelerator named "bipolar pulse accelerator" was proposed. The accelerator consists of two acceleration gaps (an ion source gap and a post acceleration gap) and a drift tube, and a bipolar pulse is applied to the drift tube to accelerate the beam. In the accelerator intended ions are selectively accelerated and the purity of the ion beam is enhanced. As the first step of the development of the accelerator, a Br-type magnetically insulated acceleration gap is developed. The gap has an ion source of coaxial gas puff plasma gun on the grounded anode and a negative pulse is applied to the cathode to accelerate the ion beam. By using the plasma gun, ion source plasma (nitrogen) of current density around 100 A/cm2 is obtained. In the paper, the experimental results of the evaluation of the ion beam and the characteristics of the gap are shown with the principle and the design concept of the proposed accelerator.

  1. Atherosclerosis induced by arsenic in drinking water in rats through altering lipid metabolism

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cheng, Tain-Junn; Department of Neurology, Chi Mei Medical Center, 901 Chung-Hwa Road, Tainan 710, Taiwan; Department of Occupational Medicine, Chi Mei Medical Center, 901 Chung-Hwa Road, Yongkang, Tainan 710, Taiwan

    2011-10-15

    Arsenic in drinking water is a global environmental health problem, and the exposure may increase cardiovascular and cerebrovascular diseases mortalities, most likely through causing atherosclerosis. However, the mechanism of atherosclerosis formation after arsenic exposure is still unclear. To study the mechanism of atherosclerosis formation after arsenic exposure and explore the role of high cholesterol diet (HCD) in this process, we fed spontaneous hypertensive rats and Wistar Kyoto rats with basal diet or HCD and provided with them drinking water containing arsenic at different ages and orders for 20 consecutive weeks. We measured high density lipoprotein cholesterol (HDL-C), low density lipoproteinmore » cholesterol (LDL-C), total cholesterol, triglycerides, heat shock protein 70 (HSP 70), and high sensitive C-reactive protein (hs-CRP) at predetermined intervals and determined expressions of cholesteryl ester transfer protein-1 (CETP-1) and liver X receptor {beta} (LXR{beta}) in the liver. Atherosclerosis was determined by examining the aorta with hematoxylin and eosin stain. After 20 weeks, we found arsenic, alone or combined with HCD, may promote atherosclerosis formation with transient increases in HSP 70 and hs-CRP. Early combination exposure decreased the HDL-C/LDL-C ratio without changing the levels of total cholesterol and triglyceride until 30 weeks old. Both CETP-1 and LXR{beta} activities were suppressed, most significantly in early combination exposure. In conclusion, arsenic exposure may induce atherosclerosis through modifying reverse cholesterol transport in cholesterol metabolism and suppressing LXR{beta} and CEPT-1 expressions. For decreasing atherosclerosis related mortality associated with arsenic, preventing exposure from environmental sources in early life is an important element. - Highlights: > Arsenic causes cardiovascular and cerebrovascular diseases through atherosclerosis. > Arsenic may promote atherosclerosis with transient

  2. Nonalcoholic fatty liver disease is an independent risk factor for atherosclerosis in young adult men.

    PubMed

    Ozturk, Kadir; Uygun, Ahmet; Guler, Ahmet Kerem; Demirci, Hakan; Ozdemir, Cafer; Cakir, Mehmet; Sakin, Yusuf Serdar; Turker, Turker; Sari, Sebahattin; Demirbas, Seref; Karslıoğlu, Yıldırım; Saglam, Mutlu

    2015-06-01

    The possible cause of accelerated atherosclerosis in NAFLD may be the relationship with the MetS and its components. Our primary goal was to evaluate the relationship between NAFLD and subclinical atherosclerosis in adult male patients between 20 and 40 years of age. Moreover, we aimed to investigate the changes in this association according to the presence or absence of MetS. Sixty-one male patients with biopsy-proven NAFLD and 41 healthy male volunteers were enrolled. In order to exclude any interference of confounding factors, we studied a specifically selected group with no additional cardiovascular risk. PWV, CIMT and FMD levels were measured in all patients and controls. The levels of cf-PWV were significantly higher in SS and NASH patients compared to the control group (P < 0.001); no significant difference was found between SS and NASH patients (P > 0.05). We found significantly decreased FMD levels in patients with SS and NASH compared with control subjects (P < 0.001). Subjects with NASH had significantly greater CIMT measurements than the SS and controls (P = 0.026, P < 0.001, respectively). Although, NAFLD patients with MetS had increased cf-PWV and CIMT and reduced FMD compared to healthy subjects (P < 0.05), no significant difference existed between NAFLD with Mets and NAFLD without MetS in terms of cf-PWV, CIMT and FMD (P > 0.05) CONCLUSION: The present study showed that the presence of NAFLD leads to increased risk of endothelial dysfunction and atherosclerosis in adult male patients, independent of MetS. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. Farnesoid-X Receptor (FXR) as a Promising Pharmaceutical Target in Atherosclerosis.

    PubMed

    Moris, Demetrios; Giaginis, Constantinos; Tsourouflis, Gerasimos; Theocharis, Stamatios

    2017-05-31

    Atherosclerosis (AS) is a major cause of death and morbidity in Western world and is strongly connected with atherogenic lipoproteins and inflammation. Bile acids (BA) act as activating signals of endogenous ligands such as Farnesoid-X receptor (FXR). Primary data indicate a potential role of FXR in AS. The therapeutic value of FXR ligands in AS is unknown. With the present review, we analyzed the efficacy of FXR agonists as a therapeutic modalities against AS. In this aspect, we performed an electronic search through Pub- Med/MEDLINE database by using the key terms: FXR*, Farnesoid X receptor*, atherosclerosis*, bile acids* and agonism*. According to our analysis, the FXR seems to be a promising therapeutic target in the atherosclerosis natural history. FXR agonism could exert protective effects in the development and evolution of AS. However, concomitant side effects such as the reduction of plasma HDL have been reported. Finally, results from undergoing clinical trials with synthetic FXR agonists will shed more light to the precise role of FXR agonism in AS treatment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis

    PubMed Central

    Luo, Yongting; Duan, Hongxia; Qian, Yining; Feng, Liqun; Wu, Zhenzhen; Wang, Fei; Feng, Jing; Yang, Dongling; Qin, Zhihai; Yan, Xiyun

    2017-01-01

    The persistence of cholesterol-engorged macrophages (foam cells) in the artery wall fuels the development of atherosclerosis. However, the mechanism that regulates the formation of macrophage foam cells and impedes their emigration out of inflamed plaques is still elusive. Here, we report that adhesion receptor CD146 controls the formation of macrophage foam cells and their retention within the plaque during atherosclerosis exacerbation. CD146 is expressed on the macrophages in human and mouse atheroma and can be upregulated by oxidized low-density lipoprotein (oxLDL). CD146 triggers macrophage activation by driving the internalization of scavenger receptor CD36 during lipid uptake. In response to oxLDL, macrophages show reduced migratory capacity toward chemokines CCL19 and CCL21; this capacity can be restored by blocking CD146. Genetic deletion of macrophagic CD146 or targeting of CD146 with an antibody result in much less complex plaques in high-fat diet-fed ApoE−/− mice by causing lipid-loaded macrophages to leave plaques. Collectively, our findings identify CD146 as a novel retention signal that traps macrophages within the artery wall, and a promising therapeutic target in atherosclerosis treatment. PMID:28084332

  5. Graduate Student Program in Materials and Engineering Research and Development for Future Accelerators

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Spentzouris, Linda

    The objective of the proposal was to develop graduate student training in materials and engineering research relevant to the development of particle accelerators. Many components used in today's accelerators or storage rings are at the limit of performance. The path forward in many cases requires the development of new materials or fabrication techniques, or a novel engineering approach. Often, accelerator-based laboratories find it difficult to get top-level engineers or materials experts with the motivation to work on these problems. The three years of funding provided by this grant was used to support development of accelerator components through a multidisciplinary approachmore » that cut across the disciplinary boundaries of accelerator physics, materials science, and surface chemistry. The following results were achieved: (1) significant scientific results on fabrication of novel photocathodes, (2) application of surface science and superconducting materials expertise to accelerator problems through faculty involvement, (3) development of instrumentation for fabrication and characterization of materials for accelerator components, (4) student involvement with problems at the interface of material science and accelerator physics.« less

  6. Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis

    PubMed Central

    Roth Flach, Rachel J.; Skoura, Athanasia; Matevossian, Anouch; Danai, Laura V.; Zheng, Wei; Cortes, Christian; Bhattacharya, Samit K.; Aouadi, Myriam; Hagan, Nana; Yawe, Joseph C.; Vangala, Pranitha; Menendez, Lorena Garcia; Cooper, Marcus P.; Fitzgibbons, Timothy P.; Buckbinder, Leonard; Czech, Michael P.

    2015-01-01

    Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe−/− mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe−/− and Ldlr−/− mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFκB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis. PMID:26688060

  7. Defining the Relationship Between Biomarkers of Oxidative and Inflammatory Stress and the Risk for Atherosclerosis in Astronauts During and After Long-Duration Spaceflight

    NASA Technical Reports Server (NTRS)

    Lee, Stuart M. C.; Westby, Christian M.; Stenger, Michael B.; Ploutz-Snyder, Robert J.; Smith, Scott M.; Platts, Steven H.

    2011-01-01

    Future human space travel will primarily consist of long-duration missions aboard the International Space Station (ISS) or exploration class missions to Mars, its moons, or nearby asteroids. These missions will expose astronauts to increased risk of oxidative and inflammatory damage primarily from radiation, but also from psychological stress, reduced physical activity, diminished nutritional status, and, in the case of extravehicular activity, hyperoxic exposure. There is evidence that increased oxidative damage and inflammation can accelerate the development of atherosclerosis. PURPOSE The purpose of this proposal is to identify biomarkers of oxidative and inflammatory stress and to correlate them to indices of atherosclerosis risk before, during, and after long-duration spaceflight. METHODS To meet the objectives of the study, we will study astronauts before, during, and up to 5 years after long-duration missions aboard ISS. Biomarkers of oxidative and inflammatory stress, some of which we have previously shown to be elevated with spaceflight, will be measured before, during, and after spaceflight. Arterial structure will be monitored using ultrasound to measure carotid intima-medial thickness before, during, and after weightlessness. Carotid intima-medial thickness has been shown to be a better indicator than Framingham Risk scores for prediction of atherosclerosis. Arterial function will be monitored using brachial flow-mediated dilation before flight and after landing. Brachial flow-mediated dilation is a good index of endothelium-dependent vasodilation, which is a sensitive predictor of atherosclerotic risk. This is the first study to propose assessing atherosclerotic risk using biochemical, structural, and functional measures before, during, and immediately after spaceflight and structural functional measures for up to 5 years after landing. EXPECTED RESULTS We hypothesize that these biomarkers of oxidative and inflammatory stress will be increased with

  8. Effect of plasma homocysteine level and urinary monomethylarsonic acid on the risk of arsenic-associated carotid atherosclerosis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wu, M.-M.; Graduate Institute of Medicine, College of Medicine, Fu-Jen Catholic University, Taipei, Taiwan; Chiou, H.-Y.

    2006-10-01

    Arsenic-contaminated well water has been shown to increase the risk of atherosclerosis. Because of involving S-adenosylmethionine, homocysteine may modify the risk by interfering with the biomethylation of ingested arsenic. In this study, we assessed the effect of plasma homocysteine level and urinary monomethylarsonic acid (MMA{sup V}) on the risk of atherosclerosis associated with arsenic. In total, 163 patients with carotid atherosclerosis and 163 controls were studied. Lifetime cumulative arsenic exposure from well water for study subjects was measured as index of arsenic exposure. Homocysteine level was determined by high-performance liquid chromatography (HPLC). Proportion of MMA{sup V} (MMA%) was calculated bymore » dividing with total arsenic species in urine, including arsenite, arsenate, MMA{sup V}, and dimethylarsinic acid (DMA{sup V}). Results of multiple linear regression analysis show a positive correlation of plasma homocysteine levels to the cumulative arsenic exposure after controlling for atherosclerosis status and nutritional factors (P < 0.05). This correlation, however, did not change substantially the effect of arsenic exposure on the risk of atherosclerosis as analyzed in a subsequent logistic regression model. Logistic regression analyses also show that elevated plasma homocysteine levels did not confer an independent risk for developing atherosclerosis in the study population. However, the risk of having atherosclerosis was increased to 5.4-fold (95% CI, 2.0-15.0) for the study subjects with high MMA% ({>=}16.5%) and high homocysteine levels ({>=}12.7 {mu}mol/l) as compared to those with low MMA% (<9.9%) and low homocysteine levels (<12.7 {mu}mol/l). Elevated homocysteinemia may exacerbate the formation of atherosclerosis related to arsenic exposure in individuals with high levels of MMA% in urine.« less

  9. Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation*

    PubMed Central

    Gregory, Jill C.; Buffa, Jennifer A.; Org, Elin; Wang, Zeneng; Levison, Bruce S.; Zhu, Weifei; Wagner, Matthew A.; Bennett, Brian J.; Li, Lin; DiDonato, Joseph A.; Lusis, Aldons J.; Hazen, Stanley L.

    2015-01-01

    Recent studies indicate both clinical and mechanistic links between atherosclerotic heart disease and intestinal microbial metabolism of certain dietary nutrients producing trimethylamine N-oxide (TMAO). Here we test the hypothesis that gut microbial transplantation can transmit choline diet-induced TMAO production and atherosclerosis susceptibility. First, a strong association was noted between atherosclerotic plaque and plasma TMAO levels in a mouse diversity panel (n = 22 strains, r = 0.38; p = 0.0001). An atherosclerosis-prone and high TMAO-producing strain, C57BL/6J, and an atherosclerosis-resistant and low TMAO-producing strain, NZW/LacJ, were selected as donors for cecal microbial transplantation into apolipoprotein e null mice in which resident intestinal microbes were first suppressed with antibiotics. Trimethylamine (TMA) and TMAO levels were initially higher in recipients on choline diet that received cecal microbes from C57BL/6J inbred mice; however, durability of choline diet-dependent differences in TMA/TMAO levels was not maintained to the end of the study. Mice receiving C57BL/6J cecal microbes demonstrated choline diet-dependent enhancement in atherosclerotic plaque burden as compared with recipients of NZW/LacJ microbes. Microbial DNA analyses in feces and cecum revealed transplantation of donor microbial community features into recipients with differences in taxa proportions between donor strains that were transmissible to recipients and that tended to show coincident proportions with TMAO levels. Proportions of specific taxa were also identified that correlated with plasma TMAO levels in donors and recipients and with atherosclerotic lesion area in recipients. Atherosclerosis susceptibility may be transmitted via transplantation of gut microbiota. Gut microbes may thus represent a novel therapeutic target for modulating atherosclerosis susceptibility. PMID:25550161

  10. Computer assessment of atherosclerosis from angiographic images

    NASA Technical Reports Server (NTRS)

    Selzer, R. H.; Blankenhorn, D. H.; Brooks, S. H.; Crawford, D. W.; Cashin, W. L.

    1982-01-01

    A computer method for detection and quantification of atherosclerosis from angiograms has been developed and used to measure lesion change in human clinical trials. The technique involves tracking the vessel edges and measuring individual lesions as well as the overall irregularity of the arterial image. Application of the technique to conventional arterial-injection femoral and coronary angiograms is outlined and an experimental study to extend the technique to analysis of intravenous angiograms of the carotid and cornary arteries is described.

  11. Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice.

    PubMed

    Steffensen, Lasse B; Conover, Cheryl A; Bjørklund, Martin M; Ledet, Thomas; Bentzon, Jacob F; Oxvig, Claus

    2016-05-01

    The metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) has been suggested as a proatherogenic molecule by its ability to locally increase insulin-like growth factor signaling. Stanniocalcin-2 (STC2) was recently discovered to be a potent inhibitor of PAPP-A activity, but has not previously been implicated in vascular disease. The aim of this study was to substantiate the interaction between PAPP-A and STC2 as a potential local regulatory mechanism in the artery wall. We found that PAPP-A is secreted from cultured primary smooth muscle cells obtained from human aortas as a covalent complex with STC2, devoid of proteolytic activity. Extracts of human carotid atherosclerotic plaques contain both complexed and uncomplexed PAPP-A, and we show by immunohistochemistry that PAPP-A and STC2 are present in the tissue throughout early human lesion development. We then used adeno-associated virus-mediated expression of STC2 to increase the fraction of PAPP-A present in the inhibited state and found that it decreased the development of atherosclerosis by 47% (P = 0.0005) in apolipoprotein E-deficient mice challenged with a Western type diet compared to controls. This study is the first to suggest the involvement of STC2 in regulating PAPP-A activity during the development of atherosclerosis. Furthermore, we demonstrate that lesion development can be inhibited in an experimental model by driving the balance towards inhibited PAPP-A. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. EXPERIMENTAL ATHEROSCLEROSIS AND BLOOD PRESSURE IN THE RABBIT

    PubMed Central

    Dominguez, R.

    1927-01-01

    1. Van Leersum's range for the normal blood pressure in the rabbit, as recorded by his method, is confirmed. 2. Van Leersum's conclusion concerning the influence of a liver diet on the blood pressure of the rabbit is not substantiated by his data, since the fluctuations of blood pressure he obtained do not surpass his own recorded figures for normal animals. 3. Fluctuations of systolic blood pressure beyond the "normal" range are not necessary for the production of experimental atherosclerosis of the aorta in rabbits. Inversely, egg yolk feeding experiments in rabbits in which atherosclerosis of varying degree, even extreme, is obtained, are not accompanied by an elevation of blood pressure outside the "normal" range. 4. The fluctuations of blood pressure observed during experimental atherosclerosis do not simulate the condition of essential hypertension in man. PMID:19869349

  13. Accelerated Leadership Development: Fast Tracking School Leaders

    ERIC Educational Resources Information Center

    Earley, Peter; Jones, Jeff

    2010-01-01

    "Accelerated Leadership Development" captures and communicates the lessons learned from successful fast-track leadership programmes in the private and public sector, and provides a model which schools can follow and customize as they plan their own leadership development strategies. As large numbers of headteachers and other senior staff…

  14. [Mechanism of Tongsaimai tablet for atherosclerosis based on network pharmacology].

    PubMed

    Li, Na; Zhang, Xin-Zhuang; Wang, Yan-Ru; Cao, Liang; Ding, Gang; Wang, Zhen-Zhong; Xiao, Wei; Xu, Xiao-Jie

    2016-05-01

    Network pharmacology method was adopted in this study to explore the active compounds and mechanism of Tongsaimai tablets for atherosclerosis. In molecular docking and molecular-target protein network analysis, 97 molecules in Tongsaimai tablets showed good interaction with the atherosclerosis-related target protein (docking score ≥ 7), and 37 molecules of them could act on more than 2 targets (≥ 2) with higher betweenness, suggesting that these 37 molecules might be the main active compounds group in Tongsaimai tablets for atherosclerosis treatment. Furthermore, the predicted active compounds contained more flavonoids and saponins, reminding more attention should be paid on flavonoids and saponins in study of effective compounds and quality standards of Tongsaimai tablets. Targets network analysis showed that, the active compounds of Tongsaimai tablets could regulate inflammation, stabilize plaque, protect vascular endothelial cell, regulate blood lipid and inhibit blood coagulation through acting on the main 22 target proteins, such as Toll-like receptors (TLR1, TLR2), matrix metalloproteinase (MMP1, MMP2, MMP3, MMP9), angiotensin converting enzyme (ACE), leukotriene A4 hydrolase (LTA4-H), 5-lipoxidase (5-LOX), peroxisome proliferators-activated receptors (PPARα, PPARγ). These active compounds can participate in regulating different pathologic stages of atherosclerosis and thus treat atherosclerosis finally. This study revealed the main active compounds and possible mechanism of Tongsaimai tablets for treatment of atherosclerosis and meanwhile, verified the characteristics of multi-components, multi-targets and integral regulation for Tongsaimai tablets, providing theoretical references for the following systematic laboratory experiments on effective compounds and action mechanism of Tongsaimai Tablet. Copyright© by the Chinese Pharmaceutical Association.

  15. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations.

    PubMed

    Thompson, Randall C; Allam, Adel H; Lombardi, Guido P; Wann, L Samuel; Sutherland, M Linda; Sutherland, James D; Soliman, Muhammad Al-Tohamy; Frohlich, Bruno; Mininberg, David T; Monge, Janet M; Vallodolid, Clide M; Cox, Samantha L; Abd el-Maksoud, Gomaa; Badr, Ibrahim; Miyamoto, Michael I; el-Halim Nur el-Din, Abd; Narula, Jagat; Finch, Caleb E; Thomas, Gregory S

    2013-04-06

    Atherosclerosis is thought to be a disease of modern human beings and related to contemporary lifestyles. However, its prevalence before the modern era is unknown. We aimed to evaluate preindustrial populations for atherosclerosis. We obtained whole body CT scans of 137 mummies from four different geographical regions or populations spanning more than 4000 years. Individuals from ancient Egypt, ancient Peru, the Ancestral Puebloans of southwest America, and the Unangan of the Aleutian Islands were imaged. Atherosclerosis was regarded as definite if a calcified plaque was seen in the wall of an artery and probable if calcifications were seen along the expected course of an artery. Probable or definite atherosclerosis was noted in 47 (34%) of 137 mummies and in all four geographical populations: 29 (38%) of 76 ancient Egyptians, 13 (25%) of 51 ancient Peruvians, two (40%) of five Ancestral Puebloans, and three (60%) of five Unangan hunter gatherers (p=NS). Atherosclerosis was present in the aorta in 28 (20%) mummies, iliac or femoral arteries in 25 (18%), popliteal or tibial arteries in 25 (18%), carotid arteries in 17 (12%), and coronary arteries in six (4%). Of the five vascular beds examined, atherosclerosis was present in one to two beds in 34 (25%) mummies, in three to four beds in 11 (8%), and in all five vascular beds in two (1%). Age at time of death was positively correlated with atherosclerosis (mean age at death was 43 [SD 10] years for mummies with atherosclerosis vs 32 [15] years for those without; p<0·0001) and with the number of arterial beds involved (mean age was 32 [SD 15] years for mummies with no atherosclerosis, 42 [10] years for those with atherosclerosis in one or two beds, and 44 [8] years for those with atherosclerosis in three to five beds; p<0·0001). Atherosclerosis was common in four preindustrial populations including preagricultural hunter-gatherers. Although commonly assumed to be a modern disease, the presence of atherosclerosis in

  16. The biology of atherosclerosis: general paradigms and distinct pathogenic mechanisms among HIV-infected patients.

    PubMed

    Lo, Janet; Plutzky, Jorge

    2012-06-01

    Complications of atherosclerosis, including myocardial infarction and stroke, are the leading cause of death and disability worldwide. Recent data strongly implicate cardiovascular death as a contributor to mortality among patients with human immunodeficiency virus (HIV) infection, with evidence suggesting increased incidence of atherosclerosis among these patients. Therefore, greater understanding of atherosclerotic mechanisms and how these responses may be similar or distinct in HIV-infected patients is needed. Key concepts in atherosclerosis are reviewed, including the evidence that inflammation and abnormal metabolism are major drivers of atherosclerosis, and connected to the current literature regarding atherosclerosis in the context of HIV.

  17. Protein kinase C isoforms in atherosclerosis: pro- or anti-inflammatory?

    PubMed

    Fan, Hueng-Chuen; Fernández-Hernando, Carlos; Lai, Jenn-Haung

    2014-03-15

    Atherosclerosis is a pathologic condition caused by chronic inflammation in response to lipid deposition in the arterial wall. There are many known contributing factors such as long-term abnormal glucose levels, smoking, hypertension, and hyperlipidemia. Under the influence of such factors, immune and non-immune effectors cells are activated and participate during the progression of atherosclerosis. Protein kinase C (PKC) family isoforms are key players in the signal transduction pathways of cellular activation and have been associated with several aspects of the atherosclerotic vascular disease. This review article summarizes the current knowledge of PKC isoforms functions during atherogenesis, and addresses differential roles and disputable observations of PKC isoforms. Among PKC isoforms, both PKCβ and PKCδ are the most attractive and potential therapeutic targets. This commentary discusses in detail the outcomes and current status of clinical trials on PKCβ and PKCδ inhibitors in atherosclerosis-associated disorders like diabetes and myocardial infarction. The risk and benefit of these inhibitors for clinical purposes will be also discussed. This review summarizes what is already being done and what else needs to be done in further targeting PKC isoforms, especially PKCβ and PKCδ, for therapy of atherosclerosis and atherosclerosis-associated vasculopathies in the future. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. The Therapeutic Potential of Anti-Inflammatory Exerkines in the Treatment of Atherosclerosis

    PubMed Central

    Yu, Megan; Tsai, Sheng-Feng; Kuo, Yu-Min

    2017-01-01

    Although many cardiovascular (CVD) medications, such as antithrombotics, statins, and antihypertensives, have been identified to treat atherosclerosis, at most, many of these therapeutic agents only delay its progression. A growing body of evidence suggests physical exercise could be implemented as a non-pharmacologic treatment due to its pro-metabolic, multisystemic, and anti-inflammatory benefits. Specifically, it has been discovered that certain anti-inflammatory peptides, metabolites, and RNA species (collectively termed “exerkines”) are released in response to exercise that could facilitate these benefits and could serve as potential therapeutic targets for atherosclerosis. However, much of the relationship between exercise and these exerkines remains unanswered, and there are several challenges in the discovery and validation of these exerkines. This review primarily highlights major anti-inflammatory exerkines that could serve as potential therapeutic targets for atherosclerosis. To provide some context and comparison for the therapeutic potential of exerkines, the anti-inflammatory, multisystemic benefits of exercise, the basic mechanisms of atherosclerosis, and the limited efficacies of current anti-inflammatory therapeutics for atherosclerosis are briefly summarized. Finally, key challenges and future directions for exploiting these exerkines in the treatment of atherosclerosis are discussed. PMID:28608819

  19. MicroRNA-30c Mimic Mitigates Hypercholesterolemia and Atherosclerosis in Mice*

    PubMed Central

    Irani, Sara; Pan, Xiaoyue; Peck, Bailey C. E.; Iqbal, Jahangir; Sethupathy, Praveen; Hussain, M. Mahmood

    2016-01-01

    High plasma cholesterol levels are a major risk factor for atherosclerosis. Plasma cholesterol can be reduced by inhibiting lipoprotein production; however, this is associated with steatosis. Previously we showed that lentivirally mediated hepatic expression of microRNA-30c (miR-30c) reduced hyperlipidemia and atherosclerosis in mice without causing hepatosteatosis. Because viral therapy would be formidable, we examined whether a miR-30c mimic can be used to mitigate hyperlipidemia and atherosclerosis without inducing steatosis. Delivery of a miR-30c mimic to the liver diminished diet-induced hypercholesterolemia in C57BL/6J mice. Reductions in plasma cholesterol levels were significantly correlated with increases in hepatic miR-30c levels. Long term dose escalation studies showed that miR-30c mimic caused sustained reductions in plasma cholesterol with no obvious side effects. Furthermore, miR-30c mimic significantly reduced hypercholesterolemia and atherosclerosis in Apoe−/− mice. Mechanistic studies showed that miR-30c mimic had no effect on LDL clearance but reduced lipoprotein production by down-regulating microsomal triglyceride transfer protein expression. MiR-30c had no effect on fatty acid oxidation but reduced lipid synthesis. Additionally, whole transcriptome analysis revealed that miR-30c mimic significantly down-regulated hepatic lipid synthesis pathways. Therefore, miR-30c lowers plasma cholesterol and mitigates atherosclerosis by reducing microsomal triglyceride transfer protein expression and lipoprotein production and avoids steatosis by diminishing lipid syntheses. It mitigates atherosclerosis most likely by reducing lipoprotein production and plasma cholesterol. These findings establish that increasing hepatic miR-30c levels is a viable treatment option for reducing hypercholesterolemia and atherosclerosis. PMID:27365390

  20. Atherosclerosis, cholesterol, nutrition, and statins – a critical review

    PubMed Central

    Gebbers, Jan-Olaf

    2007-01-01

    Atherosclerosis, which causes approximately half of all deaths of adults over age 60 in industrialized nations, is a pandemic among inappropriately nourished and/or physically hypoactive children, adolescents, and adults world wide. Although nowadays statins are widely prescribed to middle age and elderly adults with high blood lipid levels as pharmacological prevention for the late complications of atherosclerosis, from a critical point of view statins seem not to solve the problem, especially when compared with certain natural ingredients of our nutrition like micronutrients as alternative strategy. Statin ingestion is associated with lowering of serum cholesterol and low-density lipoprotein concentrations; some prospective studies have shown statistical associations with subsequent modest reduction of mortality from cardiovascular disease. However, specific biochemical pathways and pharmacological roles of statins in prevention of atherosclerosis, if any, are unknown. Moreover, there have been no systematic cost-benefit analyses of life-style prophylaxis versus statin prophylaxis versus combined life-style plus statin prophylaxis versus neither life-style nor statin prophylaxis for clinically significant complications of cardiovascular diseases in the elderly. Further, in the trials of effectiveness statins were not compared with management of nutrition, which is the most appropriate alternative intervention. Such studies seem to be important, as the ever increasing world population, especially in developing countries, now demand expensive statins, which may be unaffordable for mitigating the pandemic. Studies of this kind are necessary to identify more precisely those patients for whom cardiovascular benefits will outweigh the risks and costs of the statin treatment in comparison with nutritional interventions. Against the background of the current pathogenetic concept of atherogenesis some of its possible risk factors, particularly the roles of cholesterol and

  1. Citrullus lanatus `Sentinel' (Watermelon) Extract Reduces Atherosclerosis in LDL Receptor Deficient Mice

    PubMed Central

    Poduri, Aruna; Rateri, Debra L.; Saha, Shubin K.; Saha, Sibu; Daugherty, Alan

    2012-01-01

    Watermelon (Citrullus lanatus or C. lanatus) has many potentially bioactive compounds including citrulline, which may influence atherosclerosis. In this study, we determined the effects of C. lanatus, provided as an extract of the cultivar `sentinel', on hypercholesterolemia-induced atherosclerosis in mice. Male LDL receptor deficient mice at 8 weeks old were given either C. lanatus `sentinel' extract (2% vol/vol; n=10) or a mixture of matching carbohydrates (2% vol/vol; n=8) as the control in drinking water, while fed a saturated fat-enriched diet for 12 weeks ad libitum. Mice consuming C. lanatus `sentinel' extract had significantly increased plasma citrulline concentrations. Systolic blood pressure was comparable between the two groups. Consumption of C. lanatus `sentinel' extract led to lower body weight and fat mass without influencing lean mass. There were no differences in food and water intake, and urine output between the two groups. C. lanatus `sentinel' extract administration decreased plasma cholesterol concentrations that were attributed to reductions of intermediate/low density lipoprotein cholesterol. Plasma concentrations of MCP-1 and IFN-γ were decreased and IL-10 increased in mice consuming C. lanatus `sentinel' extract. Intake of C. lanatus `sentinel' extract resulted in reductions of atherosclerosis in both aortic arch and thoracic regions. In conclusion, consumption of C. lanatus `sentinel' extract led to reduced body weight gain, decreased plasma cholesterol concentrations, improved homeostasis of pro- and anti-inflammatory cytokines, and attenuated development of atherosclerosis without affecting systolic blood pressure in hypercholesterolemic mice. PMID:22902326

  2. Gender-Specific Association of Desacylated Ghrelin with Subclinical Atherosclerosis in the Metabolic Syndrome.

    PubMed

    Zanetti, Michela; Gortan Cappellari, Gianluca; Semolic, Annamaria; Burekovic, Ismet; Fonda, Maurizio; Cattin, Luigi; Barazzoni, Rocco

    2017-07-01

    Ghrelin, a gastric hormone with pleiotropic effects modulates vascular function and may influence atherosclerosis. Plasma ghrelin is reduced in the metabolic syndrome (MS), which is also characterized by early atherosclerosis. Ghrelin circulates in acylated (AG) and desacylated (DAG) forms. Their relative impact and that of gender on subclinical atherosclerosis in MS is unknown. To investigate potential associations of total, AG and DAG with carotid atherosclerosis and with gender in the MS. Plasma total ghrelin, AG, DAG and carotid artery IMT (cIMT) were measured in 46 MS patients (NCEP-ATP III criteria, 22M/24F). Compared with males, females had higher (p <0.05) total and DAG. In the association analysis, age and plasma glucose were positively (p <0.05) correlated with cIMT in all MS patients. The positive (p <0.05) association between cIMT and age was also confirmed in males, while that between cIMT and glucose was significant in women. In contrast, neither total ghrelin nor AG and DAG were associated with cIMT in all MS patients nor in the male subgroup. In females, a negative (p <0.05) association between carotid artery IMT, DAG and glucose was detected, but not between cIMT, total ghrelin and AG. In multivariate modeling, DAG remained negatively (p <0.05) associated with cIMT after adjusting for plasma glucose and cardiovascular risk factors. These data indicate a negative independent association between DAG and cIMT in middle-aged women with the MS and suggest a gender-specific modulatory function of DAG in the development of atherosclerosis. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.

  3. 76 FR 33305 - Medicare Program; Accelerated Development Sessions for Accountable Care Organizations-June 20, 21...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-08

    ... as accelerated development sessions (ADSs) instead of accelerated development learning sessions... Sessions'' is corrected to read ``Accelerated Development Learning Sessions''. (2) In the SUMMARY, the... first of four accelerated development learning sessions (ADLSs) that will provide executives with the...

  4. Lineage tracing of cells involved in atherosclerosis.

    PubMed

    Albarrán-Juárez, Julián; Kaur, Harmandeep; Grimm, Myriam; Offermanns, Stefan; Wettschureck, Nina

    2016-08-01

    Despite the clinical importance of atherosclerosis, the origin of cells within atherosclerotic plaques is not fully understood. Due to the lack of a definitive lineage-tracing strategy, previous studies have provided controversial results about the origin of cells expressing smooth muscle and macrophage markers in atherosclerosis. We here aim to identify the origin of vascular smooth muscle (SM) cells and macrophages within atherosclerosis lesions. We combined a genetic fate mapping approach with single cell expression analysis in a murine model of atherosclerosis. We found that 16% of CD68-positive plaque macrophage-like cells were derived from mature SM cells and not from myeloid sources, whereas 31% of αSMA-positive smooth muscle-like cells in plaques were not SM-derived. Further analysis at the single cell level showed that SM-derived CD68(+) cells expressed higher levels of inflammatory markers such as cyclooxygenase 2 (Ptgs2, p = 0.02), and vascular cell adhesion molecule (Vcam1, p = 0.05), as well as increased mRNA levels of genes related to matrix synthesis such as Col1a2 (p = 0.01) and Fn1 (p = 0.04), than non SM-derived CD68(+) cells. These results demonstrate that smooth muscle cells within atherosclerotic lesions can switch to a macrophage-like phenotype characterized by higher expression of inflammatory and synthetic markers genes that may further contribute to plaque progression. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  5. Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis.

    PubMed

    Knight, Jason S; Luo, Wei; O'Dell, Alexander A; Yalavarthi, Srilakshmi; Zhao, Wenpu; Subramanian, Venkataraman; Guo, Chiao; Grenn, Robert C; Thompson, Paul R; Eitzman, Daniel T; Kaplan, Mariana J

    2014-03-14

    Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-α-producing plasmacytoid dendritic cells in diseased arteries. Peptidylarginine deiminase inhibition is a strategy that can decrease in vivo NET formation. To test whether peptidylarginine deiminase inhibition, a novel approach to targeting arterial disease, can reduce vascular damage and inhibit innate immune responses in murine models of atherosclerosis. Apolipoprotein-E (Apoe)(-/-) mice demonstrated enhanced NET formation, developed autoantibodies to NETs, and expressed high levels of interferon-α in diseased arteries. Apoe(-/-) mice were treated for 11 weeks with daily injections of Cl-amidine, a peptidylarginine deiminase inhibitor. Peptidylarginine deiminase inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial interferon-α expression. Pharmacological interventions that block NET formation can reduce atherosclerosis burden and arterial thrombosis in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses.

  6. Raman spectroscopy imaging reveals interplay between atherosclerosis and medial calcification in the human aorta

    PubMed Central

    You, Amanda Y. F.; Bergholt, Mads S.; St-Pierre, Jean-Philippe; Kit-Anan, Worrapong; Pence, Isaac J.; Chester, Adrian H.; Yacoub, Magdi H.; Bertazzo, Sergio; Stevens, Molly M.

    2017-01-01

    Medial calcification in the human aorta accumulates during aging and is known to be aggravated in several diseases. Atherosclerosis, another major cause of cardiovascular calcification, shares some common aggravators. However, the mechanisms of cardiovascular calcification remain poorly understood. To elucidate the relationship between medial aortic calcification and atherosclerosis, we characterized the cross-sectional distributions of the predominant minerals in aortic tissue, apatite and whitlockite, and the associated extracellular matrix. We also compared the cellular changes between atherosclerotic and nonatherosclerotic human aortic tissues. This was achieved through the development of Raman spectroscopy imaging methods that adapted algorithms to distinguish between the major biomolecules present within these tissues. We present a relationship between apatite, cholesterol, and triglyceride in atherosclerosis, with the relative amount of all molecules concurrently increased in the atherosclerotic plaque. Further, the increase in apatite was disproportionately large in relation to whitlockite in the aortic media directly underlying a plaque, indicating that apatite is more pathologically significant in atherosclerosis-aggravated medial calcification. We also discovered a reduction of β-carotene in the whole aortic intima, including a plaque in atherosclerotic aortic tissues compared to nonatherosclerotic tissues. This unprecedented biomolecular characterization of the aortic tissue furthers our understanding of pathological and physiological cardiovascular calcification events in humans. PMID:29226241

  7. MAOA Genotype, Childhood Trauma and Subclinical Atherosclerosis: A Twin Study

    PubMed Central

    Zhao, Jinying; Bremner, James D.; Goldberg, Jack; Quyyumi, Arshed A.; Vaccarino, Viola

    2013-01-01

    Objective A functional promoter polymorphism in the MAOA gene has been implicated in neuropsychiatric disorders and also moderates the association between early life stress and mental disorders, which often co-occur with cardiovascular disease. No study has examined the relationship between MAOA genotype, childhood trauma and subclinical atherosclerosis. The objective of this investigation was to examine whether childhood trauma moderates the association between MAOA genotype and subclinical atherosclerosis. Methods A sample including 289 middle-aged male twin pairs was studied. Subclinical atherosclerosis was assessed by brachial flow-mediated dilation (FMD) using ultrasound. Childhood trauma, before age 18, was measured with the Early Trauma Inventory and included physical, emotional, and sexual abuse as well as general trauma. Generalized estimating equation models were used to test the main and interactive effects of the MAOA genotype and each domain of childhood trauma on FMD, adjusting for known risk factors. Results General trauma was the most prevalent childhood trauma (28.4%), followed by physical abuse (25.0%), emotional abuse (19.4%) and sexual abuse (11.6%). MAOA genotype was not associated with any domain of childhood trauma (β ≥ 0.36). There was no significant evidence for a main effect for the MAOA genotype (β = 0.02, p = 0.82) or childhood trauma (0.005 < β < 0.10, p > 0.54) on early atherosclerosis. However, a significant interaction was observed between MAOA genotype and physical (βinteraction = 0.37, p = 0.026) or emotional abuse (βinteraction = 0.43, p = 0.025) on subclinical atherosclerosis. Conclusion This study provides initial evidence that childhood trauma modulates the impact of MAOA variant on subclinical atherosclerosis, independent of traditional cardiovascular risk factors. PMID:23723362

  8. [Long non-coding RNAs in the pathophysiology of atherosclerosis].

    PubMed

    Novak, Jan; Vašků, Julie Bienertová; Souček, Miroslav

    2018-01-01

    The human genome contains about 22 000 protein-coding genes that are transcribed to an even larger amount of messenger RNAs (mRNA). Interestingly, the results of the project ENCODE from 2012 show, that despite up to 90 % of our genome being actively transcribed, protein-coding mRNAs make up only 2-3 % of the total amount of the transcribed RNA. The rest of RNA transcripts is not translated to proteins and that is why they are referred to as "non-coding RNAs". Earlier the non-coding RNA was considered "the dark matter of genome", or "the junk", whose genes has accumulated in our DNA during the course of evolution. Today we already know that non-coding RNAs fulfil a variety of regulatory functions in our body - they intervene into epigenetic processes from chromatin remodelling to histone methylation, or into the transcription process itself, or even post-transcription processes. Long non-coding RNAs (lncRNA) are one of the classes of non-coding RNAs that have more than 200 nucleotides in length (non-coding RNAs with less than 200 nucleotides in length are called small non-coding RNAs). lncRNAs represent a widely varied and large group of molecules with diverse regulatory functions. We can identify them in all thinkable cell types or tissues, or even in an extracellular space, which includes blood, specifically plasma. Their levels change during the course of organogenesis, they are specific to different tissues and their changes also occur along with the development of different illnesses, including atherosclerosis. This review article aims to present lncRNAs problematics in general and then focuses on some of their specific representatives in relation to the process of atherosclerosis (i.e. we describe lncRNA involvement in the biology of endothelial cells, vascular smooth muscle cells or immune cells), and we further describe possible clinical potential of lncRNA, whether in diagnostics or therapy of atherosclerosis and its clinical manifestations.Key words

  9. Characteristics of erythrocyte-derived microvesicles and its relation with atherosclerosis.

    PubMed

    Li, Kai-Yin; Zheng, Lei; Wang, Qian; Hu, Yan-Wei

    2016-12-01

    Microvesicles are formed under many circumstances, especially in atheromatous plaques. Erythrocyte-derived microvesicles (ErMVs) have been proved to promote atherosclerosis by promoting hypercoagulation, mediating inflammation and inducing cell adhesion. Several clinical studies have reported potential roles of ErMVs in cardiovascular disease diagnosis, but the current understanding of ErMVs remains insufficient. In this paper, we will review current research on the formation and degradation of ErMVs and the possible effects of ErMVs in atherosclerosis, discuss potential clinical applications in cardiovascular disease, and hope to raise awareness of the relation with atherosclerosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Lasting monitoring of immune state in patients with coronary atherosclerosis

    NASA Astrophysics Data System (ADS)

    Malinova, Lidia I.; Denisova, Tatyana P.; Tuchin, Valery V.

    2007-02-01

    Immune state monitoring is an expensive, invasive and sometimes difficult necessity in patients with different disorders. Immune reaction dynamics study in patients with coronary atherosclerosis provides one of the leading components to complication development, clinical course prognosis and treatment and rehabilitation tactics. We've chosen intravenous glucose injection as metabolic irritant in the following four groups of patients: men with proved coronary atherosclerosis (CA), non insulin dependent diabetes mellitus (NIDDM), men hereditary burden by CA and NIDDM and practically healthy persons with longlivers in generation. Immune state parameters such as quantity of leukocytes and lymphocytes, circulating immune complexes levels, serum immunoglobulin levels, HLA antigen markers were studied at 0, 30 and 60 minutes during glucose loading. To obtain continues time function of studied parameters received data were approximated by polynomials of high degree with after going first derivatives. Time functions analyze elucidate principally different dynamics studied parameters in all chosen groups of patients, which couldn't be obtained from discontinuous data compare. Leukocyte and lymphocyte levels dynamics correlated HLA antigen markers in all studied groups. Analytical estimation of immune state in patients with coronary atherosclerosis shows the functional "margin of safety" of immune system state under glucose disturbance. Proposed method of analytical estimation also can be used in immune system monitoring in other groups of patients.

  11. Incremental prognostic value of coronary and systemic atherosclerosis after myocardial infarction.

    PubMed

    Calais, Fredrik; Eriksson Östman, Maja; Hedberg, Pär; Rosenblad, Andreas; Leppert, Jerzy; Fröbert, Ole

    2018-06-15

    The role of systemic atherosclerosis in myocardial infarction (MI) patients is not fully understood. We investigated the incremental prognostic value of coronary and systemic atherosclerosis after acute MI by estimating extra-cardiac artery disease (ECAD) and extent of coronary atherosclerosis. The study included 544 prospective MI patients undergoing coronary angiography. For all patients, the longitudinal coronary atherosclerotic extent, expressed as Sullivan extent score (SES) was calculated. In addition, the patients underwent non-invasive screening for ECAD in the carotid, aortic, renal and lower limb. SES was found to be associated with ECAD independent of baseline clinical parameters [adjusted odds ratio (OR) 1.04 95% confidence interval (CI) 1.02-1.06, P < 0.001]. Extensive systemic atherosclerosis, defined as the combination of extensive coronary disease (SES ≥ 17) and ECAD, was associated with higher risk for all-cause mortality compared to limited systemic atherosclerosis (SES < 17 and no ECAD) (hazard ratio [HR] 2.9 95% CI 1.9-4.5, P < 0.001, adjusted for Global Registry of Acute Coronary Events risk score parameters 1.8, 95% CI 1.1-3.0, P = 0.019). The risk for the composite endpoint of cardiovascular death or hospitalization was significantly higher in patients with extensive systemic atherosclerosis compared to patients with limited systemic atherosclerosis (HR 3.1, 95% CI 2.1-4.7, P < 0.001, adjusted HR 1.9, 95% CI 1.2-3.1, P < 0.004). Visual estimation of the longitudinal coronary atherosclerotic extent at the time of MI predicts ECAD. Coexistence of extensive coronary disease and ECAD defines a group with particularly poor prognosis after MI. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  12. MicroRNA-30c Mimic Mitigates Hypercholesterolemia and Atherosclerosis in Mice.

    PubMed

    Irani, Sara; Pan, Xiaoyue; Peck, Bailey C E; Iqbal, Jahangir; Sethupathy, Praveen; Hussain, M Mahmood

    2016-08-26

    High plasma cholesterol levels are a major risk factor for atherosclerosis. Plasma cholesterol can be reduced by inhibiting lipoprotein production; however, this is associated with steatosis. Previously we showed that lentivirally mediated hepatic expression of microRNA-30c (miR-30c) reduced hyperlipidemia and atherosclerosis in mice without causing hepatosteatosis. Because viral therapy would be formidable, we examined whether a miR-30c mimic can be used to mitigate hyperlipidemia and atherosclerosis without inducing steatosis. Delivery of a miR-30c mimic to the liver diminished diet-induced hypercholesterolemia in C57BL/6J mice. Reductions in plasma cholesterol levels were significantly correlated with increases in hepatic miR-30c levels. Long term dose escalation studies showed that miR-30c mimic caused sustained reductions in plasma cholesterol with no obvious side effects. Furthermore, miR-30c mimic significantly reduced hypercholesterolemia and atherosclerosis in Apoe(-/-) mice. Mechanistic studies showed that miR-30c mimic had no effect on LDL clearance but reduced lipoprotein production by down-regulating microsomal triglyceride transfer protein expression. MiR-30c had no effect on fatty acid oxidation but reduced lipid synthesis. Additionally, whole transcriptome analysis revealed that miR-30c mimic significantly down-regulated hepatic lipid synthesis pathways. Therefore, miR-30c lowers plasma cholesterol and mitigates atherosclerosis by reducing microsomal triglyceride transfer protein expression and lipoprotein production and avoids steatosis by diminishing lipid syntheses. It mitigates atherosclerosis most likely by reducing lipoprotein production and plasma cholesterol. These findings establish that increasing hepatic miR-30c levels is a viable treatment option for reducing hypercholesterolemia and atherosclerosis. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Mice deficient in PKCbeta and apolipoprotein E display decreased atherosclerosis.

    PubMed

    Harja, Evis; Chang, Jong Sun; Lu, Yan; Leitges, Michael; Zou, Yu Shan; Schmidt, Ann Marie; Yan, Shi-Fang

    2009-04-01

    Endothelial activation is a central initiating event in atheroma formation. Evidence from our laboratory and others has demonstrated links between activation of early growth response-1 (Egr-1) and atherosclerosis and also has demonstrated that activated protein kinase C (PKC) betaII is a critical upstream regulator of Egr-1 in response to vascular stress. We tested the role of PKCbeta in regulating key events linked to atherosclerosis and show that the aortas of apoE(-/-) mice display an age-dependent increase in PKCbetaII antigen in membranous fractions vs. C57BL/6 animals with a approximately 2-fold increase at age 6 wk and a approximately 4.5-fold increase at age 24 wk. Consistent with important roles for PKCbeta in atherosclerosis, a significant decrease in atherosclerotic lesion area was evident in PKCbeta(-/-)/apoE(-/-) vs. apoE(-/-) mice by approximately 5-fold, in parallel with significantly reduced vascular transcripts for Egr-1 and matrix metalloproteinase (MMP)-2 antigen and activity vs. apoE(-/-) mice. Significant reduction in atherosclerosis of approximately 2-fold was observed in apoE(-/-) mice fed ruboxistaurin chow (PKCbeta inhibitor) vs. vehicle. In primary murine and human aortic endothelial cells, the PKCbeta-JNK mitogen-activated protein kinase pathway importantly contributes to oxLDL-mediated induction of MMP2 expression. Blockade of PKCbeta may be beneficial in mitigating endothelial perturbation and atherosclerosis.

  14. Effects of stress reduction on carotid atherosclerosis in hypertensive African Americans.

    PubMed

    Castillo-Richmond, A; Schneider, R H; Alexander, C N; Cook, R; Myers, H; Nidich, S; Haney, C; Rainforth, M; Salerno, J

    2000-03-01

    African Americans suffer disproportionately higher cardiovascular disease mortality rates than do whites. Psychosocial stress influences the development and progression of atherosclerosis. Carotid intima-media thickness (IMT) is a valid surrogate measure for coronary atherosclerosis, is a predictor of coronary outcomes and stroke, and is associated with psychosocial stress factors. Stress reduction with the Transcendental Meditation (TM) program decreases coronary heart disease risk factors and cardiovascular mortality in African Americans. B-mode ultrasound is useful for the noninvasive evaluation of carotid atherosclerosis. This randomized controlled clinical trial evaluated the effects of the TM program on carotid IMT in hypertensive African American men and women, aged >20 years, over a 6- to 9-month period. From the initially enrolled 138 volunteers, 60 subjects completed pretest and posttest carotid IMT data. The assigned interventions were either the TM program or a health education group. By use of B-mode ultrasound, mean maximum IMT from 6 carotid segments was used to determine pretest and posttest IMT values. Regression analysis and ANCOVA were performed. Age and pretest IMT were found to be predictors of posttest IMT values and were used as covariates. The TM group showed a significant decrease of -0.098 mm (95% CI -0. 198 to 0.003 mm) compared with an increase of 0.054 mm (95% CI -0.05 to 0.158 mm) in the control group (P=0.038, 2-tailed). Stress reduction with the TM program is associated with reduced carotid atherosclerosis compared with health education in hypertensive African Americans. Further research with this stress-reduction technique is warranted to confirm these preliminary findings.

  15. Innate lymphoid cells in atherosclerosis.

    PubMed

    Engelbertsen, Daniel; Lichtman, Andrew H

    2017-12-05

    The family of innate lymphoid cells (ILCs) consisting of NK cells, lymphoid tissue inducer cells and the 'helper'-like ILC subsets ILC1, ILC2 and ILC3 have been shown to have important roles in protection against microbes, regulation of inflammatory diseases and involved in allergic reactions. ILC1s produce IFN-γ upon stimulation with IL-12 and IL-18, ILC2s produce IL-5 and IL-13 responding to IL-33 and IL-25 while ILC3s produce IL-17 and IL-22 after stimulation with IL-23 or IL-1. Although few studies have directly investigated the role for ILCs in atherosclerosis, several studies have investigated transcription factors and cytokines shared by ILCs and T helper cells. In this review we summarize our current understanding of the role of ILC in atherosclerosis and discuss future directions. Copyright © 2017. Published by Elsevier B.V.

  16. Multiple roles of connexins in atherosclerosis- and restenosis-induced vascular remodelling.

    PubMed

    Morel, Sandrine

    2014-01-01

    Endothelial dysfunction is the initial step in atherosclerotic plaque development in large- and medium-sized arteries. This progressive disease, which starts during childhood, is characterized by the accumulation of lipids, macrophages, neutrophils, T lymphocytes and smooth muscle cells in the intima of the vessels. Erosion and rupture of the atherosclerotic plaque may induce myocardial infarction and cerebrovascular accidents, which are responsible for a large percentage of sudden deaths. The most common treatment for atherosclerosis is angioplasty and stent implantation, but these surgical interventions favour a vascular reaction called restenosis and the associated de-endothelialization increases the risk of thrombosis. This review provides an overview of the role of connexins, a large family of transmembrane proteins, in vascular remodelling associated with atherosclerosis and restenosis. The connexins expressed in the vascular wall are Cx37, Cx40, Cx43 and Cx45; their expressions vary with vascular territory and species. Connexins form hemichannels or gap junction channels, allowing the exchange of ions and small metabolites between the cytosol and extracellular space or between neighbouring cells, respectively. Connexins have important roles in vascular physiology; they support radial and longitudinal cell-to-cell communication in the vascular wall, and significant changes in their expression patterns have been described during atherosclerosis and restenosis.

  17. An alternative method for quantifying coronary artery calcification: the multi-ethnic study of atherosclerosis (MESA).

    PubMed

    Liang, C Jason; Budoff, Matthew J; Kaufman, Joel D; Kronmal, Richard A; Brown, Elizabeth R

    2012-07-02

    Extent of atherosclerosis measured by amount of coronary artery calcium (CAC) in computed tomography (CT) has been traditionally assessed using thresholded scoring methods, such as the Agatston score (AS). These thresholded scores have value in clinical prediction, but important information might exist below the threshold, which would have important advantages for understanding genetic, environmental, and other risk factors in atherosclerosis. We developed a semi-automated threshold-free scoring method, the spatially weighted calcium score (SWCS) for CAC in the Multi-Ethnic Study of Atherosclerosis (MESA). Chest CT scans were obtained from 6814 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The SWCS and the AS were calculated for each of the scans. Cox proportional hazards models and linear regression models were used to evaluate the associations of the scores with CHD events and CHD risk factors. CHD risk factors were summarized using a linear predictor. Among all participants and participants with AS > 0, the SWCS and AS both showed similar strongly significant associations with CHD events (hazard ratios, 1.23 and 1.19 per doubling of SWCS and AS; 95% CI, 1.16 to 1.30 and 1.14 to 1.26) and CHD risk factors (slopes, 0.178 and 0.164; 95% CI, 0.162 to 0.195 and 0.149 to 0.179). Even among participants with AS = 0, an increase in the SWCS was still significantly associated with established CHD risk factors (slope, 0.181; 95% CI, 0.138 to 0.224). The SWCS appeared to be predictive of CHD events even in participants with AS = 0, though those events were rare as expected. The SWCS provides a valid, continuous measure of CAC suitable for quantifying the extent of atherosclerosis without a threshold, which will be useful for examining novel genetic and environmental risk factors for atherosclerosis.

  18. Accelerating Adverse Outcome Pathway Development Using ...

    EPA Pesticide Factsheets

    The adverse outcome pathway (AOP) concept links molecular perturbations with organism and population-level outcomes to support high-throughput toxicity testing. International efforts are underway to define AOPs and store the information supporting these AOPs in a central knowledgebase, however, this process is currently labor-intensive and time-consuming. Publicly available data sources provide a wealth of information that could be used to define computationally-predicted AOPs (cpAOPs), which could serve as a basis for creating expert-derived AOPs in a much more efficient way. Computational tools for mining large datasets provide the means for extracting and organizing the information captured in these public data sources. Using cpAOPs as a starting point for expert-derived AOPs should accelerate AOP development. Coupling this with tools to coordinate and facilitate the expert development efforts will increase the number and quality of AOPs produced, which should play a key role in advancing the adoption of twenty-first century toxicity testing strategies. This review article describes how effective knowledge management and automated approaches to AOP development can enhance and accelerate the development and use of AOPs. As the principles documented in this review are put into practice, we anticipate that the quality and quantity of AOPs available will increase substantially. This, in turn, will aid in the interpretation of ToxCast and other high-throughput tox

  19. Epicardial fat is associated with severity of subclinical coronary atherosclerosis in familial hypercholesterolemia.

    PubMed

    Mangili, Leonardo C; Mangili, Otavio C; Bittencourt, Márcio S; Miname, Márcio H; Harada, Paulo H; Lima, Leonardo M; Rochitte, Carlos E; Santos, Raul D

    2016-11-01

    Familial hypercholesterolemia (FH) is a common genetic disorder characterized by elevated blood cholesterol, increased prevalence of subclinical atherosclerosis and high risk of premature coronary heart disease. However, this risk is not explained solely by elevated LDL-cholesterol concentrations, and other factors may influence atherosclerosis development. There is evidence that increased adiposity may predispose to atherosclerosis in FH. Epicardial fat has been associated with subclinical coronary atherosclerosis in the general population. This study evaluated the association of epicardial fat (EFV) volume with the presence and extent of subclinical coronary atherosclerosis detected by computed tomography angiography in FH patients. Ninety-seven FH subjects (35% male, mean age 45 ± 13 years, LDL-C 281 ± 56 mg/dL, 67% with proven molecular defects) underwent computed tomography angiography and coronary artery calcium (CAC) scoring. EFV was measured in non-contrast images using a semi-automated method. Segment-stenosis score (SSS) and segment-involvement score (SIS) were calculated. Multivariate Poisson regression was utilized to assess an independent association of EFV with coronary atherosclerotic burden. EFV was positively associated with age, body mass index, waist circumference, blood glucose, the presence of the metabolic syndrome components, but not with LDL-C. After adjusting for confounders and abdominal circumference, an independent association (shown as β coefficients and 95% confidence intervals) of EVF with CAC scores [β = 0.263 (0.234; 0.292), p=0.000], SIS [β = 0.304 (0.141; 0.465) p=0.000] and SSS [β = 0.296 (0.121; 0.471), p=0.001] was found. In FH, EFV was independently associated with coronary atherosclerotic presence and severity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Cell signaling by reactive nitrogen and oxygen species in atherosclerosis

    NASA Technical Reports Server (NTRS)

    Patel, R. P.; Moellering, D.; Murphy-Ullrich, J.; Jo, H.; Beckman, J. S.; Darley-Usmar, V. M.

    2000-01-01

    The production of reactive oxygen and nitrogen species has been implicated in atherosclerosis principally as means of damaging low-density lipoprotein that in turn initiates the accumulation of cholesterol in macrophages. The diversity of novel oxidative modifications to lipids and proteins recently identified in atherosclerotic lesions has revealed surprising complexity in the mechanisms of oxidative damage and their potential role in atherosclerosis. Oxidative or nitrosative stress does not completely consume intracellular antioxidants leading to cell death as previously thought. Rather, oxidative and nitrosative stress have a more subtle impact on the atherogenic process by modulating intracellular signaling pathways in vascular tissues to affect inflammatory cell adhesion, migration, proliferation, and differentiation. Furthermore, cellular responses can affect the production of nitric oxide, which in turn can strongly influence the nature of oxidative modifications occurring in atherosclerosis. The dynamic interactions between endogenous low concentrations of oxidants or reactive nitrogen species with intracellular signaling pathways may have a general role in processes affecting wound healing to apoptosis, which can provide novel insights into the pathogenesis of atherosclerosis.

  1. Citrullus lanatus 'sentinel' (watermelon) extract reduces atherosclerosis in LDL receptor-deficient mice.

    PubMed

    Poduri, Aruna; Rateri, Debra L; Saha, Shubin K; Saha, Sibu; Daugherty, Alan

    2013-05-01

    Watermelon (Citrullus lanatus or C. lanatus) has many potentially bioactive compounds including citrulline, which may influence atherosclerosis. In this study, we determined the effects of C. lanatus, provided as an extract of the cultivar 'sentinel,' on hypercholesterolemia-induced atherosclerosis in mice. Male low-density lipoprotein receptor-deficient mice at 8 weeks old were given either C. lanatus 'sentinel' extract (2% vol/vol; n=10) or a mixture of matching carbohydrates (2% vol/vol; n=8) as the control in drinking water while being fed a saturated fat-enriched diet for 12 weeks ad libitum. Mice consuming C. lanatus 'sentinel' extract had significantly increased plasma citrulline concentrations. Systolic blood pressure was comparable between the two groups. Consumption of C. lanatus 'sentinel' extract led to lower body weight and fat mass without influencing lean mass. There were no differences in food and water intake and in urine output between the two groups. C. lanatus 'sentinel' extract administration decreased plasma cholesterol concentrations that were attributed to reductions of intermediate-/low-density lipoprotein cholesterol. Plasma concentrations of monocyte chemoattractant protein-1 and interferon-gamma were decreased and those of interleukin-10 were increased in mice consuming C. lanatus 'sentinel' extract. Intake of C. lanatus 'sentinel' extract resulted in reductions of atherosclerosis in both aortic arch and thoracic regions. In conclusion, consumption of C. lanatus 'sentinel' extract led to reduced body weight gain, decreased plasma cholesterol concentrations, improved homeostasis of pro- and anti-inflammatory cytokines, and attenuated development of atherosclerosis without affecting systolic blood pressure in hypercholesterolemic mice. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Race-Specific Associations of Myeloperoxidase with Atherosclerosis in a Population-Based Sample: The Dallas Heart Study

    PubMed Central

    Chen, Lu; Rohatgi, Anand; Ayers, Colby R.; Das, Sandeep R.; Khera, Amit; Berry, Jarett D.; McGuire, Darren K.; de Lemos, James A.

    2011-01-01

    Objective Myeloperoxidase (MPO) is a leukocyte-derived enzyme that appears to be directly involved in atherosclerosis development. We evaluated the association of circulating MPO with coronary and aortic atherosclerosis in a large, multiethnic population. Methods and Results Plasma levels of MPO were measured in 3294 subjects participating in the Dallas Heart Study, a probability-based population sample. Coronary artery calcification (CAC) was measured by EBCT, and abdominal aorta plaque prevalence (AP) and burden (APB), as well as abdominal aorta wall thickness (AWT) were determined by MRI. Associations between MPO and atherosclerosis phenotypes were assessed in multivariable analyses adjusting for traditional atherosclerosis risk factors. MPO levels in the 4th compared with 1st quartile independently associated with prevalent AP (OR 1.41, 95% CI 1.08–1.84), APB (beta coefficient 0.23, p=0.02), and AWT (beta coefficient 0.04, p=0.03), but not with prevalent CAC (OR 0.84, 95% CI 0.61–1.17). MPO remained associated with aortic atherosclerosis phenotypes but not coronary calcification after adjustment for other inflammatory biomarkers. A significant interaction was observed between race/ethnicity, MPO and AP (pinteraction=0.038), such that MPO levels in the 4th vs 1st quartile associated with prevalent AP in African Americans, (OR 1.81, 95% CI 1.23–2.65) but not in White or Hispanic participants (OR 0.99, 95% CI 0.68–1.44). Conclusion Higher levels of MPO associated with aortic but not coronary atherosclerosis, with significant associations limited to African American participants. These findings suggest that MPO might be a novel risk factor contributing to racial disparities in peripheral vascular disease. PMID:21917261

  3. Factors Significantly Associated With the Increased Prevalence of Carotid Atherosclerosis in a Northeast Chinese Middle-aged and Elderly Population: A Cross-sectional Study.

    PubMed

    Pan, Xi-Feng; Lai, Ya-Xin; Gu, Jian-Qiu; Wang, Hao-Yu; Liu, Ai-Hua; Shan, Zhong-Yan

    2016-04-01

    Carotid atherosclerosis is associated with many serious cardiovascular diseases; hence, it is necessary to identify factors related to its occurrence in order to develop preventive and therapeutic strategies. This study was conducted to identify risk factors associated with carotid atherosclerosis among the population residing in Northeast China.This epidemiological survey was conducted in a representative group of relatively healthy community residents. All participants answered questions about their medical histories and underwent physical examination, blood biochemical analysis, and ultrasonography examinations of their necks and abdomens. The prevalence rates of carotid atherosclerosis under different factors and conditions were then analyzed.The results of this study showed that age, gender, and diabetes significantly affected the prevalence of carotid atherosclerosis in this Northeast Chinese population. In addition, gender-based subgroup analysis revealed additional factors correlated with the prevalence of carotid atherosclerosis in men or women, although their correlations were not significant in the overall population. While high serum TC and LDL-C levels were risk factors for carotid atherosclerosis in men, it showed no clear correlation with the prevalence of carotid atherosclerosis in women. In contrast, the prevalence of carotid atherosclerosis in female participants with high serum TG level, hypertension, obesity and nonalcoholic fatty liver disease were higher than that of the control population, a trend not observed in male participants.Older age, male sex, and diabetes were independently associated with increased risk of carotid atherosclerosis in Northeast China. These findings could lead to improved screening for carotid atherosclerosis for better disease management.

  4. Plasma Cholesterol–Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis

    PubMed Central

    Björkegren, Johan L. M.; Hägg, Sara; Jain, Rajeev K.; Cedergren, Cecilia; Shang, Ming-Mei; Rossignoli, Aránzazu; Takolander, Rabbe; Melander, Olle; Hamsten, Anders; Michoel, Tom; Skogsberg, Josefin

    2014-01-01

    Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr−/−Apob 100/100 Mttp flox/floxMx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions. PMID:24586211

  5. Experimental diet-induced atherosclerosis in Quaker parrots (Myiopsitta monachus).

    PubMed

    Beaufrère, H; Nevarez, J G; Wakamatsu, N; Clubb, S; Cray, C; Tully, T N

    2013-11-01

    Spontaneous atherosclerosis is common in psittaciformes, and clinical signs associated with flow-limiting stenosis are encountered in pet birds. Nevertheless, a psittacine model of atherosclerosis has not been developed for research investigations. Sixteen captive-bred Quaker parrots (Myiopsitta monachus) were used in this study. While 4 control birds were fed a maintenance diet, 12 other birds were fed an atherogenic diet composed of 1% cholesterol controlling for a calorie-to-protein ratio for periods ranging from 2 to 8 months. The birds were euthanized at the end of their respective food trial period. Histopathology, transmission electron microscopy, and cholesterol measurement were performed on the ascending aorta and brachiocephalic and pulmonary arteries. Plasma lipoproteins, cholesterol, and triglycerides were also measured on a monthly basis. Significant atherosclerotic lesions were induced within 2 months and advanced atherosclerotic lesions within 4 to 6 months. The advanced lesions were histologically similar to naturally occurring lesions identified in the same parrot species with a lipid core and a fibrous cap. Ultrastructurally, there were extracellular lipid, foam cell, and endothelial changes. Arterial cholesterol content increased linearly over time. Plasma cholesterol and low-density lipoprotein (LDL) significantly increased over time by an average of 5- and 15-fold, respectively, with a shift from high-density lipoprotein to LDL as the main plasma lipoprotein. Quaker parrots also exhibited high plasma cholesteryl ester transfer protein activity that increased, although not significantly, over time. This experiment demonstrates that in Quaker parrots fed 1% cholesterol, advanced atherosclerosis can be induced relatively quickly, and lesions resemble those found in other avian models and humans.

  6. Development of wide area environment accelerator operation and diagnostics method

    NASA Astrophysics Data System (ADS)

    Uchiyama, Akito; Furukawa, Kazuro

    2015-08-01

    Remote operation and diagnostic systems for particle accelerators have been developed for beam operation and maintenance in various situations. Even though fully remote experiments are not necessary, the remote diagnosis and maintenance of the accelerator is required. Considering remote-operation operator interfaces (OPIs), the use of standard protocols such as the hypertext transfer protocol (HTTP) is advantageous, because system-dependent protocols are unnecessary between the remote client and the on-site server. Here, we have developed a client system based on WebSocket, which is a new protocol provided by the Internet Engineering Task Force for Web-based systems, as a next-generation Web-based OPI using the Experimental Physics and Industrial Control System Channel Access protocol. As a result of this implementation, WebSocket-based client systems have become available for remote operation. Also, as regards practical application, the remote operation of an accelerator via a wide area network (WAN) faces a number of challenges, e.g., the accelerator has both experimental device and radiation generator characteristics. Any error in remote control system operation could result in an immediate breakdown. Therefore, we propose the implementation of an operator intervention system for remote accelerator diagnostics and support that can obviate any differences between the local control room and remote locations. Here, remote-operation Web-based OPIs, which resolve security issues, are developed.

  7. CXCR4 blockade induces atherosclerosis by affecting neutrophil function

    PubMed Central

    Bot, Ilze; Daissormont, Isabelle T.M.N.; Zernecke, Alma; van Puijvelde, Gijs H.M.; Kramp, Birgit; de Jager, Saskia C.A.; Sluimer, Judith C.; Manca, Marco; Hérias, Veronica; Westra, Marijke M.; Bot, Martine; van Santbrink, Peter J.; van Berkel, Theo J.C.; Su, Lishan; Skjelland, Mona; Gullestad, Lars; Kuiper, Johan; Halvorsen, Bente; Aukrust, Paul; Koenen, Rory R.; Weber, Christian; Biessen, Erik A.L.

    2015-01-01

    Aims The SDF-1α/CXCR4 dyad was previously shown by us and others to be instrumental in intimal hyperplasia as well as early stage atherosclerosis. We here sought to investigate its impact on clinically relevant stages of atherosclerosis in mouse and man. Methods and results Immunohistochemical analysis of CXCR4 expression in human atherosclerotic lesions revealed a progressive accumulation of CXCR4+ cells during plaque progression. To address causal involvement of CXCR4 in advanced stages of atherosclerosis we reconstituted LDLr−/− mice with autologous bone marrow infected with lentivirus encoding SDF-1α antagonist or CXCR4 degrakine, which effects proteasomal degradation of CXCR4. Functional CXCR4 blockade led to progressive plaque expansion with disease progression, while also promoting intraplaque haemorrhage. Moreover, CXCR4 knockdown was seen to augment endothelial adhesion of neutrophils. Concordant with this finding, inhibition of CXCR4 function increased adhesive capacity and reduced apoptosis of neutrophils and resulted in hyperactivation of circulating neutrophils. Compatible with a role of the neutrophil CXCR4 in end-stage atherosclerosis, CXCR4 expression by circulating neutrophils was lowered in patients with acute cardiovascular syndromes. Conclusion In conclusion, CXCR4 contributes to later stages of plaque progression by perturbing neutrophil function. PMID:24816217

  8. Genomic Analysis of Circulating Cells: A Window into Atherosclerosis

    PubMed Central

    Kang, Ju-Gyeong; Patino, Willmar D.; Matoba, Satoaki; Hwang, Paul M.

    2006-01-01

    Translational studies using genomic techniques in cardiovascular diseases are still in their infancy. Access to disease-associated cardiovascular tissues from patients has been a major impediment to progress in contrast to the diagnostic advances made by oncologists using gene expression on readily available tumor samples. Nonetheless, progress is being made for atherosclerosis by carefully designed experiments using diseased tissue or surrogate specimens. This review details the rationale and findings of a study using freshly isolated blood mononuclear cells from patients undergoing carotid endarterectomy due to atherosclerotic stenosis and from matched normal subjects. Using this cardiovascular tissue surrogate, the mRNA levels of the Finkel-Biskis-Jinkins osteosarcoma (FOS) gene in circulating monocytes were found to correlate with atherosclerosis severity in patients, and with HMG CoA reductase inhibitor (statin) therapy in normal subjects. The major finding of this investigation is discussed in relation to observations from other human atherosclerosis gene expression studies. These distinct studies converge to demonstrate the unequivocal importance of inflammation in atherosclerosis. Although the clinical utility of the specific findings remains open, the identification of similar genes by different investigations serves to validate their reports. They also provide us with insights into pathogenesis that may impact future translational applications. PMID:16781950

  9. Inhibition of leukocyte-type 12-lipoxygenase by guava tea leaves prevents development of atherosclerosis.

    PubMed

    Takahashi, Yoshitaka; Otsuki, Akemi; Mori, Yoshiko; Kawakami, Yuki; Ito, Hideyuki

    2015-11-01

    Oxidation of low-density lipoprotein (LDL) is one of the crucial steps for atherosclerosis development, and an essential role of leukocyte-type 12-lipoxygenase expressed in macrophages in this process has been demonstrated. The biochemical mechanism of the oxidation of circulating LDL by leukocyte-type 12-lipoxygenase in macrophages has been proposed. The major ingredients in guava tea leaves which inhibited the catalytic activity of leukocyte-type 12-lipoxygenase were quercetin and ethyl gallate. Administration of extracts from guava tea leaves to apoE-deficient mice significantly attenuated atherogenic lesions in the aorta and aortic sinus. We recently showed that Qing Shan Lu Shui inhibited the catalytic activity of leukocyte-type 12-lipoxygenase. The major components inhibiting the enzyme contained in Qing Shan Lu Shui were identified to be novel monoterpene glycosides. The anti-atherogenic effect of the tea leaves might be attributed to the inhibition of leukocyte-type 12-lipoxygenase by these components. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. The impact of atherosclerosis and vascular collagen on energy-based vessel sealing.

    PubMed

    Martin, Kimberly; Krugman, Kimberly; Latimer, Cassandra; Moore, Camille

    2013-12-01

    Bipolar energy ligation of vessels in surgery is common. Although rare, serious failures occur. Atherosclerosis may contribute to seal failures by altering vascular compressibility and collagen content; however, no data exist. Femoral and iliac arteries of six Yucatan swine with an identified genetic locus predisposing them to atherosclerosis were denuded with a Fogarty catheter. Animals were fed a high-fat diet for 28 wk. A Yorkshire pig was used as a normal control and fed a standard diet. At 28 wk, arteries were measured for their diameters, sealed, and divided in vivo with LigaSure. The sealed artery sections were excised and subjected to burst pressure testing. Half of the seal distal to the aorta was kept intact for histology and collagen and elastin quantification. A multiple linear regression model was used to assess variables contributing to burst pressure. Covariates included were vessel diameter, degree of atherosclerosis, and collagen content. Experimental animals were hypercholesterolemic. Atherosclerosis occurred in 90% of seals in induced animals, with severe atherosclerosis in 62% of seals. There was site-selective deposition of atherosclerotic plaques in larger diameter iliac vessels. A model including collagen and size best predicted burst pressure. Every 10-U increase in collagen resulted in 15% increase in burst pressure (95% confidence interval = 0.2%-32%, P = 0.047, R(2) = 0.36). Atherosclerosis was unrelated to burst pressure controlling for collagen and size. Collagen and size provide the best model fit for predicting burst pressure. Quantitative research in human vasculature is warranted to better understand the influence of atherosclerosis and collagen content on seal failures. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Predictive value of apolipoprotein for coronary atherosclerosis in asymptomatic non-diabetic population.

    PubMed

    Song, Xiang; Tian, Shu-ping; Ju, Hai-yue; Zhang, Fan; Li, Ying-na; Wu, Fang; Yang, Li

    2015-02-01

    To explore the potential correlation between apolipoprotein (Apo) levels and coronary atherosclerosis and investigate its predictive value for coronary artery lesions in asymptomatic population without diabetes. We performed a retrospective analysis of data collected from 401 asymptomatic patients who took health check-ups. They were divided into atherosclerosis group (n=224)and control group (n=177) based on the outcome of CT angiography and blood biochemical findings. The risk factors, lipid profiles, and Apo levels were compared between these two groups. The best biochemical indicators for predicting the coronary atherosclerosis were explored. The levels of ApoB, ApoC2,ApoC3,and ApoE and ApoB/ApoA1 ratio were significantly higher in the atherosclerosis group than in the control group (all P<0.01), whereas the ApoA1,ApoA2, and lipoprotein a levels showed no such significant difference (all P>0.05). Logistic regression analysis revealed that age, male, hypertension,ApoC3(OR=1.572,95%CI 1.200-2.061) and ApoB/ApoA1 ratio (OR=1.767,95% CI 1.335-2.338) were independently correlated with coronary atherosclerosis (all P<0.01). In the prediction of the presence of plaque, ApoB had the largest area under curves, and the optimal cutoff point was 1.005 g/L. ApoC3 is closely associated with subclinical coronary atherosclerosis,while the decrease of ApoA1 level is not obvious during this period. Compared with other lipid indicators, ApoB is the strongest predictor for coronary atherosclerosis in asymptomatic non-diabetic population.

  12. Effect of atherosclerosis on endothelium-dependent inhibition of platelet activation in humans.

    PubMed

    Diodati, J G; Dakak, N; Gilligan, D M; Quyyumi, A A

    1998-07-07

    We investigated whether luminal release of nitric oxide (NO) contributes to inhibition of platelet activation and whether these effects are reduced in patients with atherosclerosis. Femoral blood flow velocity and ex vivo whole blood platelet aggregation by impedance aggregometry were measured in femoral venous blood during femoral arterial infusion of acetylcholine (ACh; 30 microg/min) in 30 patients, 19 of whom had angiographic atherosclerosis. Measurements were repeated with sodium nitroprusside (40 microg/min), L-arginine (160 micromol/min), and N(G)-monomethyl-L-arginine (L-NMMA; 16 micromol/min). There was significant inhibition of collagen-induced platelet aggregation with ACh (45+/-9.5% lower, P<0.001), and this inhibition was greater in patients without atherosclerosis (68.7+/-10.4% reduction) than in those with atherosclerosis (32.5+/-8.1%, P=0.04). The magnitude of inhibition correlated with vasodilation with ACh, indicating an association between the smooth muscle and antiplatelet effects of endothelium-dependent stimulation. Neither L-NMMA nor sodium nitroprusside altered platelet aggregation. L-Arginine inhibited platelet aggregation equally in vitro (34+/-8% reduction, P<0.01) and in vivo (37+/-13% reduction, P<0.01). Stimulation of NO release into the vascular lumen with ACh inhibits platelet aggregation, an effect that is attenuated in patients with atherosclerosis and endothelial dysfunction. Basal NO release does not appear to contribute to platelet passivation in vivo. L-Arginine inhibited platelet aggregation by its direct action on platelets. These findings provide a pathophysiological basis for the observed increase in thrombotic events in atherosclerosis. Use of L-arginine and other strategies to improve endothelial NO activity may impact favorably on thrombotic events in atherosclerosis.

  13. Atherosclerosis associated with pericardial effusion in a central bearded dragon (Pogona vitticeps).

    PubMed

    Schilliger, Lionel; Lemberger, Karin; Chai, Norin; Bourgeois, Aude; Charpentier, Maud

    2010-09-01

    Atherosclerosis is a common disease in pet birds, particularly in psittacines, and is frequently found when performing postmortem examinations on adult and old dogs, in which it is mainly associated with endocrine diseases, such as hypothyroidism and diabetes mellitus. However, atherosclerosis is poorly documented in reptiles and consequently poorly understood. In the current case report, atherosclerosis and pericardial effusion were diagnosed in a 2-year-old male central bearded dragon (Pogona vitticeps) based on ultrasound visualization, necropsy, and histologic examination.

  14. Hematocrit is associated with carotid atherosclerosis in men but not in women.

    PubMed

    Irace, Concetta; Ciamei, Monica; Crivaro, Andrea; Fiaschi, Elio; Madia, Angela; Cortese, Claudio; Gnasso, Agostino

    2003-06-01

    It is known that blood and plasma viscosities are associated with clinical manifestations of atherosclerosis, though evidence is not conclusive particularly in women. To verify whether hematocrit and blood and plasma viscosities are independently associated with carotid atherosclerosis and whether their measurement can improve the definition of the global coronary heart disease (CHD) risk. Eight hundred and ninety-two participants in a cardiovascular disease prevention campaign were examined with regard to conventional CHD risk factors (age, blood pressure, lipids, glucose, body mass index, waist/hip ratio, cigarette smoking and diabetes), hematocrit and blood and plasma viscosities. According to the degree of carotid atherosclerosis, investigated by echo-Doppler, participants were divided in three groups: those without atherosclerosis, those with a low degree of atherosclerosis and those with a high degree of atherosclerosis. In men, age, blood pressure, intima-media thickness (IMT), hematocrit (47.4+/-3.7%, 47.8+/-3.7%, 48.4+/-3.7%, P<0.05) and blood viscosity (4.69+/-0.51 cP, 4.77+/-0.55 cP, 4.82+/-0.51 cP, P=0.05) increased with increasing degree of carotid atherosclerosis. In women, age, blood pressure, total cholesterol and low-density lipoprotein-cholesterol, IMT and plasma viscosity (1.42+/-0.12 cP, 1.44+/-0.11 cP, 1.46+/-0.13 cP, P<0.05) increased with increasing carotid score. Analysis of covariance (ANCOVA) showed that after adjusting for hematocrit, blood viscosity was no longer different in the three groups. In discriminant analysis, hematocrit, among the hemorheological variables investigated, was independently associated with carotid score in men (F=3.66, P<0.05). Neither hematocrit nor blood and plasma viscosities were significantly associated with carotid score in women. These findings suggest that in men, both hematocrit and blood viscosity are related to carotid atherosclerosis but hematocrit would appear to have an independent effect over and

  15. Acceleration modules in linear induction accelerators

    NASA Astrophysics Data System (ADS)

    Wang, Shao-Heng; Deng, Jian-Jun

    2014-05-01

    The Linear Induction Accelerator (LIA) is a unique type of accelerator that is capable of accelerating kilo-Ampere charged particle current to tens of MeV energy. The present development of LIA in MHz bursting mode and the successful application into a synchrotron have broadened LIA's usage scope. Although the transformer model is widely used to explain the acceleration mechanism of LIAs, it is not appropriate to consider the induction electric field as the field which accelerates charged particles for many modern LIAs. We have examined the transition of the magnetic cores' functions during the LIA acceleration modules' evolution, distinguished transformer type and transmission line type LIA acceleration modules, and re-considered several related issues based on transmission line type LIA acceleration module. This clarified understanding should help in the further development and design of LIA acceleration modules.

  16. Peptidylarginine Deiminase Inhibition Reduces Vascular Damage and Modulates Innate Immune Responses in Murine Models of Atherosclerosis

    PubMed Central

    Knight, Jason S.; Luo, Wei; O’Dell, Alexander A.; Yalavarthi, Srilakshmi; Zhao, Wenpu; Subramanian, Venkataraman; Guo, Chiao; Grenn, Robert C.; Thompson, Paul R.; Eitzman, Daniel T.; Kaplan, Mariana J.

    2014-01-01

    Rationale Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-α-producing plasmacytoid dendritic cells in diseased arteries. Peptidylarginine deiminase inhibition is a strategy that can decrease in vivo NET formation. Objective To test whether peptidylarginine deiminase inhibition, a novel approach to targeting arterial disease, can reduce vascular damage and inhibit innate immune responses in murine models of atherosclerosis. Methods and Results Apolipoprotein-E (Apoe)−/− mice demonstrated enhanced NET formation, developed autoantibodies to NETs, and expressed high levels of interferon-α in diseased arteries. Apoe−/− mice were treated for 11 weeks with daily injections of Cl-amidine, a peptidylarginine deiminase inhibitor. Peptidylarginine deiminase inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial interferon-α expression. Conclusions Pharmacological interventions that block NET formation can reduce atherosclerosis burden and arterial thrombosis in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses. PMID:24425713

  17. Hepatic Insulin Resistance is Sufficient to Produce Dyslipidemia and Susceptibility to Atherosclerosis

    PubMed Central

    Biddinger, Sudha B.; Hernandez-Ono, Antonio; Rask-Madsen, Christian; Haas, Joel T.; Alemán, José O.; Suzuki, Ryo; Scapa, Erez F.; Agarwal, Chhavi; Carey, Martin C.; Stephanopoulos, Gregory; Cohen, David E.; King, George L.; Ginsberg, Henry; Kahn, C. Ronald

    2014-01-01

    Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced HDL cholesterol and VLDL particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apoB-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of PGC-1β, which promotes VLDL secretion, but decreased expression of SREBP-1c, SREBP-2 and their targets, the lipogenic enzymes and the LDL receptor. Within twelve weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome. PMID:18249172

  18. Molecular imaging of inflammation in the ApoE -/- mouse model of atherosclerosis with IodoDPA

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Foss, Catherine A., E-mail: cfoss1@jhmi.edu; Bedja, Djahida; Faculty of Medicine and Health Sciences, Macquarie University, Sydney

    Background: Atherosclerosis is a common and serious vascular disease predisposing individuals to myocardial infarction and stroke. Intravascular plaques, the pathologic lesions of atherosclerosis, are largely composed of cholesterol-laden luminal macrophage-rich infiltrates within a fibrous cap. The ability to detect those macrophages non-invasively within the aorta, carotid artery and other vessels would allow physicians to determine plaque burden, aiding management of patients with atherosclerosis. Methods and results: We previously developed a low-molecular-weight imaging agent, [{sup 125}I]iodo-DPA-713 (iodoDPA), which selectively targets macrophages. Here we use it to detect both intravascular macrophages and macrophage infiltrates within the myocardium in the ApoE -/- mousemore » model of atherosclerosis using single photon emission computed tomography (SPECT). SPECT data were confirmed by echocardiography, near-infrared fluorescence imaging and histology. SPECT images showed focal uptake of radiotracer at the aortic root in all ApoE -/- mice, while the age-matched controls were nearly devoid of radiotracer uptake. Focal radiotracer uptake along the descending aorta and within the myocardium was also observed in affected animals. Conclusions: IodoDPA is a promising new imaging agent for atherosclerosis, with specificity for the macrophage component of the lesions involved. - Highlights: • [{sup 125}I]iodoDPA SPECT detects atherosclerotic plaques in ApoE -/- mice with high contrast. • Plaques are detected in ApoE -/- mice regardless of diet with iodoDPA. • iodoDPA has very low uptake in healthy tissue including healthy TSPO + tissues at 24 h.« less

  19. Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoEnull Mice

    PubMed Central

    Chukkapalli, Sasanka S.; Velsko, Irina M.; Rivera-Kweh, Mercedes F.; Zheng, Donghang; Lucas, Alexandra R.; Kesavalu, Lakshmyya

    2015-01-01

    Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoEnull mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoEnull hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoEnull mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection

  20. Habitual fish intake and clinically silent carotid atherosclerosis

    PubMed Central

    2014-01-01

    Background Fish consumption is recommended as part of a healthy diet. However, there is a paucity of data concerning the relation between fish consumption and carotid atherosclerosis. We investigated the association between habitual fish consumption and asymptomatic carotid atherosclerosis, defined as the presence of plaques and/or increased intima-media thickness (≥ 0.90 mm), in non-diabetic participants. Methods Nine hundred-sixty-one (range of age: 18–89 yrs; 37.1% males) adult participants without clinically known atherosclerotic disease were randomly recruited among the customers of a shopping mall in Palermo, Italy, and cross-sectionally investigated. Each participant answered a food frequency questionnaire and underwent high-resolution ultrasonographic evaluation of both carotid arteries. Routine laboratory blood measurements were obtained in a subsample of 507 participants. Results Based on habitual fish consumption, participants were divided into three groups: non-consumers or consumers of less than 1 serving a week (24.0%), consumers of 1 serving a week (38.8%), and consumers of ≥ 2 servings a week (37.2%). Age-adjusted prevalence of carotid atherosclerosis (presence of plaques or intima media thickness ≥ 0.9 mm) was higher in the low fish consumption group (13.3%, 12.1% and 6.6%, respectively; P = 0.003). Multivariate analysis evidenced that carotid atherosclerosis was significantly associated with age (OR = 1.12; 95% CI = 1.09-1.14), hypertension on pharmacologic treatment (OR = 1.81; 95% CI = 1.16-2.82), and pulse pressure (OR = 1.03; 95% CI = 1.01-1.04), while consuming ≥2 servings of fish weekly was protective compared with the condition of consumption of <1 serving of fish weekly (OR = 0.46; 95% CI = 0.26-0.80). Conclusions High habitual fish consumption seems to be associated with less carotid atherosclerosis, though adequate interventional trials are necessary to confirm the role of fish

  1. Habitual fish intake and clinically silent carotid atherosclerosis.

    PubMed

    Buscemi, Silvio; Nicolucci, Antonio; Lucisano, Giuseppe; Galvano, Fabio; Grosso, Giuseppe; Belmonte, Serena; Sprini, Delia; Migliaccio, Silvia; Cianferotti, Luisella; Brandi, Maria Luisa; Rini, Giovam Battista

    2014-01-09

    Fish consumption is recommended as part of a healthy diet. However, there is a paucity of data concerning the relation between fish consumption and carotid atherosclerosis. We investigated the association between habitual fish consumption and asymptomatic carotid atherosclerosis, defined as the presence of plaques and/or increased intima-media thickness (≥ 0.90 mm), in non-diabetic participants. Nine hundred-sixty-one (range of age: 18-89 yrs; 37.1% males) adult participants without clinically known atherosclerotic disease were randomly recruited among the customers of a shopping mall in Palermo, Italy, and cross-sectionally investigated. Each participant answered a food frequency questionnaire and underwent high-resolution ultrasonographic evaluation of both carotid arteries. Routine laboratory blood measurements were obtained in a subsample of 507 participants. Based on habitual fish consumption, participants were divided into three groups: non-consumers or consumers of less than 1 serving a week (24.0%), consumers of 1 serving a week (38.8%), and consumers of ≥ 2 servings a week (37.2%). Age-adjusted prevalence of carotid atherosclerosis (presence of plaques or intima media thickness ≥ 0.9 mm) was higher in the low fish consumption group (13.3%, 12.1% and 6.6%, respectively; P = 0.003). Multivariate analysis evidenced that carotid atherosclerosis was significantly associated with age (OR = 1.12; 95% CI = 1.09-1.14), hypertension on pharmacologic treatment (OR = 1.81; 95% CI = 1.16-2.82), and pulse pressure (OR = 1.03; 95% CI = 1.01-1.04), while consuming ≥2 servings of fish weekly was protective compared with the condition of consumption of <1 serving of fish weekly (OR = 0.46; 95% CI = 0.26-0.80). High habitual fish consumption seems to be associated with less carotid atherosclerosis, though adequate interventional trials are necessary to confirm the role of fish consumption in prevention of cardiovascular

  2. Cell-derived microparticles in atherosclerosis: biomarkers and targets for pharmacological modulation?

    PubMed Central

    Baron, Morgane; Boulanger, Chantal M; Staels, Bart; Tailleux, Anne; Simionescu, M

    2012-01-01

    Abstract Cardiovascular diseases remain an important cause of morbi-mortality. Atherosclerosis, which predisposes to cardiovascular disorders such as myocardial infarction and stroke, develops silently over several decades. Identification of circulating biomarkers to evaluate cardiovascular event risk and pathology prognosis is of particular importance. Microparticles (MPs) are small vesicles released from cells upon apoptosis or activation. Microparticles are present in blood of healthy individuals. Studies showing a modification of their concentrations in patients with cardiovascular risk factors and after cardiovascular events identify MPs as potential biomarkers of disease. Moreover, the pathophysiological properties of MPs may contribute to atherosclerosis development. In addition, pharmacological compounds, used in the treatment of cardiovascular disease, can reduce plasma MP concentrations. Nevertheless, numerous issues remain to be solved before MP measurement can be applied as routine biological tests to improve cardiovascular risk prediction. In particular, prospective studies to identify the predictive values of MPs in pathologies such as cardiovascular diseases are needed to demonstrate whether MPs are useful biomarkers for the early detection of the disease and its progression. PMID:22050954

  3. [Chronic mild inflammation links obesity, metabolic syndrome, atherosclerosis and diabetes].

    PubMed

    Andel, M; Polák, J; Kraml, P; Dlouhý, P; Stich, V

    2009-01-01

    Chronic low grade inflammation is relatively new concept in metabolic medicine. This concept describes the relations between the inflammation and adipose tissue, insulin resistence, atherosclerosis and type 2 diabetes mellitus. Macrophages and lymphocytes deposed in adipose tissue produce proinflammatory cytokines which directly or through the CRP liver secretion are targeting endothelial cells, hepatocytes and beta cells of Langerhans islets of pancreas. The dysfunction of these cells follows often further disturbances and in case of beta cells - the cell death. The connection between the adipose tissue insulin resistence, atherosclerosis and type 2 diabetes was earlier described with endocrine and metabolic descriptors. The concept of chronic low grade inflammation creates also another description of multilateral connections in metabolic syndome. The salicylates and the drugs related to them seem to have some glucose lowering properties. The recent development in the field ofchronic low grade inflammation represents also certain therapeutic hope for antiinflammatory intervention in type 2 diabetes.

  4. Dysfunctional HDL as a therapeutic target for atherosclerosis prevention.

    PubMed

    Ossoli, Alice; Pavanello, Chiara; Giorgio, Eleonora; Calabresi, Laura; Gomaraschi, Monica

    2018-03-15

    Hypercholesterolemia is one of the main risk factors for the development of atherosclerosis. Among the various lipoprotein classes, however, high density lipoproteins (HDL) are inversely associated with the incidence of atherosclerosis, since they are able to exert a series of atheroprotective functions. The central role of HDL within the reverse cholesterol transport, their antioxidant and anti-inflammatory properties and their ability to preserve endothelial homeostasis are likely responsible for HDL-mediated atheroprotection. However, drugs that effectively raise HDL-C failed to result in a decreased incidence of cardiovascular event, suggesting that plasma levels of HDL-C and HDL function are not always related. Several evidences are showing that different pathologic conditions, especially those associated with an inflammatory response, can cause dramatic alterations of HDL protein and lipid cargo resulting in HDL dysfunction. Established and investigational drugs designed to affect lipid metabolism and to increase HDL-C are only partly effective in correcting HDL dysfunction. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Immunoproteasome subunit ß5i/LMP7-deficiency in atherosclerosis.

    PubMed

    Hewing, Bernd; Ludwig, Antje; Dan, Cristian; Pötzsch, Max; Hannemann, Carmen; Petry, Andreas; Lauer, Dilyara; Görlach, Agnes; Kaschina, Elena; Müller, Dominik N; Baumann, Gert; Stangl, Verena; Stangl, Karl; Wilck, Nicola

    2017-10-17

    Management of protein homeostasis by the ubiquitin-proteasome system is critical for atherosclerosis development. Recent studies showed controversial results on the role of immunoproteasome (IP) subunit β5i/LMP7 in maintenance of protein homeostasis under cytokine induced oxidative stress. The present study aimed to investigate the effect of β5i/LMP7-deficiency on the initiation and progression of atherosclerosis as a chronic inflammatory, immune cell driven disease. LDLR -/- LMP7 -/- and LDLR -/- mice were fed a Western-type diet for either 6 or 24 weeks to induce early and advanced stage atherosclerosis, respectively. Lesion burden was similar between genotypes in both stages. Macrophage content and abundance of polyubiquitin conjugates in aortic root plaques were unaltered by β5i/LMP7-deficiency. In vitro experiments using bone marrow-derived macrophages (BMDM) showed that β5i/LMP7-deficiency did not influence macrophage polarization or accumulation of polyubiquitinated proteins and cell survival upon hydrogen peroxide and interferon-γ treatment. Analyses of proteasome core particle composition by Western blot revealed incorporation of standard proteasome subunits in β5i/LMP7-deficient BMDM and spleen. Chymotrypsin-, trypsin- and caspase-like activities assessed by using short fluorogenic peptides in BMDM whole cell lysates were similar in both genotypes. Taken together, deficiency of IP subunit β5i/LMP7 does not disturb protein homeostasis and does not aggravate atherogenesis in LDLR -/- mice.

  6. Prevention of Coronary Atherosclerosis: The Role of a College Health Service.

    ERIC Educational Resources Information Center

    Manchester, Ralph A.; Greenland, Philip

    1987-01-01

    This paper reviews the concept of behavioral risk factors for atherosclerosis which become entrenched in adolescence or young adulthood. Evidence favoring intervention in the adolescent years and a screening program at the University of Rochester Health Service are described. A preliminary strategy for prevention of atherosclerosis on campus is…

  7. Atherosclerosis-Associated Endothelial Cell Apoptosis by MiR-429-Mediated Down Regulation of Bcl-2.

    PubMed

    Zhang, Tao; Tian, Feng; Wang, Jing; Jing, Jing; Zhou, Shan-Shan; Chen, Yun-Dai

    2015-01-01

    Endothelial cell injury and subsequent apoptosis play a key role in the development and pathogenesis of atherosclerosis, which is hallmarked by dysregulated lipid homeostasis, aberrant immunity and inflammation, and plaque-instability-associated coronary occlusion. Nevertheless, our understanding of the mechanisms underlying endothelial cell apoptosis is still limited. MicroRNA-429 (miR-29) is a known cancer suppressor that promotes cancer cell apoptosis. However, it is unknown whether miR-429 may be involved in the development of atherosclerosis through similar mechanisms. We addressed these questions in the current study. We examined the levels of endothelial cell apoptosis in ApoE (-/-) mice suppled with high-fat diet (HFD), a mouse model for atherosclerosis (simplified as HFD mice). We analyzed the levels of anti-apoptotic protein Bcl-2 and the levels of miR-429 in the purified CD31+ endothelial cells from mouse aorta. Prediction of the binding between miR-429 and 3'-UTR of Bcl-2 mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. The effects of miR-429 were further analyzed in an in vitro model using oxidized low-density lipoprotein (ox-LDL)-treated human aortic endothelial cells (HAECs). HFD mice developed atherosclerosis in 12 weeks, while the control ApoE (-/-) mice that had received normal diet (simplified as NOR mice) did not. HFD mice had significantly lower percentage of endothelial cells and significantly higher percentage of mesenchymal cells in the aorta than NOR mice. Significantly higher levels of endothelial cell apoptosis were detected in HFD mice, resulting from decreases in Bcl-2 protein, but not mRNA. The decreases in Bcl-2 in endothelial cells were due to increased levels of miR-429, which suppressed the translation of Bcl-2 mRNA via 3'-UTR binding. These in vivo findings were reproduced in vitro on ox-LDL-treated HAECs. Atherosclerosis-associated endothelial cell apoptosis may result from down

  8. Frequency of Subclinical Atherosclerosis in Brazilian HIV-Infected Patients.

    PubMed

    Salmazo, Péricles Sidnei; Bazan, Silméia Garcia Zanati; Shiraishi, Flávio Gobbis; Bazan, Rodrigo; Okoshi, Katashi; Hueb, João Carlos

    2018-04-09

    AIDS as well as atherosclerosis are important public health problems. The longer survival among HIV-infected is associated with increased number of cardiovascular events in this population, and this association is not fully understood. To identify the frequency of subclinical atherosclerosis in HIV-infected patients compared to control subjects; to analyze associations between atherosclerosis and clinical and laboratory variables, cardiovascular risk factors, and the Framingham coronary heart disease risk score (FCRS). Prospective cross-sectional case-control study assessing the presence of subclinical atherosclerosis in 264 HIV-infected patients and 279 controls. Clinical evaluation included ultrasound examination of the carotid arteries, arterial stiffness by pulse wave velocity (PWV) and augmentation index (AIx), laboratory analysis of peripheral blood, and cardiovascular risk according to FCRS criteria. The significance level adopted in the statistical analysis was p < 0.05. Plaques were found in 37% of the HIV group and 4% of controls (p < 0.001). Furthermore, carotid intima-media thickness was higher in the HIV group than in controls (p < 0.001). Patients with carotid plaque had higher fasting glucose, total cholesterol, low-density lipoprotein cholesterol, and triglycerides than those without plaques. The presence of HIV, adjusted for age, overweight/obesity, and smoking increased by almost fivefold the risk of atherosclerotic carotid plaque (OR: 4.9; 95%CI: 2.5-9.9; p < 0.001). Exposure to protease inhibitors did not influence carotid intima-media thickness, was not associated with carotid plaque frequency, and did not alter the mechanical characteristics of the arterial system (PWV and AIx). HIV-infected patients are at increased risk of atherosclerosis in association with classical cardiovascular risk factors. Treatment with protease inhibitors does not promote functional changes in the arteries, and shows no association with increased frequency of

  9. Atherosclerosis and Nanotechnology: Diagnostic and Therapeutic Applications

    PubMed Central

    Kratz, Jeremy D.; Chaddha, Ashish; Bhattacharjee, Somnath

    2016-01-01

    Over the past several decades, tremendous advances have been made in the understanding, diagnosis, and treatment of coronary artery disease (CAD). However, with shifting demographics and evolving risk factors we now face new challenges that must be met in order to further advance are management of patients with CAD. In parallel with advances in our mechanistic appreciation of CAD and atherosclerosis, nanotechnology approaches have greatly expanded, offering the potential for significant improvements in our diagnostic and therapeutic management of CAD. To realize this potential we must go beyond to recognize new frontiers including knowledge gaps between understanding atherosclerosis to the translation of targeted molecular tools. This review highlights nanotechnology applications for imaging and therapeutic advancements in CAD. PMID:26809711

  10. Atherosclerosis and Nanotechnology: Diagnostic and Therapeutic Applications.

    PubMed

    Kratz, Jeremy D; Chaddha, Ashish; Bhattacharjee, Somnath; Goonewardena, Sascha N

    2016-02-01

    Over the past several decades, tremendous advances have been made in the understanding, diagnosis, and treatment of coronary artery disease (CAD). However, with shifting demographics and evolving risk factors we now face new challenges that must be met in order to further advance are management of patients with CAD. In parallel with advances in our mechanistic appreciation of CAD and atherosclerosis, nanotechnology approaches have greatly expanded, offering the potential for significant improvements in our diagnostic and therapeutic management of CAD. To realize this potential we must go beyond to recognize new frontiers including knowledge gaps between understanding atherosclerosis to the translation of targeted molecular tools. This review highlights nanotechnology applications for imaging and therapeutic advancements in CAD.

  11. Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with progressive atherosclerosis and incident cardiovascular disease.

    PubMed

    Pechlaner, Raimund; Willeit, Peter; Summerer, Monika; Santer, Peter; Egger, Georg; Kronenberg, Florian; Demetz, Egon; Weiss, Günter; Tsimikas, Sotirios; Witztum, Joseph L; Willeit, Karin; Iglseder, Bernhard; Paulweber, Bernhard; Kedenko, Lyudmyla; Haun, Margot; Meisinger, Christa; Gieger, Christian; Müller-Nurasyid, Martina; Peters, Annette; Willeit, Johann; Kiechl, Stefan

    2015-01-01

    The enzyme heme oxygenase-1 (HO-1) exerts cytoprotective effects in response to various cellular stressors. A variable number tandem repeat polymorphism in the HO-1 gene promoter region has previously been linked to cardiovascular disease. We examined this association prospectively in the general population. Incidence of stroke, myocardial infarction, or vascular death was registered between 1995 and 2010 in 812 participants of the Bruneck Study aged 45 to 84 years (49.4% males). Carotid atherosclerosis progression was quantified by high-resolution ultrasound. HO-1 variable number tandem repeat length was determined by polymerase chain reaction. Subjects with ≥32 tandem repeats on both HO-1 alleles compared with the rest of the population (recessive trait) featured substantially increased cardiovascular disease risk (hazard ratio [95% confidence interval], 5.45 [2.39, 12.42]; P<0.0001), enhanced atherosclerosis progression (median difference in atherosclerosis score [interquartile range], 2.1 [0.8, 5.6] versus 0.0 [0.0, 2.2] mm; P=0.0012), and a trend toward higher levels of oxidized phospholipids on apolipoprotein B-100 (median oxidized phospholipids/apolipoprotein B level [interquartile range], 11364 [4160, 18330] versus 4844 [3174, 12284] relative light units; P=0.0554). Increased cardiovascular disease risk in those homozygous for ≥32 repeats was also detected in a pooled analysis of 7848 participants of the Bruneck, SAPHIR, and KORA prospective studies (hazard ratio [95% confidence interval], 3.26 [1.50, 7.33]; P=0.0043). This study found a strong association between the HO-1 variable number tandem repeat polymorphism and cardiovascular disease risk confined to subjects with a high number of repeats on both HO-1 alleles and provides evidence for accelerated atherogenesis and decreased antioxidant defense in this vascular high-risk group. © 2014 American Heart Association, Inc.

  12. Metabolic profiling of murine plasma reveals eicosapentaenoic acid metabolites protecting against endothelial activation and atherosclerosis.

    PubMed

    Liu, Yajin; Fang, Xuan; Zhang, Xu; Huang, Jing; He, Jinlong; Peng, Liyuan; Ye, Chenji; Wang, Yingmei; Xue, Fengxia; Ai, Ding; Li, Dan; Zhu, Yi

    2018-04-01

    Atherosclerosis results from a maladaptive inflammatory response initiated by the intramural retention of LDL in susceptible areas of the arterial vasculature. The ω-3 polyunsaturated fatty acids (ω-3) have protective effects in atherosclerosis; however, their molecular mechanism is still largely unknown. The present study used a metabolomic approach to reveal the atheroprotective metabolites of ω-3 and investigate the underlying mechanisms. We evaluated the development of atherosclerosis in LDL receptor-deficient mice (LDLR -/- ) fed a Western-type diet (WTD) plus ω-3 and also LDLR -/- and fat-1 transgenic (LDLR -/- -fat-1 tg ) mice fed a WTD. The profiles of ω-3 in the plasma were screened by LC-MS/MS using unbiased systematic metabolomics analysis. We also studied the effect of metabolites of eicosapentaenoic acid (EPA) on endothelial activation in vitro. The ω-3 diet and fat-1 transgene decreased monocyte infiltration, inhibited the expression of pro-inflammatory genes and significantly attenuated atherosclerotic plaque formation and enhanced plaque stability in LDLR -/- mice. The content of 18-hydroxy-eicosapentaenoic acid (18-HEPE) and 17,18-epoxy-eicosatetraenoic acid (17,18-EEQ), from the cytochrome P450 pathway of EPA, was significantly higher in plasma from both ω-3-treated LDLR -/- and LDLR -/- -fat-1 tg mice as compared with WTD-fed LDLR -/- mice. In vitro in endothelial cells, 18-HEPE or 17,18-EEQ decreased inflammatory gene expression induced by TNFα via NF-κB signalling and thereby inhibited monocyte adhesion to endothelial cells. EPA protected against the development of atherosclerosis in atheroprone mice via the metabolites 18-HEPE and/or 17,18-EEQ, which reduced endothelial activation. These compounds may have therapeutic implications in atherosclerosis. This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10

  13. History and Technology Developments of Radio Frequency (RF) Systems for Particle Accelerators

    NASA Astrophysics Data System (ADS)

    Nassiri, A.; Chase, B.; Craievich, P.; Fabris, A.; Frischholz, H.; Jacob, J.; Jensen, E.; Jensen, M.; Kustom, R.; Pasquinelli, R.

    2016-04-01

    This article attempts to give a historical account and review of technological developments and innovations in radio frequency (RF) systems for particle accelerators. The evolution from electrostatic field to the use of RF voltage suggested by R. Wideröe made it possible to overcome the shortcomings of electrostatic accelerators, which limited the maximum achievable electric field due to voltage breakdown. After an introduction, we will provide reviews of technological developments of RF systems for particle accelerators.

  14. Overview of Atherosclerosis and Chemical Stressors

    EPA Science Inventory

    Dr. Cascio’s presentation at the workshop titled, “titled “Understanding the Combined Effects of Environmental Chemical and Non-Chemical Stressors: Atherosclerosis as a Model” will highlight atherosclerosis’s rapidly growing role as a cause of increa...

  15. Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis.

    PubMed

    Belmokhtar, Karim; Robert, Thomas; Ortillon, Jeremy; Braconnier, Antoine; Vuiblet, Vincent; Boulagnon-Rombi, Camille; Diebold, Marie Danièle; Pietrement, Christine; Schmidt, Ann Marie; Rieu, Philippe; Touré, Fatouma

    2016-05-01

    Cardiovascular disease is the leading cause of death in patients with end-stage renal disease. Serum amyloid A (SAA) is an acute phase protein and a binding partner for the multiligand receptor for advanced glycation end products (RAGE). We investigated the role of the interaction between SAA and RAGE in uremia-related atherogenesis. We used a mouse model of uremic vasculopathy, induced by 5 of 6 nephrectomy in the Apoe(-/-) background. Sham-operated mice were used as controls. Primary cultures of Ager(+/+) and Ager(-/-) vascular smooth muscle cells (VSMCs) were stimulated with recombinant SAA, S100B, or vehicle alone. Relevance to human disease was assessed with human VSMCs. The surface area of atherosclerotic lesions at the aortic roots was larger in uremic Apoe(-/-) than in sham-operated Apoe(-/-) mice (P<0.001). Furthermore, atherosclerotic lesions displayed intense immunostaining for RAGE and SAA, with a pattern similar to that of α-SMA. Ager transcript levels in the aorta were 6× higher in uremic animals than in controls (P<0.0001). Serum SAA concentrations were higher in uremic mice, not only after 4 weeks of uremia but also at 8 and 12 weeks of uremia, than in sham-operated animals. We investigated the functional role of RAGE in uremia-induced atherosclerosis further, in animals lacking RAGE. We found that the induction of uremia in Apoe(-/-) Ager(-/-) mice did not accelerate atherosclerosis. In vitro, the stimulation of Ager(+/+) but not of Ager(-/-) VSMCs with SAA or S100B significantly induced the production of reactive oxygen species, the phosphorylation of AKT and mitogen-activated protein kinase-extracellular signal-regulated kinases and cell migration. Reactive oxygen species inhibition with N-acetyl cysteine significantly inhibited both the phosphorylation of AKT and the migration of VSMCs. Similar results were obtained for human VSMCs, except that the phosphorylation of mitogen-activated protein kinase-extracellular signal-regulated kinases

  16. Platelet and leukocyte activation, atherosclerosis and inflammation in European and South Asian men.

    PubMed

    Dotsenko, O; Chaturvedi, N; Thom, S A McG; Wright, A R; Mayet, J; Shore, A; Schalkwijk, C; Hughes, A D

    2007-10-01

    Increased platelet activation occurs in ischemic heart disease (IHD), but increased platelet activation is also seen in cerebrovascular atherosclerosis and peripheral artery disease. It is not clear therefore whether platelet activation is an indicator of IHD or a marker of generalized atherosclerosis and inflammation. South Asian subjects are at high risk of IHD, but little is known regarding differences in platelet and leukocyte function between European and South Asian subjects. Fifty-four male subjects (age 49-79 years) had coronary artery calcification measured by multislice computed tomography (CT), aortic atherosclerosis assessed by measurement of carotid-femoral pulse wave velocity (aortic PWV), and femoral and carotid atherosclerosis measured by B-mode ultrasound. Platelet and leukocyte activation was assessed by flow cytometry of platelet-monocyte complexes (PMC), platelet expression of PAC-1 binding site and CD62P, and expression of L-selectin on leukocytes. Elevated circulating PMC correlated significantly with elevated aortic PWV and PMC were higher in subjects with femoral plaques. In contrast PMC did not differ by increasing coronary artery calcification category or presence of carotid plaques. Higher numbers of PMC were independently related to elevated levels of C-reactive protein (CRP), higher aortic PWV, hypertension and smoking in a multivariate model. Markers of platelet and leukocyte activation did not differ significantly by ethnicity. Increased PMC are related to the extent of aortic and femoral atherosclerosis rather than coronary or carotid atherosclerosis. The association between elevated CRP and increased PMC suggests that inflammation in relation to generalized atherosclerosis may play an important role in PMC activation.

  17. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis?

    PubMed

    Nieto, F J; Iribarren, C; Gross, M D; Comstock, G W; Cutler, R G

    2000-01-01

    the evidence of a potential beneficial role of antioxidants in preventing atherosclerotic disease is not entirely consistent. to assess the longitudinal association of serum total antioxidant capacity and serum antioxidants with the presence of subclinical carotid atherosclerosis. Prospective case-control study nested within an historical cohort. Cases were 150 individuals with elevated carotid intimal-medial thickness measured by B-mode ultrasound at the first two examinations of the Atherosclerosis Risk in Communities Study (1987-92). Controls were 150 age-gender-matched individuals with low carotid intimal-medial thickness. Serum antioxidant vitamins, uric acid, and serum total antioxidant capacity were measured in frozen serum samples collected from the same individuals in 1974 (13-15 years prior to the determination of case-control status). Compared to controls, atherosclerosis cases had significantly higher levels of serum total antioxidant capacity in 1974 than controls. This difference was almost entirely explained by increased serum concentration of uric acid in cases. In contrast with cross-sectional results, uric acid serum concentration in 1974, was significantly higher in cases than in controls, even after adjusting for the main cardiovascular risk factors. Cases had significantly lower levels of alpha-carotene in the 1974 sera than controls, but no other differences in serum antioxidant vitamin concentrations were observed. The higher serum uric acid concentration seemed associated with elevated total serum antioxidant capacity among individuals with atherosclerosis. This finding is consistent with experimental evidence suggesting that hyperuricemia may be a compensatory mechanism to counteract oxidative damage related to atherosclerosis and aging in humans.

  18. Myeloid Kdm6b deficiency results in advanced atherosclerosis.

    PubMed

    Neele, Annette E; Gijbels, Marion J J; van der Velden, Saskia; Hoeksema, Marten A; Boshuizen, Marieke C S; Prange, Koen H M; Chen, Hung-Jen; Van den Bossche, Jan; van Roomen, Cindy P P A; Shami, Annelie; Levels, Johannes H M; Kroon, Jeffrey; Lucas, Tina; Dimmeler, Stefanie; Lutgens, Esther; de Winther, Menno P J

    2018-06-01

    Atherosclerosis is a lipid-driven chronic inflammatory disorder of the arteries, and monocytes and macrophages play a central role in this process. Within the atherosclerotic lesion, macrophages can scavenge modified lipids and become the so-called foam cells. We previously reported that the epigenetic enzyme Kdm6b (also known as Jmjd3) controls the pro-fibrotic transcriptional profile of peritoneal foam cells. Given the importance of these cells in atherosclerosis, we now studied the effect of myeloid Kdm6b on disease progression. Bone marrow of myeloid Kdm6b deficient (Kdm6b del ) mice or wild type littermates (Kdm6b wt ) was transplanted to lethally irradiated Ldlr -/- mice fed a high fat diet for 9 weeks to induce atherosclerosis. Lesion size was similar in Kdm6b wt and Kdm6b del transplanted mice. However, lesions of Kdm6b del mice contained more collagen and were more necrotic. Pathway analysis on peritoneal foam cells showed that the pathway involved in leukocyte chemotaxis was most significantly upregulated. Although macrophage and neutrophil content was similar after 9 weeks of high fat diet feeding, the relative increase in collagen content and necrosis revealed that atherosclerotic lesions in Kdm6b del mice progress faster. Myeloid Kdm6b deficiency results in more advanced atherosclerosis. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  19. Development of a residual acceleration data reduction and dissemination plan

    NASA Technical Reports Server (NTRS)

    Rogers, Melissa J. B.

    1992-01-01

    A major obstacle in evaluating the residual acceleration environment in an orbiting space laboratory is the amount of data collected during a given mission: gigabytes of data will be available as SAMS units begin to fly regularly. Investigators taking advantage of the reduced gravity conditions of space should not be overwhelmed by the accelerometer data which describe these conditions. We are therefore developing a data reduction and analysis plan that will allow principal investigators of low-g experiments to create experiment-specific residual acceleration data bases for post-flight analysis. The basic aspects of the plan can also be used to characterize the acceleration environment of earth orbiting laboratories. Our development of the reduction plan is based on the following program of research: the identification of experiment sensitivities by order of magnitude estimates and numerical modelling; evaluation of various signal processing techniques appropriate for the reduction, supplementation, and dissemination of residual acceleration data; and testing and implementation of the plan on existing acceleration data bases. The orientation of the residual acceleration vector with respect to some set of coordinate axes is important for experiments with known directional sensitivity. Orientation information can be obtained from the evaluation of direction cosines. Fourier analysis is commonly used to transform time history data into the frequency domain. Common spectral representations are the amplitude spectrum which gives the average of the components of the time series at each frequency and the power spectral density which indicates the power or energy present in the series per unit frequency interval. The data reduction and analysis scheme developed involves a two tiered structure to: (1) identify experiment characteristics and mission events that can be used to limit the amount of accelerator data an investigator should be interested in; and (2) process the

  20. Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice.

    PubMed

    Praticò, D; Tillmann, C; Zhang, Z B; Li, H; FitzGerald, G A

    2001-03-13

    The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substantially in humans. Because deletion of the PGI(2) receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF(1alpha) by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI(2) biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.

  1. What can ancient mummies teach us about atherosclerosis?

    PubMed

    Wann, Samuel; Thomas, Gregory S

    2014-10-01

    Ancient mummies have captivated a wide variety of audiences for centuries. In order to better understand the evolution and causative features of atherosclerosis, the Horus group is applying modern scientific methods to study ancient mummies. We have used CT scanning to detect calcification in arteries as an indication of the presence of atherosclerosis, and are correlating these results with cultural and lifestyle features of various populations of ancient people as represented by their ancient mummified remains. We are also pursuing related studies of ancient DNA to define genotypes associated with atherosclerotic phenotypes. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Operational Assessment of Tools for Accelerating Leader Development (ALD): Volume 2, Appendices

    DTIC Science & Technology

    2009-06-01

    Qual Qualitative Quant Quantitative RC Reserve Component R&D Research and Development re: reference reqts requirements ROTC Reserve Officer...part in the Accelerating Leader Development program, please complete the Pretest , Training, and Posttest . Of course, you may complete the longer...ARI Research Note 2009-09 Operational Assessment of Tools for Accelerating Leader Development (ALD): Volume II, Appendices Bruce

  3. Natural human apoA-I mutations L141RPisa and L159RFIN alter HDL structure and functionality and promote atherosclerosis development in mice.

    PubMed

    Tiniakou, Ioanna; Kanaki, Zoi; Georgopoulos, Spiros; Chroni, Angeliki; Van Eck, Miranda; Fotakis, Panagiotis; Zannis, Vassilis I; Kardassis, Dimitris

    2015-11-01

    Mutations in human apolipoprotein A-I (apoA-I) are associated with low high-density lipoprotein (HDL) cholesterol levels and pathological conditions such as premature atherosclerosis and amyloidosis. In this study we functionally characterized two natural human apoA-I mutations, L141RPisa and L159RFIN, in vivo. We generated transgenic mice expressing either wild-type (WT) or the two mutant forms of human apoA-I on a mouse apoA-I(-/-) background and analyzed for abnormalities in their lipid and lipoprotein profiles. HDL structure and functionality, as well as atherosclerosis development following a 14-week high-fat diet were assessed in these mice. The expression of either apoA-I mutant was associated with markedly reduced serum apoA-I (<10% of WT apoA-I), total and HDL-cholesterol levels (∼20% and ∼7% of WT apoA-I, respectively) and the formation of few small size HDL particles with preβ2 and α3, α4 electrophoretic mobility. HDL particles containing either of the two apoA-I mutants exhibited attenuated anti-oxidative properties as indicated by their inability to prevent low-density lipoprotein oxidation, and by decreased activities of paraoxonase-1 and platelet-activating factor acetylhydrolase. However, the apoA-I(L141R)Pisa or apoA-I(L159R)FIN-containing HDL particles demonstrated increased capacity to promote ATP-Binding Cassette Transporter A1-mediated cholesterol efflux from macrophages. Expression of apoA-I(L141R)Pisa or apoA-I(L159R)FIN mutations in mice was associated with increased diet-induced atherosclerosis compared to either WT apoA-I transgenic or apoA-I(-/-) mice. These findings suggest that natural apoA-I mutations L141RPisa and L159RFIN affect the biogenesis and the functionality of HDL in vivo and predispose to diet-induced atherosclerosis in the absence of any other genetic defect. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Development of a Dielectric-Loaded Accelerator Test Facility Based on an X-Band Magnicon Amplifier

    NASA Astrophysics Data System (ADS)

    Gold, S. H.; Kinkead, A. K.; Gai, W.; Power, J. G.; Konecny, R.; Jing, C.; Tantawi, S. G.; Nantista, C. D.; Hu, Y.; Du, X.; Tang, C.; Lin, Y.; Bruce, R. W.; Bruce, R. L.; Fliflet, A. W.; Lewis, D.

    2006-01-01

    The Naval Research Laboratory (NRL) and Argonne National Laboratory (ANL), in collaboration with the Stanford Linear Accelerator Center (SLAC), are developing a dielectric-loaded accelerator (DLA) test facility powered by the 11.424-GHz magnicon amplifier that was developed jointly by NRL and Omega-P, Inc. Thus far, DLA structures developed by ANL have been tested at the NRL Magnicon Facility without injected electrons, including tests of alumina and magnesium calcium titanate structures at gradients up to ˜8 MV/m. The next step is to inject electrons in order to build a compact DLA test accelerator. The Accelerator Laboratory of Tsinghua University in Beijing, China has developed a 5-MeV electron injector for the accelerator, and SLAC is developing a means to combine the two magnicon output arms, and to drive the injector and an accelerator section with separate control of the power ratio and relative phase. Also, RWBruce Associates, working with NRL, is developing a means to join ceramic tubes to produce long accelerating sections using a microwave brazing process. The installation and commissioning of the first dielectric-loaded test accelerator, including injector, DLA structure, and spectrometer, should take place within the next year.

  5. Endothelin-1 overexpression exacerbates atherosclerosis and induces aortic aneurysms in apolipoprotein E knockout mice.

    PubMed

    Li, Melissa W; Mian, Muhammad Oneeb Rehman; Barhoumi, Tlili; Rehman, Asia; Mann, Koren; Paradis, Pierre; Schiffrin, Ernesto L

    2013-10-01

    Endothelin (ET)-1 plays a role in vascular reactive oxygen species production and inflammation. ET-1 has been implicated in human atherosclerosis and abdominal aortic aneurysm (AAA) development. ET-1 overexpression exacerbates high-fat diet-induced atherosclerosis in apolipoprotein E(-/-) (Apoe(-/-)) mice. ET-1-induced reactive oxygen species and inflammation may contribute to atherosclerosis progression and AAA development. Eight-week-old male wild-type mice, transgenic mice overexpressing ET-1 selectively in endothelium (eET-1), Apoe(-/-) mice, and eET-1/Apoe(-/-) mice were fed high-fat diet for 8 weeks. eET-1/Apoe(-/-) had a 45% reduction in plasma high-density lipoprotein (P<0.05) and presented ≥ 2-fold more aortic atherosclerotic lesions compared with Apoe(-/-) (P<0.01). AAAs were detected only in eET-1/Apoe(-/-) (8/21; P<0.05). Reactive oxygen species production was increased ≥ 2-fold in perivascular fat, media, or atherosclerotic lesions in the ascending aorta and AAAs of eET-1/Apoe(-/-) compared with Apoe(-/-) (P<0.05). Monocyte/macrophage infiltration was enhanced ≥ 2.5-fold in perivascular fat of ascending aorta and AAAs in eET-1/Apoe(-/-) compared with Apoe(-/-) (P<0.05). CD4(+) T cells were detected almost exclusively in perivascular fat (3/6) and atherosclerotic lesions (5/6) in ascending aorta of eET-1/Apoe(-/-) (P<0.05). The percentage of spleen proinflammatory Ly-6C(hi) monocytes was enhanced 26% by ET-1 overexpression in Apoe(-/-) (P<0.05), and matrix metalloproteinase-2 was increased 2-fold in plaques of eET-1/Apoe(-/-) (P<0.05) compared with Apoe(-/-). ET-1 plays a role in progression of atherosclerosis and AAA formation by decreasing high-density lipoprotein, and increasing oxidative stress, inflammatory cell infiltration, and matrix metalloproteinase-2 in perivascular fat, vascular wall, and atherosclerotic lesions.

  6. Macrophage Mitochondrial Oxidative Stress Promotes Atherosclerosis and NF-κB-Mediated Inflammation in Macrophages

    PubMed Central

    Wang, Ying; Wang, Gary Z.; Rabinovitch, Peter S.; Tabas, Ira

    2014-01-01

    Rationale Mitochondrial oxidative stress (mitoOS) has been shown to correlate with the progression of human atherosclerosis. However, definitive cell-type specific causation studies in vivo are lacking, and the molecular mechanisms of potential pro-atherogenic effects remain to be determined. Objective To assess the importance of macrophage mitoOS in atherogenesis and explore the underlying molecular mechanisms. Methods & Results We first validated Western-type diet-fed Ldlr-/- mice as a model of human mitoOS-atherosclerosis association by showing that a marker of mitoOS in lesional macrophages, non-nuclear oxidative DNA damage, correlates with aortic root lesion development. To investigate the importance of macrophage-mitoOS, we used a genetic engineering strategy in which the OS suppressor catalase was ectopically expressed in mitochondria (mCAT) in macrophages. MitoOS in lesional macrophages was successfully suppressed in these mice, and this led to a significant reduction in aortic root lesional area. The mCAT lesions had less monocyte-derived cells, less Ly6chi monocyte infiltration into lesions, and lower levels of the monocyte chemotactic protein-1 (MCP-1). The decrease in lesional MCP-1 was associated with suppression of other markers of inflammation and with decreased phosphorylation of RelA (NF-κB p65), indicating decreased activation of the pro-inflammatory NF-κB pathway. Using models of mitoOS in cultured macrophages, we showed that mCAT suppressed MCP-1 expression by decreasing activation of the Iκ-kinase-RelA NF-κB pathway. Conclusions MitoOS in lesional macrophages amplifies atherosclerotic lesion development by promoting NF-κB-mediated entry of monocytes and other inflammatory processes. In view of the mitoOS-atherosclerosis link in human atheromata, these findings reveal a potentially new therapeutic target to prevent the progression of atherosclerosis. PMID:24297735

  7. Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE null Mice.

    PubMed

    Chukkapalli, Sasanka S; Velsko, Irina M; Rivera-Kweh, Mercedes F; Zheng, Donghang; Lucas, Alexandra R; Kesavalu, Lakshmyya

    2015-01-01

    Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoE null mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoE null hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoE null mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal

  8. Embryonic development during chronic acceleration

    NASA Technical Reports Server (NTRS)

    Smith, A. H.; Abbott, U. K.

    1982-01-01

    Experiments carried out on chicken eggs indicate that the embryo is affected during very early development, especially over the first four days, and during hatching. In the first four days, the brain develops as well as the anlage for all other organs. In addition, the heart commences to function and the extraembryonic membranes that compartmentalize the egg contents form. The latter require an appreciable extension and folding of tissue which may be disrupted by the mechanical load. Observations of embryonic abnormalities that occur during chronic acceleration suggest an inhibition of development of the axial skeleton, which is rarely seen otherwise, a general retardation of embryonic growth, and circulatory problems. The final stages of development (after 18 days) involve the uptake of fluids, the transition to aerial respiration, and the reorientation of the embryo into a normal hatching position. At 4 G mortality is very high during this period, with a majority of embryos failing to reorient into the normal hatching position.

  9. [Screening for atherosclerosis to prevent cardiovascular risk : a pro-contra debate].

    PubMed

    Nanchen, David; Genest, Jacques

    2018-02-28

    Detecting atherosclerosis using imaging techniques is the subject of intense debate in the scientific community. Among the arguments in favor of screening, a better identification or better stratification of cardiovascular risk is mentioned, compared to cardiovascular risk scores based solely on traditional risk factors, such as blood pressure or cholesterol levels. Imaging techniques are also used to monitor the progression of atherosclerosis among patients using lipid-lowering or antihypertensive drugs in primary prevention. However, several experts in recent years have challenged the clinical utility of these imaging techniques in asymptomatic adults. This article proposes a debate « for or against » to describe the main arguments for or against the use of imaging for screening for atherosclerosis.

  10. Pentosan polysulfate inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits: differential modulation of metalloproteinase-2 and -9.

    PubMed

    Lupia, Enrico; Zheng, Feng; Grosjean, Fabrizio; Tack, Ivan; Doublier, Sophie; Elliot, Sharon J; Vlassara, Helen; Striker, Gary E

    2012-02-01

    Pentosan polysulfate (PPS), a heparinoid compound essentially devoid of anticoagulant activity, modulates cell growth and decreases inflammation. We investigated the effect of PPS on the progression of established atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. After severe atherosclerosis developed on an atherogenic diet, WHHL rabbits were treated with oral PPS or tap water for 1 month. The aortic intima-to-media ratio and macrophage infiltration were reduced, plaque collagen content was increased, and plaque fibrous caps were preserved by PPS treatment. Plasma lipid levels and post-heparin hepatic lipase activity remained unchanged. However, net collagenolytic activity in aortic extracts was decreased, and the levels of matrix metalloproteinase (MMP)-2 and tissue inhibitor of metalloproteinase (TIMP) activity were increased by PPS. Moreover, PPS treatment decreased tumor necrosis factor α (TNFα)-stimulated proinflammatory responses, in particular activation of nuclear factor-κB and p38, and activation of MMPs in macrophages. In conclusion, oral PPS treatment prevents progression of established atherosclerosis in WHHL rabbits. This effect may be partially mediated by increased MMP-2 and TIMP activities in the aortic wall and reduced TNFα-stimulated inflammation and MMP activation in macrophages. Thus, PPS may be a useful agent in inhibiting the progression of atherosclerosis.

  11. Pentosan polysulfate inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits: differential modulation of metalloproteinase-2 and -9

    PubMed Central

    Lupia, Enrico; Zheng, Feng; Grosjean, Fabrizio; Tack, Ivan; Doublier, Sophie; Elliot, Sharon J; Vlassara, Helen; Striker, Gary E

    2013-01-01

    Pentosan polysulfate (PPS), a heparinoid compound essentially devoid of anticoagulant activity, modulates cell growth and decreases inflammation. We investigated the effect of PPS on the progression of established atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. After severe atherosclerosis developed on an atherogenic diet, WHHL rabbits were treated with oral PPS or tap water for 1 month. The aortic intima-to-media ratio and macrophage infiltration were reduced, plaque collagen content was increased, and plaque fibrous caps were preserved by PPS treatment. Plasma lipid levels and post-heparin hepatic lipase activity remained unchanged. However, net collagenolytic activity in aortic extracts was decreased, and the levels of matrix metalloproteinase (MMP)-2 and tissue inhibitor of metalloproteinase (TIMP) activity were increased by PPS. Moreover, PPS treatment decreased tumor necrosis factor α (TNFα)-stimulated proinflammatory responses, in particular activation of nuclear factor-κB and p38, and activation of MMPs in macrophages. In conclusion, oral PPS treatment prevents progression of established atherosclerosis in WHHL rabbits. This effect may be partially mediated by increased MMP-2 and TIMP activities in the aortic wall and reduced TNFα-stimulated inflammation and MMP activation in macrophages. Thus, PPS may be a useful agent in inhibiting the progression of atherosclerosis. PMID:22042083

  12. Circulating smooth muscle progenitor cells in atherosclerosis and plaque rupture: current perspective and methods of analysis.

    PubMed

    Bentzon, Jacob F; Falk, Erling

    2010-01-01

    Smooth muscle cells play a critical role in the development of atherosclerosis and its clinical complications. They were long thought to derive entirely from preexisting smooth muscle cells in the arterial wall, but this understanding has been challenged by the claim that circulating bone marrow-derived smooth muscle progenitor cells are an important source of plaque smooth muscle cells in human and experimental atherosclerosis. This theory is today accepted by many cardiovascular researchers and authors of contemporary review articles. Recently, however, we and others have refuted the existence of bone marrow-derived smooth muscle cells in animal models of atherosclerosis and other arterial diseases based on new experiments with high-resolution microscopy and improved techniques for smooth muscle cell identification and tracking. These studies have also pointed to a number of methodological deficiencies in some of the seminal papers in the field. For those unaccustomed with the methods used in this research area, it must be difficult to decide what to believe and why to do so. In this review, we summarize current knowledge about the origin of smooth muscle cells in atherosclerosis and direct the reader's attention to the methodological challenges that have contributed to the confusion in the field. 2009 Elsevier Inc. All rights reserved.

  13. Bone mineral density and atherosclerosis: The Multi-Ethnic Study of Atherosclerosis, Abdominal Aortic Calcium Study

    PubMed Central

    Hyder, Joseph A; Allison, Matthew A; Barrett-Connor, Elizabeth; Detrano, Robert; Wong, Nathan D; Sirlin, Claude; Gapstur, Susan M; Ouyang, Pamela; Carr, J Jeffrey; Criqui, Michael H

    2009-01-01

    Context Molecular and cell biology studies have demonstrated an association between bone and arterial wall disease, but the significance of a population-level association is less clear and potentially confounded by inability to account for shared risk factors. Objective To test population-level associations between atherosclerosis types and bone integrity. Main Outcome Measures Volumetric trabecular lumbar bone mineral density (vBMD), ankle-brachial index (ABI), intima-media thickness of the common carotid (CCA-IMT) and internal carotid (ICA-IMT) arteries, and carotid plaque echogenicity. Design, Setting and Participants A random subset of participants from the Multi-Ethnic Study of Atherosclerosis (MESA) assessed between 2002 and 2005. Results 904 post-menopausal female (62.4 years; 62% non-white; 12% ABI<1; 17% CCA-IMT>1mm; 33% ICA-IMT>1mm) and 929 male (61.4 years; 58% non-white; 6% ABI<1; 25% CCA-IMT>1mm; 40% ICA-IMT>1mm) were included. In serial, sex-specific regression models adjusting for age, ethnicity, body mass index, dyslipidemia, hypertension, smoking, alcohol consumption, diabetes, homocysteine, interleukin-6, sex hormones, and renal function, lower vBMD was associated with lower ABI in men (p for trend <0.01) and greater ICA-IMT in men (p for trend <0.02). CCA-IMT was not associated with vBMD in men or women. Carotid plaque echogenicity was independently associated with lower vBMD in both men (trend p=0.01) and women (trend p<0.04). In all models, adjustment did not materially affect results. Conclusions Lower vBMD is independently associated with structural and functional measures of atherosclerosis in men and with more advanced and calcified carotid atherosclerotic plaques in both sexes. PMID:19819456

  14. Lipoicmethylenedioxyphenol Reduces Experimental Atherosclerosis through Activation of Nrf2 Signaling

    PubMed Central

    Ying, Zhekang; Chen, Minjie; Xie, Xiaoyun; Wang, Xiaoke; Kherada, Nisharahmed; Desikan, Rajagopal; Mihai, Georgeta; Burns, Patrick; Sun, Qinghua; Rajagopalan, Sanjay

    2016-01-01

    Objective Oxidative stress is implicated in the pathogenesis of atherosclerosis, and Nrf2 is the transcriptional factor central in cellular antioxidant responses. In the present study, we investigate the effect of a dihydrolipoic acid derivative lipoicmethylenedioxyphenol (LMDP) on the progression of atherosclerosis and test whether its effect on atherosclerosis is mediated by Nrf2. Methods and Results Both magnetic resonance imaging (MRI) scanning and en face analysis reveal that 14 weeks of treatment with LMDP markedly reduced atherosclerotic burden in a rabbit balloon vascular injury model. Myograph analyses show decreased aortic contractile response to phenylephrine and increased aortic response to acetylcholine and insulin in LMDP-treated animals, suggesting that LMDP inhibits atherosclerosis through improving vascular function. A role of Nrf2 signaling in mediating the amelioration of vascular function by LMDP was supported by increased Nrf2 translocation into nuclear and increased expression of Nrf2 target genes. Furthermore, chemotaxis analysis with Boydem chamber shows that leukocytes isolated from LMDP-treated rabbits had reduced chemotaxis, and knock-down of Nrf2 significantly reduced the effect of LMDP on the chemotaxis of mouse macrophages. Conclusion Our results support that LMDP has an anti-atherosclerotic effect likely through activation of Nrf2 signaling and subsequent inhibition of macrophage chemotaxis. PMID:26859892

  15. Evaluation of the biomechanics of atherosclerosis by acoustic microscopy

    NASA Astrophysics Data System (ADS)

    Saijo, Yoshifumi; Nitta, Shin-ichi; Schiott Jorgensen, Claus; Falk, Erling

    2001-07-01

    Acoustic microscopy provides not only the morphology, but also the biomechanical properties of the biological soft tissues. The biomechanics of atherosclerosis is important because the pathophysiology of atherosclerosis is closely related with mechanical properties and mechanical stress. Rupture of the fibrous cap of atheromatous plaque is the initial event in acute coronary syndrome such as acute myocardial infarction or unstable angina. In addition to extrinsic physical stresses to the plaque, the intrinsic biomechanical property of the plaque is important for assessing the mechanism of the rupture. Two sets of SAMs operating in 100 to 200 MHz and in 800 MHz to 1.3 GHz were equipped to measure the acoustic properties of atherosclerosis of human or mouse arteries. The values of attenuation and sound speed in the tissue components of atherosclerosis were measured by analyzing the frequency dependent characteristics of the amplitude and phase signals. Both values were highest in calcification and lowest in lipid pool. Although attenuation and sound speed were relatively high in intimal fibrosis, the inhomogeneity of acoustic parameters was found within the fibrous cap. Polarized microscopy for the collagen stained with Picrosirius red showed that the attenuation of ultrasound was significantly higher in type I collagen with orange polarized color compared to type III collagen with green color. SAM has shown the possibility to detect the plaque vulnerability and it might improve our understanding of the sudden rupture from micro-mechanical point of view.

  16. Short Telomeres, but Not Telomere Attrition Rates, Are Associated With Carotid Atherosclerosis.

    PubMed

    Toupance, Simon; Labat, Carlos; Temmar, Mohamed; Rossignol, Patrick; Kimura, Masayuki; Aviv, Abraham; Benetos, Athanase

    2017-08-01

    Short telomeres are associated with atherosclerosis. However, the temporal relationship between atherosclerosis and telomere length is unclear. The objective of this work was to examine the temporal formation and progression of carotid atherosclerotic plaques in relation to telomere dynamics. In a longitudinal study, comprising 154 French men and women (aged 31-76 years at baseline), carotid plaques were quantified by echography, and telomere length on leucocytes was measured by Southern blots at baseline and follow-up examinations. Telomere attrition rates during the 9.5-year follow-up period were not different in individuals with plaques at both baseline and follow-up examinations (23.3±2.0 base pairs/y) than in individuals who developed plaques during the follow-up period (26.5±2.0 base pairs/y) and those without plaques at either baseline or follow-up examination (22.5±2.3 base pairs/y; P =0.79). At baseline, telomere length was associated with presence of carotid plaques ( P =0.02) and with the number of regions with plaques ( P =0.005). An interaction ( P =0.03) between age and the presence of plaques was observed, such that the association between plaques and telomere length was more pronounced at a younger age. In conclusion, carotid atherosclerosis is not associated with increased telomere attrition during a 9.5-year follow-up period. Short telomere length is more strongly associated with early-onset than late-onset carotid atherosclerosis. Our results support the thesis that heightened telomere attrition during adult life might not explain the short telomeres observed in subjects with atherosclerotic disease. Rather, short telomeres antecedes the clinical manifestation of the disease. © 2017 American Heart Association, Inc.

  17. Coronary calcification in SLE: comparison with the Multi-Ethnic Study of Atherosclerosis.

    PubMed

    Kiani, Adnan N; Magder, Laurence S; Post, Wendy S; Szklo, Moyses; Bathon, Joan M; Schreiner, Pam J; O'Leary, Daniel; Petri, Michelle

    2015-11-01

    Accelerated atherosclerosis is a major cause of morbidity and death in SLE. The purpose of this study was to determine whether the prevalence and extent of coronary artery calcium (CAC) is higher in female SLE patients compared with a non-SLE sample from the Multi-Ethnic Study of Atherosclerosis (MESA). CAC was measured in 80 female SLE patients and 241 female MESA controls from the Baltimore Field Centre, ages 45-64 years, without evidence of clinical cardiovascular disease. Binary regression was used to estimate the ratio of CAC prevalence in SLE vs MESA controls, controlling for demographic and cardiovascular risk factors. To compare the groups with respect to the quantity of CAC among those with non-zero Agatston scores, we used linear models in which the outcome was a log-transformed Agatston score. The prevalence of CAC was substantially higher in SLE. The differences were most pronounced and statistically significant in those aged 45-54 years (58% vs 20%, P < 0.0001), but were still observed among those aged 55-65 years (57% vs 36%, P = 0.069). After controlling for age, ethnicity, education, income, diabetes mellitus, hypertension, hyperlipidaemia, high-density lipoprotein levels, smoking, education and BMI, SLE patients still had a significantly higher prevalence of CAC than controls. Among those with CAC, the mean log Agatston score did not differ significantly between SLE and MESA participants. Women with SLE have a higher prevalence of CAC than comparable women without SLE, even after adjusting for traditional cardiovascular risk factors, especially among those aged 45-54 years. Published by Oxford University Press 2015. This work is written by US Government employees and is in the public domain in the US.

  18. Cell-derived microparticles in atherosclerosis: biomarkers and targets for pharmacological modulation?

    PubMed

    Baron, Morgane; Boulanger, Chantal M; Staels, Bart; Tailleux, Anne

    2012-07-01

    Cardiovascular diseases remain an important cause of morbi-mortality. Atherosclerosis, which predisposes to cardiovascular disorders such as myocardial infarction and stroke, develops silently over several decades. Identification of circulating biomarkers to evaluate cardiovascular event risk and pathology prognosis is of particular importance. Microparticles (MPs) are small vesicles released from cells upon apoptosis or activation. Microparticles are present in blood of healthy individuals. Studies showing a modification of their concentrations in patients with cardiovascular risk factors and after cardiovascular events identify MPs as potential biomarkers of disease. Moreover, the pathophysiological properties of MPs may contribute to atherosclerosis development. In addition, pharmacological compounds, used in the treatment of cardiovascular disease, can reduce plasma MP concentrations. Nevertheless, numerous issues remain to be solved before MP measurement can be applied as routine biological tests to improve cardiovascular risk prediction. In particular, prospective studies to identify the predictive values of MPs in pathologies such as cardiovascular diseases are needed to demonstrate whether MPs are useful biomarkers for the early detection of the disease and its progression. © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  19. [25 year experience with using surgical correction of dislipidemia in treatment of patients with atherosclerosis].

    PubMed

    Sedov, V M; Mirchuk, K K; Sedletskiĭ, Iu I

    2011-01-01

    An analysis of results of using partial ileoshunting for the treatment of dislipidemia in 159 patients with atherosclerosis has shown that operation of partial ileoshunting has an obligatory, pronounced and lifelong lipidcorrecting effect. An antiatherogenic effect of the operation of partial ileoshunting is manifested as the improvement of the clinical course of the disease caused by atherosclerosis, by less number of thrombotic complications of atherosclerosis and less lethality from cardio-vascular diseases. At a longer follow-up period, the efficiency of partial ileoshunting as a means of secondary prophylactics of atherosclerosis is confirmed but in case of liquidation after operation of dislipoproteidemia.

  20. Healthy Lifestyle Change and Subclinical Atherosclerosis in Young Adults: Coronary Artery Risk Development in Young Adults (CARDIA) Study

    PubMed Central

    Spring, Bonnie; Moller, Arlen C.; Colangelo, Laura A.; Siddique, Juned; Roehrig, Megan; Daviglus, Martha L.; Polak, Joseph F.; Reis, Jared P.; Sidney, Stephen; Liu, Kiang

    2015-01-01

    Background The benefits of healthy habits are well-established, but it is unclear whether making health behavior changes as an adult can still alter coronary artery disease risk. Methods and Results The Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study (n = 3538) assessed 5 healthy lifestyle factors (HLFs) among young adults between ages 18–30 (Year 0 baseline) and 20 years later (Year 20): not overweight/obese, low alcohol intake, healthy diet, physically active, nonsmoker. We tested whether change from Year 0 to 20 in a continuous composite HLF score (HLF change; range: −5 to +5) is associated with subclinical atherosclerosis [coronary artery calcification (CAC) and carotid intima-media thickness (IMT)] at Year 20, after adjustment for demographics, medications, and baseline HLFs. By Year 20, 25·3% of the sample improved (HLF change ≥ +1); 40·4% deteriorated (had fewer HLFs); 34·4% stayed the same; 19·2% had CAC (>0). Each increase in HLFs was associated with reduced odds of detectable CAC (OR = .85, 95% CI: .74 – .98) and lower IMT (carotid bulb β = −.024, p = 0.001), and each decrease in HLFs was predictive to a similar degree of greater odds of CAC (OR = 1.17, 95% CI: 1.02 – 1.33) and greater IMT (β = +.020, p < 0.01). Conclusions Healthy lifestyle changes during young adulthood are associated with decreased, and unhealthy lifestyle changes with increased risk for subclinical atherosclerosis in middle age. PMID:24982115

  1. Vehicle Systems Integration Laboratory Accelerates Powertrain Development

    ScienceCinema

    None

    2018-05-23

    ORNL's Vehicle Systems Integration (VSI) Laboratory accelerates the pace of powertrain development by performing prototype research and characterization of advanced systems and hardware components. The VSI Lab is capable of accommodating a range of platforms from advanced light-duty vehicles to hybridized Class 8 powertrains with the goals of improving overall system efficiency and reducing emissions.

  2. Animal models of surgically manipulated flow velocities to study shear stress-induced atherosclerosis.

    PubMed

    Winkel, Leah C; Hoogendoorn, Ayla; Xing, Ruoyu; Wentzel, Jolanda J; Van der Heiden, Kim

    2015-07-01

    Atherosclerosis is a chronic inflammatory disease of the arterial tree that develops at predisposed sites, coinciding with locations that are exposed to low or oscillating shear stress. Manipulating flow velocity, and concomitantly shear stress, has proven adequate to promote endothelial activation and subsequent plaque formation in animals. In this article, we will give an overview of the animal models that have been designed to study the causal relationship between shear stress and atherosclerosis by surgically manipulating blood flow velocity profiles. These surgically manipulated models include arteriovenous fistulas, vascular grafts, arterial ligation, and perivascular devices. We review these models of manipulated blood flow velocity from an engineering and biological perspective, focusing on the shear stress profiles they induce and the vascular pathology that is observed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. A Correlational Study on Cerebral Microbleeds and Carotid Atherosclerosis in Patients with Ischemic Stroke.

    PubMed

    Zhao, Fang-Fang; Gao, Hao-Yuan; Gao, Yuan; Zhao, Zhuan; Li, Juan; Ning, Fang-Bo; Zhang, Xin-Na; Wang, Zhi-Gao; Yu, Ai-Ling; Guo, Yan-Yong; Sun, Bao-Liang

    2018-05-11

    This study aimed to investigate the correlation between cerebral microbleeds and carotid atherosclerosis in patients with ischemic stroke. Patients with ischemic stroke treated in a hospital in China from 2016 to 2017 were enrolled in the study. Based on the results from susceptibility-weighted imaging, the patients were divided into cerebral microbleed and noncerebral microbleed groups. The degree of carotid atherosclerosis was assessed with carotid intima-media thickness (CIMB) and Crouse score of carotid plaque. The details of patients' demographic information, cerebrovascular disease-related risk factors, carotid atherosclerosis indices, cerebral microbleed distribution, and grading were recorded, compared, and analyzed. Logistic regression analysis of the 198 patients showed that CIMB and Crouse score were significantly correlated with the occurrence of cerebral microbleeds. The CIMB thickening group (P = .03) and the plaque group (P = .01) were more susceptible to cerebral microbleeds. In the distribution of cerebral microbleed sites, Crouse scores were the highest in the mixed group and showed a statistically significant difference (P < .01). As the degree of carotid atherosclerosis increased, the average number of cerebral microbleeds also increased (P < .01). The receiver operating characteristic curve analysis of the carotid atherosclerosis indices showed a statistically significant difference. The CIMB value combined with the Crouse score was the best indicator (P < .01). In patients with ischemic stroke, cerebral microbleeds are closely related to carotid atherosclerosis. Active control of carotid atherosclerosis is important to prevent cerebral microbleeds in patients with ischemic stroke. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  4. Cytokines in atherosclerosis: Key players in all stages of disease and promising therapeutic targets

    PubMed Central

    Ramji, Dipak P.; Davies, Thomas S.

    2015-01-01

    Atherosclerosis, a chronic inflammatory disorder of the arteries, is responsible for most deaths in westernized societies with numbers increasing at a marked rate in developing countries. The disease is initiated by the activation of the endothelium by various risk factors leading to chemokine-mediated recruitment of immune cells. The uptake of modified lipoproteins by macrophages along with defective cholesterol efflux gives rise to foam cells associated with the fatty streak in the early phase of the disease. As the disease progresses, complex fibrotic plaques are produced as a result of lysis of foam cells, migration and proliferation of vascular smooth muscle cells and continued inflammatory response. Such plaques are stabilized by the extracellular matrix produced by smooth muscle cells and destabilized by matrix metalloproteinase from macrophages. Rupture of unstable plaques and subsequent thrombosis leads to clinical complications such as myocardial infarction. Cytokines are involved in all stages of atherosclerosis and have a profound influence on the pathogenesis of this disease. This review will describe our current understanding of the roles of different cytokines in atherosclerosis together with therapeutic approaches aimed at manipulating their actions. PMID:26005197

  5. Aging, Atherosclerosis, and IGF-1

    PubMed Central

    Higashi, Yusuke; Sukhanov, Sergiy; Anwar, Asif; Shai, Shaw-Yung

    2012-01-01

    Insulin-like growth factor 1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that circulates at high levels in the plasma and is expressed in most cell types. IGF-1 has major effects on development, cell growth and differentiation, and tissue repair. Recent evidence indicates that IGF-1 reduces atherosclerosis burden and improves features of atherosclerotic plaque stability in animal models. Potential mechanisms for this atheroprotective effect include IGF-1–induced reduction in oxidative stress, cell apoptosis, proinflammatory signaling, and endothelial dysfunction. Aging is associated with increased vascular oxidative stress and vascular disease, suggesting that IGF-1 may exert salutary effects on vascular aging processes. In this review, we will provide a comprehensive update on IGF-1's ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging. PMID:22491965

  6. Xanthine Oxidase Inhibition by Febuxostat Attenuates Experimental Atherosclerosis in Mice

    PubMed Central

    Nomura, Johji; Busso, Nathalie; Ives, Annette; Matsui, Chieko; Tsujimoto, Syunsuke; Shirakura, Takashi; Tamura, Mizuho; Kobayashi, Tsunefumi; So, Alexander; Yamanaka, Yoshihiro

    2014-01-01

    Atherosclerosis is a chronic inflammatory disease due to lipid deposition in the arterial wall. Multiple mechanisms participate in the inflammatory process, including oxidative stress. Xanthine oxidase (XO) is a major source of reactive oxygen species (ROS) and has been linked to the pathogenesis of atherosclerosis, but the underlying mechanisms remain unclear. Here, we show enhanced XO expression in macrophages in the atherosclerotic plaque and in aortic endothelial cells in ApoE−/− mice, and that febuxostat, a highly potent XO inhibitor, suppressed plaque formation, reduced arterial ROS levels and improved endothelial dysfunction in ApoE−/− mice without affecting plasma cholesterol levels. In vitro, febuxostat inhibited cholesterol crystal-induced ROS formation and inflammatory cytokine release in murine macrophages. These results demonstrate that in the atherosclerotic plaque, XO-mediated ROS formation is pro-inflammatory and XO-inhibition by febuxostat is a potential therapy for atherosclerosis. PMID:24686534

  7. Apolipoprotein-containing lipoprotein subclasses and subclinical atherosclerosis in systemic lupus erythematosus.

    PubMed

    Kiani, Adnan N; Fang, Hong; Akhter, Ehtisham; Quiroga, Carmen; Simpson, Nancy; Alaupovic, Petar; Magder, Laurence S; Petri, Michelle

    2015-03-01

    Traditional classification of hyperlipidemia using high-density lipoprotein, low-density lipoprotein (LDL), and very low-density lipoprotein does not provide information on lipoprotein function. Apolipoproteins (Apos), which are protein components of plasma lipoproteins (including A, B, C, D, E) with their different composition, metabolic, and atherogenic properties, provide insight on lipoprotein functioning. In particular, the Apo B/A-I ratio is associated with atherogenic LDL and development of cardiovascular disease. We explored the baseline association between these nontraditional risk factors with subclinical measures of atherosclerosis (coronary artery calcification [CAC] and carotid intima-media thickness [IMT]) in systemic lupus erythematosus (SLE). A total of 58 SLE patients (97% women, 58% white, 40% African American, and 2% other, mean ± SD age 44 ± 11 years) had measurement of Apo and lipoproteins by immunoturbidimetric procedures, electroimmunoassays, and immunoprecipitation. CAC was measured by helical computed tomography and carotid IMT by carotid duplex. This study was based on the baseline assessment of subclinical atherosclerosis in the Lupus Atherosclerosis Prevention Study. The measurement of the lipoproteins was made on sera collected at the same time. There was no association between cardioprotective Apos (Apo A-I, LpA-I, LpA-I:A-II) and CAC (P < 0.15, P < 0.41, and P < 0.39, respectively) or carotid IMT (P < 0.97, P < 0.53, and P < 0.76, respectively). CAC and carotid IMT did not associate with atherogenic Apos either, including LpB:E+LpB:C:E, Apo B, LpB, LpB:C, Apo C-III, Apo C-III-HS, Apo C-III-HP, Apo C-III-R, LpA-II:B:C:D:E, and Apo B/Apo A-I. Measures of disease activity, including physician's global assessment and Systemic Lupus Erythematosus Disease Activity Index, were not associated with CAC or carotid IMT. Neither cardioprotective nor atherogenic lipoproteins were associated with measures of subclinical atherosclerosis in this

  8. Regulatory T cells in atherosclerosis: critical immune regulatory function and therapeutic potential.

    PubMed

    Spitz, Charlotte; Winkels, Holger; Bürger, Christina; Weber, Christian; Lutgens, Esther; Hansson, Göran K; Gerdes, Norbert

    2016-03-01

    Atherosclerosis is a chronic inflammatory disease that is mediated by innate and adaptive immune responses. The disease is characterized by sub-endothelial accumulation and modification of lipids in the artery wall triggering an inflammatory reaction which promotes lesion progression and eventual plaque rupture, thrombus formation, and the respective clinical sequelae such as myocardial infarction or stroke. During the past decade, T-cell-mediated immune responses, especially control of pro-inflammatory signals by regulatory T cells (Tregs), have increasingly attracted the interest of experimental and clinical researchers. By suppression of T cell proliferation and secretion of anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-β, Tregs exert their atheroprotective properties. Atherosclerosis-prone, hyperlipidemic mice harbor systemically less Tregs compared to wild-type mice, suggesting an imbalance of immune cells which affects local and systemic inflammatory and potentially metabolic processes leading to atherogenesis. Restoring or increasing Treg frequency and enhancing their suppressive capacity by various modulations may pose a promising approach for treating inflammatory conditions such as cardiovascular diseases. In this review, we briefly summarize the immunological basics of atherosclerosis and introduce the role and contribution of different subsets of T cells. We then discuss experimental data and current knowledge pertaining to Tregs in atherosclerosis and perspectives on manipulating the adaptive immune system to alleviate atherosclerosis and cardiovascular disease.

  9. Quantifying progression and regression of thrombotic risk in experimental atherosclerosis

    PubMed Central

    Palekar, Rohun U.; Jallouk, Andrew P.; Goette, Matthew J.; Chen, Junjie; Myerson, Jacob W.; Allen, John S.; Akk, Antonina; Yang, Lihua; Tu, Yizheng; Miller, Mark J.; Pham, Christine T. N.; Wickline, Samuel A.; Pan, Hua

    2015-01-01

    Currently, there are no generally applicable noninvasive methods for defining the relationship between atherosclerotic vascular damage and risk of focal thrombosis. Herein, we demonstrate methods to delineate the progression and regression of vascular damage in response to an atherogenic diet by quantifying the in vivo accumulation of semipermeable 200–300 nm perfluorocarbon core nanoparticles (PFC-NP) in ApoE null mouse plaques with [19F] magnetic resonance spectroscopy (MRS). Permeability to PFC-NP remained minimal until 12 weeks on diet, then increased rapidly following 12 weeks, but regressed to baseline within 8 weeks after diet normalization. Markedly accelerated clotting (53.3% decrease in clotting time) was observed in carotid artery preparations of fat-fed mice subjected to photochemical injury as defined by the time to flow cessation. For all mice on and off diet, an inverse linear relationship was observed between the permeability to PFC-NP and accelerated thrombosis (P = 0.02). Translational feasibility for quantifying plaque permeability and vascular damage in vivo was demonstrated with clinical 3 T MRI of PFC-NP accumulating in plaques of atherosclerotic rabbits. These observations suggest that excessive permeability to PFC-NP may indicate prothrombotic risk in damaged atherosclerotic vasculature, which resolves within weeks after dietary therapy.—Palekar, R. U., Jallouk, A. P., Goette, M. J., Chen, J., Myerson, J. W., Allen, J. S., Akk, A., Yang, L., Tu, Y., Miller, M. J., Pham, C. T. N., Wickline, S. A., Pan, H. Quantifying progression and regression of thrombotic risk in experimental atherosclerosis. PMID:25857553

  10. LOX-1 in atherosclerosis: biological functions and pharmacological modifiers

    PubMed Central

    Xu, Suowen; Ogura, Sayoko; Chen, Jiawei; Little, Peter J.; Moss, Joel; Liu, Peiqing

    2013-01-01

    Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1, also known as OLR-1), is a class E scavenger receptor that mediates the uptake of oxLDL by vascular cells. LOX-1 is involved in endothelial dysfunction, monocyte adhesion, the proliferation, migration, and apoptosis of smooth muscle cells, foam cell formation, platelet activation, as well as plaque instability; all of these events are critical in the pathogenesis of atherosclerosis. These LOX-1-dependent biological processes contribute to plaque instability and the ultimate clinical sequelae of plaque rupture and life-threatening tissue ischemia. Administration of anti-LOX-1 antibodies inhibits atherosclerosis by decreasing these cellular events. Over the past decade, multiple drugs including naturally occurring antioxidants, statins, antiinflammatory agents, antihypertensive and antihyperglycemic drugs have been demonstrated to inhibit vascular LOX-1 expression and activity. Therefore, LOX-1 represents an attractive therapeutic target for the treatment of human atherosclerotic diseases. This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOX-1 by vasculoprotective drugs, and the importance of LOX-1 in the pathogenesis of atherosclerosis. PMID:23124189

  11. Dihydromyricetin ameliorates atherosclerosis in LDL receptor deficient mice.

    PubMed

    Liu, Ting Ting; Zeng, Yi; Tang, Kun; Chen, XueMeng; Zhang, Wei; Xu, Xiao Le

    2017-07-01

    Dihydromyricetin, the most abundant flavonoid in Ampelopsis grossedentata, exerts numerous pharmacological activities, including anti-inflammatory, antioxidant, hepatoprotective, and lipid regulatory activities; however, its protective effect against atherosclerosis remains poorly understood. The aim of the present study was to evaluate the effects of dihydromyricetin on high fat diet (HFD)-induced atherosclerosis using LDL receptor deficient (LDLr -/- ) mice. Blood samples were collected for determination of serum lipid profiles, oxidized LDL (ox-LDL) and pro-inflammatory cytokines. Histology, hepatic lipid content, quantification of atherosclerosis, assessment of oxidative stress and inflammation were performed on liver and aorta samples by molecular biology methods. The effects of dihydromyricetin on ox-LDL-induced human umbilical vein endothelial cells (HUVECs) dysfunction and foam cell formation were further studied. (1) Dihydromyricetin ameliorated hyperlipidemia, reduced serum ox-LDL, IL-6 and TNF-α levels in HFD-fed LDLr -/- mice. Moreover, (2) dihydromyricetin suppressed hepatic lipid accumulation and increased protein expressions of PPARα, LXRα and ABCA1. (3) It inhibited atherosclerotic lesion formation and favoured features of plaque stability. (4) Dihydromyricetin prevented hepatic and aortic inflammation as evidenced by the reduced IL-6 and TNF-α mRNA expression; (5) it prevented hepatic and aortic oxidative stress by normalizing activities of antioxidant enzymes in the liver and suppressing reactive oxygen species generation and NOX2 protein expression in both liver and aorta; (6) it inhibited oxLDL-induced injury, monocytes adhesion and oxidative stress in HUVECs and (7) inhibited macrophage foam cell formation and enhanced cholesterol efflux. These findings suggest that dihydromyricetin could reduce atherosclerosis via its pleiotropic effects, including improvement of endothelial dysfunction, inhibition of macrophage foam cell formation

  12. Ambient Air Pollution and Atherosclerosis in Los Angeles

    PubMed Central

    Künzli, Nino; Jerrett, Michael; Mack, Wendy J.; Beckerman, Bernardo; LaBree, Laurie; Gilliland, Frank; Thomas, Duncan; Peters, John; Hodis, Howard N.

    2005-01-01

    Associations have been found between long-term exposure to ambient air pollution and cardiovascular morbidity and mortality. The contribution of air pollution to atherosclerosis that underlies many cardiovascular diseases has not been investigated. Animal data suggest that ambient particulate matter (PM) may contribute to atherogenesis. We used data on 798 participants from two clinical trials to investigate the association between atherosclerosis and long-term exposure to ambient PM up to 2.5 μm in aerodynamic diameter (PM2.5). Baseline data included assessment of the carotid intima-media thickness (CIMT), a measure of subclinical atherosclerosis. We geocoded subjects’ residential areas to assign annual mean concentrations of ambient PM2.5. Exposure values were assigned from a PM2.5 surface derived from a geostatistical model. Individually assigned annual mean PM2.5 concentrations ranged from 5.2 to 26.9 μg/m3 (mean, 20.3). For a cross-sectional exposure contrast of 10 μg/m3 PM2.5, CIMT increased by 5.9% (95% confidence interval, 1–11%). Adjustment for age reduced the coefficients, but further adjustment for covariates indicated robust estimates in the range of 3.9–4.3% (p-values, 0.05–0.1). Among older subjects (≥60 years of age), women, never smokers, and those reporting lipid-lowering treatment at baseline, the associations of PM2.5 and CIMT were larger with the strongest associations in women ≥60 years of age (15.7%, 5.7–26.6%). These results represent the first epidemiologic evidence of an association between atherosclerosis and ambient air pollution. Given the leading role of cardiovascular disease as a cause of death and the large populations exposed to ambient PM2.5, these findings may be important and need further confirmation. PMID:15687058

  13. Advanced low-beta cavity development for proton and ion accelerators

    NASA Astrophysics Data System (ADS)

    Conway, Z. A.; Kelly, M. P.; Ostroumov, P. N.

    2015-05-01

    Recent developments in designing and processing low-beta superconducting cavities at Argonne National Laboratory are very encouraging for future applications requiring compact proton and ion accelerators. One of the major benefits of these accelerating structures is achieving real-estate accelerating gradients greater than 3 MV/m very efficiently either continuously or for long-duty cycle operation (>1%). The technology has been implemented in low-beta accelerator cryomodules for the Argonne ATLAS heavy-ion linac where the cryomodules are required to have real-estate gradients of more than 3 MV/m. In offline testing low-beta cavities with even higher gradients have already been achieved. This paper will review this work where we have achieved surface fields greater than 166 mT magnetic and 117 MV/m electric in a 72 MHz quarter-wave resonator optimized for β = 0.077 ions.

  14. Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κB-mediated inflammation in macrophages.

    PubMed

    Wang, Ying; Wang, Gary Z; Rabinovitch, Peter S; Tabas, Ira

    2014-01-31

    Mitochondrial oxidative stress (mitoOS) has been shown to correlate with the progression of human atherosclerosis. However, definitive cell type-specific causation studies in vivo are lacking, and the molecular mechanisms of potential proatherogenic effects remain to be determined. Our aims were to assess the importance of macrophage mitoOS in atherogenesis and to explore the underlying molecular mechanisms. We first validated Western diet-fed Ldlr(-/-) mice as a model of human mitoOS-atherosclerosis association by showing that non-nuclear oxidative DNA damage, a marker of mitoOS in lesional macrophages, correlates with aortic root lesion development. To investigate the importance of macrophage mitoOS, we used a genetic engineering strategy in which the OS suppressor catalase was ectopically expressed in mitochondria (mCAT) in macrophages. MitoOS in lesional macrophages was successfully suppressed in these mice, and this led to a significant reduction in aortic root lesional area. The mCAT lesions had less monocyte-derived cells, less Ly6c(hi) monocyte infiltration into lesions, and lower levels of monocyte chemotactic protein-1. The decrease in lesional monocyte chemotactic protein-1 was associated with the suppression of other markers of inflammation and with decreased phosphorylation of RelA (NF-κB p65), indicating decreased activation of the proinflammatory NF-κB pathway. Using models of mitoOS in cultured macrophages, we showed that mCAT suppressed monocyte chemotactic protein-1 expression by decreasing the activation of the IκB-kinase β-RelA NF-κB pathway. MitoOS in lesional macrophages amplifies atherosclerotic lesion development by promoting NF-κB-mediated entry of monocytes and other inflammatory processes. In view of the mitoOS-atherosclerosis link in human atheromata, these findings reveal a potentially new therapeutic target to prevent the progression of atherosclerosis.

  15. Air pollution is associated with the development of atherosclerosis via the cooperation of CD36 and NLRP3 inflammasome in ApoE-/- mice.

    PubMed

    Du, Xihao; Jiang, Shuo; Zeng, Xuejiao; Zhang, Jia; Pan, Kun; Zhou, Ji; Xie, Yuquan; Kan, Haidong; Song, Weimin; Sun, Qinghua; Zhao, Jinzhuo

    2018-06-15

    Previous studies have indicated that the main air pollutant fine particulate matter (≤2.5 μm; PM 2.5 ) exposure is associated with the development of atherosclerosis. Although the mechanism is not fully illustrated, the inflammatory responses play an important role. The present study aimed to explore whether PM 2.5 -exacerbated atherosclerosis was mediated by the cooperation of cluster of differentiation 36 (CD36) and nucleotide-binding oligomerization domain-like receptor protein (NLRP3) inflammasome in apolipoprotein E -/- (ApoE -/- ) mice. Thirty-two ApoE -/- mice were randomly divided into two groups. One group was fed with high fat chow (HFC) for 10 weeks to establish atherosclerotic model, and the other was fed with normal chow (NC). From week 11, the mice were exposed to concentrated PM 2.5 (PM) or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System for 16 weeks. In both NC and HFC groups, PM 2.5 exposure induced the formation of atherosclerosis plaque. Similarly, PM mice appeared higher lipid content in the aortic root than that in the FA mice. Compared with the FA mice, PM mice appeared a decrease in high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 along with an increase in apolipoprotein B, low density lipoprotein-cholesterol (LDL-C) and oxidized low-density lipoprotein (ox-LDL). Moreover, PM 2.5 exposure induced increase of CD36 in serum and aorta. In both NC and HFC groups, NLRP3 inflammasome activation-related indicators were activated or increased in the aorta of the PM mice when compared with the FA mice. The cooperation of CD36 and NLRP3 inflammasome activation may be the potential mechanisms linkixposed to concentrated PM 2.5 (PM) or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System for 16 weeks. In both NC and HFC groups, PM 2.5 exposure induced the formation of atherosclerosis plaque. Similarly, PM mice appeared higher lipid content in the aortic

  16. P2Y receptors and atherosclerosis in apolipoprotein E-deficient mice

    PubMed Central

    Guns, Pieter-Jan DF; Hendrickx, Jan; Van Assche, Tim; Fransen, Paul; Bult, Hidde

    2010-01-01

    Background and purpose: P2Y nucleotide receptors are involved in the regulation of vascular tone, smooth muscle cell (SMC) proliferation and inflammatory responses. The present study investigated whether they are involved in atherosclerosis. Experimental approach: mRNA of P2Y receptors was quantified (RT-PCR) in atherosclerotic and plaque-free aorta segments of apolipoprotein E-deficient (apoE–/–) mice. Macrophage activation was assessed in J774 macrophages, and effects of non-selective purinoceptor antagonists on atherosclerosis were evaluated in cholesterol-fed apoE–/– mice. Key results: P2Y6 receptor mRNA was consistently elevated in segments with atherosclerosis, whereas P2Y2 receptor expression remained unchanged. Expression of P2Y1 or P2Y4 receptor mRNA was low or undetectable, and not influenced by atherosclerosis. P2Y6 mRNA expression was higher in cultured J774 macrophages than in cultured aortic SMCs. Furthermore, immunohistochemical staining of plaques demonstrated P2Y6-positive macrophages, but few SMCs, suggesting that macrophage recruitment accounted for the increase in P2Y6 receptor mRNA during atherosclerosis. In contrast to ATP, the P2Y6-selective agonist UDP increased mRNA expression and activity of inducible nitric oxide synthase and interleukin-6 in J774 macrophages; this effect was blocked by suramin (100–300 µM) or pyridoxal-phosphate-6-azophenyl-2′-4′-disulphonic acid (PPADS, 10–30 µM). Finally, 4-week treatment of cholesterol-fed apoE–/– mice with suramin or PPADS (50 and 25 mg·kg−1·day−1 respectively) reduced plaque size, without changing plaque composition (relative SMC and macrophage content) or cell replication. Conclusions and implications: These results suggest involvement of nucleotide receptors, particularly P2Y6 receptors, during atherosclerosis, and warrant further research with selective purinoceptor antagonists or P2Y6 receptor-deficient mice. PMID:20050854

  17. Association of subclinical atherosclerosis using carotid intima-media thickness, carotid plaque, and coronary calcium score with left ventricular dyssynchrony: the multi-ethnic Study of Atherosclerosis.

    PubMed

    Sharma, Ravi K; Donekal, Sirisha; Rosen, Boaz D; Tattersall, Matthew C; Volpe, Gustavo J; Ambale-Venkatesh, Bharath; Nasir, Khurram; Wu, Colin O; Polak, Joseph F; Korcarz, Claudia E; Stein, James H; Carr, James; Watson, Karol E; Bluemke, David A; Lima, João A C

    2015-04-01

    The role of atherosclerosis in the progression of global left ventricular dysfunction and cardiovascular events has been well recognized. Left ventricular (LV) dyssynchrony is a measure of regional myocardial dysfunction. Our objective was to investigate the relationship of subclinical atherosclerosis with mechanical LV dyssynchrony in a population-based asymptomatic multi-ethnic cohort. Participants of the Multi-Ethnic Study of Atherosclerosis (MESA) at exam 5 were evaluated using 1.5T cardiac magnetic resonance (CMR) imaging, carotid ultrasound (n = 2062) for common carotid artery (CCA) and internal carotid artery (ICA) intima-media thickness (IMT), and cardiac computed tomography (n = 2039) for coronary artery calcium (CAC) assessment (Agatston method). Dyssynchrony indices were defined as the standard deviation of time to peak systolic circumferential strain (SD-TPS) and the difference between maximum and minimum (max-min) time to peak strain using harmonic phase imaging in 12 segments (3-slices × 4 segments). Multivariable regression analyses were performed to assess associations after adjusting for participant demographics, cardiovascular risk factors, LV mass, and ejection fraction. In multivariable analyses, SD-TPS was significantly related to measures of atherosclerosis, including CCA-IMT (8.7 ms/mm change in IMT, p = 0.020), ICA-IMT (19.2 ms/mm change in IMT, p < 0.001), carotid plaque score (1.2 ms/unit change in score, p < 0.001), and log transformed CAC+1 (0.66 ms/unit log-CAC+1, p = 0.018). These findings were consistent with other parameter of LV dyssynchrony i.e. max-min. In the MESA cohort, measures of atherosclerosis are associated with parameters of subclinical LV dyssynchrony in the absence of clinical coronary event and left-bundle-branch block. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. Premenopausal Antimullerian Hormone Concentration is Associated with Subsequent Atherosclerosis

    PubMed Central

    Appt, Susan E.; Chen, Haiying; Clarkson, Thomas B.; Kaplan, Jay R.

    2012-01-01

    Objective To determine if premenopausal ovarian reserve is associated with susceptibility for atherosclerosis. Methods Female cynomologus macaques (n = 66, women’s equivalent age = 45 yrs) consumed an atherogenic diet for ~5 months prior to the measurement of a marker of ovarian reserve (antimüllerian hormone, AMH), plasma lipids, follicular phase estradiol (E2) and body weight (BW). Monkeys were then ovariectomized (OVX, n =17) remained premenopausal (PRE, n=20) or induced to have reduce ovarian reserve (ROR, n=29). After 26 additional months on the diet, atherosclerosis measurements and risk variables were reassessed. Results No differences in baseline AMH, plasma lipids, BW, E2 or post-diet lipids and BW, were observed among the groups subsequently assigned to OVX, PRE or ROR conditions. Post-diet measurements of atherosclerosis extent did not differ among the groups. However, analysis of plaque size by tertile of baseline AMH revealed that plaques were largest in monkeys that began the experiment with the lowest baseline AMH, followed by those in the middle and high tertiles (plaque extent mm2: Low AMH = 0.76 ± 0.12, Mid AMH = 0.46 ± 0.1, High AMH = 0.34 ± 0.08, p=0.02). Baseline AMH and plaque size were also correlated negatively (r = −0.31, p = 0.01). Plasma lipids were also correlated significantly with plaque extent (all p’s <0.01), but not with AMH. Conclusions We report for the first time an inverse relationship between a marker of ovarian reserve (AMH) and subsequent atherosclerosis risk. PMID:22929037

  19. Adventitial fibroblasts are activated in the early stages of atherosclerosis in the apolipoprotein E knockout mouse

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Xu Fang; Ji Jian; Li Li

    2007-01-19

    The role of the adventitia in vascular function and vascular lesion formation has been largely ignored. This study observed the activation of the adventitia and specifically the fibroblasts in the development of atherosclerosis in the apoE(-/-) mouse. The results showed a gradual increase in expression of collagen types I and III after 2, 4, and 8 weeks of hyperlipidic diet. The earliest expression of monocyte chemoattractant protein-1 (MCP-1) protein and mRNA was detected in the adventitial fibroblast before the formation of intimal lesions. Proliferation, too, was first found in the adventitial fibroblasts. We hypothesize that the adventitial fibroblast is activatedmore » in the early stage of atherosclerosis. Adventitial inflammation may be an early event in the development of atherosclerotic lesions.« less

  20. Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits.

    PubMed

    Sugano, M; Makino, N; Sawada, S; Otsuka, S; Watanabe, M; Okamoto, H; Kamada, M; Mizushima, A

    1998-02-27

    Cholesteryl ester transfer protein (CETP) is the enzyme that facilitates the transfer of cholesteryl ester from high density lipoprotein (HDL) to apolipoprotein B (apoB)-containing lipoproteins. However, the exact role of CETP in the development of atherosclerosis has not been determined. In the present study, we examined the effect of the suppression of increased plasma CETP by intravenous injection with antisense oligodeoxynucleotides (ODNs) against CETP targeted to the liver on the development of atherosclerosis in rabbits fed a cholesterol diet. The ODNs against rabbit CETP were coupled to asialoglycoprotein (ASOR) carrier molecules, which serve as an important method to regulate liver gene expression. Twenty-two male Japanese White rabbits were used in the experiment. Eighteen animals were fed a standard rabbit chow supplemented with 0.3% cholesterol throughout the experiment for 16 weeks. At 8 weeks, they were divided into three groups (six animals in each group), among which the plasma total and HDL cholesterol concentrations did not significantly change. The control group received nothing, the sense group were injected with the sense ODNs complex, and the antisense group were injected with the antisense ODNs complex, respectively, for subsequent 8 weeks. ASOR. poly(L-lysine) ODNs complex were injected via the ear veins twice a week. Four animals were fed a standard rabbit diet for 16 weeks. The total cholesterol concentrations and the CETP mass in the animals injected with antisense ODNs were all significantly decreased in 12 and 16 weeks compared with those injected with sense ODNs and the control animals. The HDL cholesterol concentrations measured by the precipitation assay did not significantly change among the groups fed a cholesterol diet, and triglyceride concentrations did not significantly change in the four groups. However, at the end of the study, when the HDL cholesterol concentrations were measured after the isolation by ultracentrifugation and

  1. The protective role of Sirt1 in vascular tissue: its relationship to vascular aging and atherosclerosis.

    PubMed

    Kitada, Munehiro; Ogura, Yoshio; Koya, Daisuke

    2016-10-15

    Cardiovascular disease (CVD) due to atherosclerosis is the main cause of death in both the elderly and patients with metabolic diseases, including diabetes. Aging processes contribute to the pathogenesis of atherosclerosis. Calorie restriction (CR) is recognized as a dietary intervention for promoting longevity and delaying age-related diseases, including atherosclerosis. Sirt1, an NAD + -dependent deacetylase, is considered an anti-aging molecule and is induced during CR. Sirt1 deacetylates target proteins and is linked to cellular metabolism, the redox state and survival pathways. Sirt1 expression/activation is decreased in vascular tissue undergoing senescence. Sirt1 deficiency in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and monocytes/macrophages contributes to increased oxidative stress, inflammation, foam cell formation, senescences impaired nitric oxide production and autophagy, thereby promoting vascular aging and atherosclerosis. Endothelial dysfunction, activation of monocytes/macrophages, and the functional and phenotypical plasticity of VSMCs are critically implicated in the pathogenesis of atherosclerosis through multiple mechanisms. Therefore, the activation of Sirt1 in vascular tissue, which includes ECs, monocytes/macrophages and VSMCs, may be a new therapeutic strategy against atherosclerosis and the increasing resistance to the metabolic disorder-related causal factors of CVD. In this review, we discuss the protective role of Sirt1 in the pathophysiology of vascular aging and atherosclerosis.

  2. The protective role of Sirt1 in vascular tissue: its relationship to vascular aging and atherosclerosis

    PubMed Central

    Kitada, Munehiro; Ogura, Yoshio; Koya, Daisuke

    2016-01-01

    Cardiovascular disease (CVD) due to atherosclerosis is the main cause of death in both the elderly and patients with metabolic diseases, including diabetes. Aging processes contribute to the pathogenesis of atherosclerosis. Calorie restriction (CR) is recognized as a dietary intervention for promoting longevity and delaying age-related diseases, including atherosclerosis. Sirt1, an NAD+-dependent deacetylase, is considered an anti-aging molecule and is induced during CR. Sirt1 deacetylates target proteins and is linked to cellular metabolism, the redox state and survival pathways. Sirt1 expression/activation is decreased in vascular tissue undergoing senescence. Sirt1 deficiency in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and monocytes/macrophages contributes to increased oxidative stress, inflammation, foam cell formation, senescences impaired nitric oxide production and autophagy, thereby promoting vascular aging and atherosclerosis. Endothelial dysfunction, activation of monocytes/macrophages, and the functional and phenotypical plasticity of VSMCs are critically implicated in the pathogenesis of atherosclerosis through multiple mechanisms. Therefore, the activation of Sirt1 in vascular tissue, which includes ECs, monocytes/macrophages and VSMCs, may be a new therapeutic strategy against atherosclerosis and the increasing resistance to the metabolic disorder-related causal factors of CVD. In this review, we discuss the protective role of Sirt1 in the pathophysiology of vascular aging and atherosclerosis. PMID:27744418

  3. Development of accelerated net nitrate uptake. [Zea mays L

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    MacKown, C.T.; McClure, P.R.

    1988-05-01

    Upon initial nitrate exposure, net nitrate uptake rates in roots of a wide variety of plants accelerate within 6 to 8 hours to substantially greater rates. Effects of solution nitrate concentrations and short pulses of nitrate ({le}1 hour) upon nitrate-induced acceleration of nitrate uptake in maize (Zea mays L.) were determined. Root cultures of dark-grown seedlings, grown without nitrate, were exposed to 250 micromolar nitrate for 0.25 to 1 hour or to various solution nitrate concentration (10-250 micromolar) for 1 hour before returning them to a nitrate-free solution. Net nitrate uptake rates were assayed at various periods following nitrate exposuremore » and compared to rates of roots grown either in the absence of nitrate (CaSO{sub 4}-grown) or with continuous nitrate for at least 20 hours. Three hours after initial nitrate exposure, nitrate pulse treatments increased nitrate uptake rates three- to four-fold compared to the rates of CaSO{sub 4}-grown roots. When cycloheximide (5 micrograms per milliliter) was included during a 1-hour pulse with 250 micromolar nitrate, development of the accelerated nitrate uptake state was delayed. Otherwise, nitrate uptake rates reached maximum values within 6 hours before declining. Maximum rates, however, were significantly less than those of roots exposed continuously for 20, 32, or 44 hours. Pulsing for only 0.25 hour with 250 micromolar nitrate and for 1 hour with 10 micromolar caused acceleration of nitrate uptake, but the rates attained were either less than or not sustained for a duration comparable to those of roots pulsed for 1 hour with 250 micromolar nitrate. These results indicate that substantial development of nitrate-induced accelerated nitrate uptake state can be achieved by small endogenous accumulations of nitrate, which appear to moderate the activity or level of root nitrate uptake.« less

  4. No Time To Kill: Entrainment and Accelerating Courseware Development.

    ERIC Educational Resources Information Center

    Millington, Paula Crnkovich

    This paper examines the concept of time in multimedia, World Wide Web-based courseware development. The biological concept of entrainment (the alignment of rhythms within and between systems) to accelerate courseware development is explored. The discussion begins with the foundational concepts of entrainment from biological systems and social…

  5. From Lipid Retention to Immune-Mediate Inflammation and Associated Angiogenesis in the Pathogenesis of Atherosclerosis.

    PubMed

    Usman, Ammara; Ribatti, Domenico; Sadat, Umar; Gillard, Jonathan H

    2015-08-26

    Atherosclerosis is a leading cause of mortality and long-term morbidity worldwide. It is a lipoprotein-driven disease that leads to plaque formation at focal areas in the arterial blood vessels through intimal inflammation, necrosis, fibrosis, and calcification. Adventitial and intimal angiogenesis contributes to the progression of intimal hyperplasia and the development of a necrotic core. The volatile nature of an atheromatous plaque is responsible for approximately 60% of symptomatic carotid artery diseases and about 75% of acute coronary events. In this review the pathogenesis of atherosclerosis is discussed from the initial step of lipid retention to advanced stages of immune-mediate inflammation and associated angiogenesis. Mechanisms of plaque rupture are also discussed.

  6. Airflow obstruction, atherosclerosis and cardiovascular risk factors in the AGES Reykjavik study.

    PubMed

    Gudmundsson, Gunnar; Margretardottir, Olof Birna; Sigurdsson, Martin Ingi; Harris, Tamara B; Launer, Lenore J; Sigurdsson, Sigurdur; Olafsson, Orn; Aspelund, Thor; Gudnason, Vilmundur

    2016-09-01

    Airflow limitation, i.e. reduced forced expiratory volume in 1-s (FEV1), is associated with increased prevalence of atherosclerosis, however, causal mechanisms remain elusive. The objective of the study was to determine if the association between airflow obstruction and markers of atherosclerosis is mediated by systemic inflammation. 1154 subjects from the longitudinal AGES Reykjavik study were included. Population characteristics, systemic inflammation markers from blood (white blood cell counts (WBC) and level of C-reactive protein (CRP)) were compared between patients with and without airflow limitation defined by reduced FEV1 on spirometry. Atherosclerosis burden was quantified by measurements of coronary artery calcium, aortic arch and distal aortic calcification in addition to carotid intimal media thickness (CIMT). Subjects were split into four groups according to smoking status and whether airflow limitation was present. There was a higher overall burden of atherosclerosis in ever-smokers compared to never-smokers, and in individuals with airflow obstruction compared to individuals without airflow obstruction. After adjusting for population characteristics, Framingham cardiovascular risk factors and markers of systemic inflammation (WBC and CRP), there was a significantly increased aortic arch and distal aorta calcification and higher CIMT measurement in individuals with airflow obstruction compared to individuals without airflow obstruction. After adjusting for population characteristics, Framingham cardiovascular risk factors and markers of systemic inflammation (WBC and CRP), there was a significantly increased aortic arch and distal aorta calcification and higher CIMT measurement in individuals with airflow obstruction compared to individuals without airflow obstruction. Systemic inflammation (WBC and CRP) does not appear to mediate the association between airflow limitation and atherosclerosis. Only airflow limitation and not systemic inflammation (WBC

  7. A case of primary hypothyroidism causing central nervous system atherosclerosis in a dog.

    PubMed

    Blois, Shauna L; Poma, Roberto; Stalker, Margaret J; Allen, Dana G

    2008-08-01

    A 2-year-old, castrated male, Australian shepherd was presented with a history of chronic mild ataxia, obesity, and lethargy. The dog was treated with levothyroxine, but the ataxia worsened. Cranial nerve abnormalities developed and the dog was euthanized. Postmortem examination revealed marked thyroid gland atrophy and widespread, severe central nervous system atherosclerosis.

  8. Ultraviolet-Visible and Fluorescence Spectroscopy Techniques Are Important Diagnostic Tools during the Progression of Atherosclerosis: Diet Zinc Supplementation Retarded or Delayed Atherosclerosis

    PubMed Central

    Abdelhalim, Mohamed Anwar K.; Moussa, Sherif A. Abdelmottaleb; AL-Mohy, Yanallah Hussain

    2013-01-01

    Background. In this study, we examined whether UV-visible and fluorescence spectroscopy techniques detect the progression of atherosclerosis in serum of rabbits fed on high-cholesterol diet (HCD) and HCD supplemented with zinc (HCD + Zn) compared with the control. Methods. The control rabbits group was fed on 100 g/day of normal diet. The HCD group was fed on Purina Certified Rabbit Chow supplemented with 1.0% cholesterol plus 1.0% olive oil (100 g/day) for the same period. The HCD + Zn group was fed on normal Purina Certified Rabbit Chow plus 1.0% cholesterol and 1.0% olive oil supplemented with 470 ppm Zn for the same feeding period. UV-visible and fluorescence spectroscopy and biochemistry in Rabbit's blood serum and blood hematology were measured in Rabbit's blood. Results. We found that the fluorescent peak of HCD shifted toward UV-visible wavelength compared with the control using fluorescent excitation of serum at 192 nm. In addition, they showed that supplementation of zinc (350 ppm) restored the fluorescent peak closely to the control. By using UV-visible spectroscopy approach, we found that the peak absorbance of HCD (about 280 nm) was higher than that of control and that zinc supplementation seemed to decrease the absorbance. Conclusions. This study demonstrates that ultraviolet-visible and fluorescence spectroscopy techniques can be applied as noninvasive techniques on a sample blood serum for diagnosing or detecting the progression of atherosclerosis. The Zn supplementation to rabbits fed on HCD delays or retards the progression of atherosclerosis. Inducing anemia in rabbits fed on HCD delays the progression of atherosclerosis. PMID:24350281

  9. S100A12 and the S100/Calgranulins - Emerging Biomarkers for Atherosclerosis and Possibly Therapeutic Targets

    PubMed Central

    Oesterle, Adam; Hofmann Bowman, Marion A

    2016-01-01

    Atherosclerosis is mediated by local and systematic inflammation. The multi-ligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans, and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell targeted expression of S100A12 demonstrate increased coronary and aortic calcification as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis susceptible Apolipoprotein E (ApoE) null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the Quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 ApoE null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis. PMID:26515415

  10. Advanced low-beta cavity development for proton and ion accelerators

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Conway, Z. A.; Kelly, M. P.; Ostroumov, P. N.

    2015-05-01

    Recent developments in designing and processing low-beta superconducting cavities at Argonne National Laboratory are very encouraging for future applications requiring compact proton and ion accelerators. One of the major benefits of these accelerating structures is achieving real-estate accelerating gradients greater than 3 MV/m very efficiently either continuously or for long-duty cycle operation (>1%). The technology has been implemented in low-beta accelerator cryomodules for the Argonne ATLAS heavy-ion linac where the cryomodules are required to have real-estate gradients of more than 3 MV/m. In offline testing low-beta cavities with even higher gradients have already been achieved. This paper will review thismore » work where we have achieved surface fields greater than 166 mT magnetic and 117 MV/m electric in a 72 MHz quarter-wave resonator optimized for beta = 0.077 ions.« less

  11. Analysis of the relationship between periodontal disease and atherosclerosis within a local clinical system: a cross-sectional observational pilot study.

    PubMed

    Kudo, Chieko; Shin, Wee Soo; Minabe, Masato; Harai, Kazuo; Kato, Kai; Seino, Hiroaki; Goke, Eiji; Sasaki, Nobuhiro; Fujino, Takemasa; Kuribayashi, Nobuichi; Pearce, Youko Onuki; Taira, Masato; Maeda, Hiroshi; Takashiba, Shogo

    2015-09-01

    It has been revealed that atherosclerosis and periodontal disease may have a common mechanism of "chronic inflammation". Several reports have indicated that periodontal infection is related to atherosclerosis, but none have yet reported such an investigation through the cooperation of local clinics. This study was performed in local Japanese clinics to examine the relationship between periodontal disease and atherosclerosis under collaborative medical and dental care. A pilot multicenter cross-sectional study was conducted on 37 medical patients with lifestyle-related diseases under consultation in participating medical clinics, and 79 periodontal patients not undergoing medical treatment but who were seen by participating dental clinics. Systemic examination and periodontal examination were performed at baseline, and the relationships between periodontal and atherosclerosis-related clinical markers were analyzed. There was a positive correlation between LDL-C level and plasma IgG antibody titer to Porphyromonas gingivalis. According to the analysis under adjusted age, at a cut-off value of 5.04 for plasma IgG titer to Porphyromonas gingivalis, the IgG titer was significantly correlated with the level of low-density lipoprotein cholesterol (LDL-C). This study suggested that infection with periodontal bacteria (Porphyromonas gingivalis) is associated with the progression of atherosclerosis. Plasma IgG titer to Porphyromonas gingivalis may be useful as the clinical risk marker for atherosclerosis related to periodontal disease. Moreover, the application of the blood examination as a medical check may lead to the development of collaborative medical and dental care within the local medical clinical system for the purpose of preventing the lifestyle-related disease.

  12. L-arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice.

    PubMed

    Aji, W; Ravalli, S; Szabolcs, M; Jiang, X C; Sciacca, R R; Michler, R E; Cannon, P J

    1997-01-21

    The potential antiatherosclerotic actions of NO were investigated in four groups of mice (n = 10 per group) lacking functional LDL receptor genes, an animal model of familial hypercholesterolemia. Group 1 was fed a regular chow diet. Groups 2 through 4 were fed a 1.25% high-cholesterol diet. In addition, group 3 received supplemental L-arginine and group 4 received L-arginine and N omega-nitro-L-arginine (L-NA), an inhibitor of NO synthase (NOS). Animals were killed at 6 months; aortas were stained with oil red O for planimetry and with antibodies against constitutive and inducible NOSs. Plasma cholesterol was markedly increased in the animals receiving the high-cholesterol diet. Xanthomas appeared in all mice fed the high-cholesterol diet alone but not in those receiving L-arginine. Aortic atherosclerosis was present in all mice on the high-cholesterol diet. The mean atherosclerotic lesion area was reduced significantly (P < .01) in the cholesterol-fed mice given L-arginine compared with those receiving the high-cholesterol diet alone. The mean atherosclerotic lesion area was significantly larger (P < .01) in cholesterol-fed mice receiving L-arginine + L-NA than in those on the high-cholesterol diet alone. Within the atherosclerotic plaques, endothelial cells immunoreacted for endothelial cell NOS; macrophages, foam cells, and smooth muscle cells immunostained strongly for inducible NOS and nitrotyrosine residues. The data indicate that L-arginine prevents xanthoma formation and reduces atherosclerosis in LDL receptor knockout mice fed a high-cholesterol diet. The abrogation of the beneficial effects of L-arginine by L-NA suggests that the antiatherosclerotic actions of L-arginine are mediated by NOS. The data suggest that L-arginine may be beneficial in familial hypercholesterolemia.

  13. A case of primary hypothyroidism causing central nervous system atherosclerosis in a dog

    PubMed Central

    Blois, Shauna L.; Poma, Roberto; Stalker, Margaret J.; Allen, Dana G.

    2008-01-01

    A 2-year-old, castrated male, Australian shepherd was presented with a history of chronic mild ataxia, obesity, and lethargy. The dog was treated with levothyroxine, but the ataxia worsened. Cranial nerve abnormalities developed and the dog was euthanized. Postmortem examination revealed marked thyroid gland atrophy and widespread, severe central nervous system atherosclerosis. PMID:18978973

  14. A Dietary Mixture Containing Fish Oil, Resveratrol, Lycopene, Catechins, and Vitamins E and C Reduces Atherosclerosis in Transgenic Mice123

    PubMed Central

    Verschuren, Lars; Wielinga, Peter Y.; van Duyvenvoorde, Wim; Tijani, Samira; Toet, Karin; van Ommen, Ben; Kooistra, Teake; Kleemann, Robert

    2011-01-01

    Chronic inflammation and proatherogenic lipids are important risk factors of cardiovascular disease (CVD). Specific dietary constituents such as polyphenols and fish oils may improve cardiovascular risk factors and may have a beneficial effect on disease outcomes. We hypothesized that the intake of an antiinflammatory dietary mixture (AIDM) containing resveratrol, lycopene, catechin, vitamins E and C, and fish oil would reduce inflammatory risk factors, proatherogenic lipids, and endpoint atherosclerosis. AIDM was evaluated in an inflammation model, male human C-reactive protein (CRP) transgenic mice, and an atherosclerosis model, female ApoE*3Leiden transgenic mice. Two groups of male human-CRP transgenic mice were fed AIDM [0.567% (wt:wt) powder and 0.933% (wt:wt oil)] or placebo for 6 wk. The effects of AIDM on basal and IL-1β–stimulated CRP expression were investigated. AIDM reduced cytokine-induced human CRP and fibrinogen expression in human-CRP transgenic mice. In the atherosclerosis study, 2 groups of female ApoE*3Leiden transgenic mice were fed an atherogenic diet supplemented with AIDM [0.567% (wt:wt) powder and 0.933% (wt:wt oil)] or placebo for 16 wk. AIDM strongly reduced plasma cholesterol, TG, and serum amyloid A concentrations compared with placebo. Importantly, long-term treatment of ApoE*3Leiden mice with AIDM markedly reduced the development of atherosclerosis by 96% compared with placebo. The effect on atherosclerosis was paralleled by a reduced expression of the vascular inflammation markers and adhesion molecules inter-cellular adhesion molecule-1 and E-selectin. Dietary supplementation of AIDM improves lipid and inflammatory risk factors of CVD and strongly reduces atherosclerotic lesion development in female transgenic mice. PMID:21411607

  15. Development of advanced technological systems for accelerator transmutation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Batskikh, G.I.; Bondarev, B.I.; Durkin, A.P.

    1995-10-01

    A development concept of the accelerator nuclear energy reactors is considered for energy generation and nuclear power plant waste conversion into short-lived nuclides along with the requirements imposed on the technological systems necessary for implementation of such projects. The state of art in the field is discussed.

  16. Accelerating Child Survival and Development in Dark Times.

    ERIC Educational Resources Information Center

    Grant, James P.

    Measures were proposed that would enable UNICEF, in association with others and despite prevailing difficult economic circumstances, to more effectively bring well-being and hope to hundreds of millions of children. Specific proposals were designed to help most countries accelerate child survival and development. Most particularly, it was…

  17. Olive oil and postprandial hyperlipidemia: implications for atherosclerosis and metabolic syndrome.

    PubMed

    Montserrat-de la Paz, Sergio; Bermudez, Beatriz; Cardelo, Magdalena P; Lopez, Sergio; Abia, Rocio; Muriana, Francisco J G

    2016-12-07

    Olive oil is the primary source of fat in the Mediterranean diet, which is associated with a significant improvement in health status, as measured by reduced mortality from several chronic diseases. The current pandemic of obesity, metabolic syndrome, and type 2 diabetes is intimately associated with an atherogenic dyslipidemic phenotype. The core components of the dyslipidemia of the metabolic syndrome, which most likely initiate atherosclerosis, are the "lipid triad" consisting of high plasma triglycerides, low levels of high-density lipoproteins, and a preponderance of small, dense low-density lipoproteins at fasting. However, postprandial (non-fasting) TGs (postprandial hyperlipidemia) are also recognized as an important component for atherosclerosis. Herein, the purpose of this review was to provide an update on the effects and mechanisms related to olive oil on postprandial hyperlipidemia and its implications for the onset and progression of atherosclerosis and metabolic syndrome.

  18. Loss of LCAT activity in the golden Syrian hamster elicits pro-atherogenic dyslipidemia and enhanced atherosclerosis.

    PubMed

    Dong, Zhao; Shi, Haozhe; Zhao, Mingming; Zhang, Xin; Huang, Wei; Wang, Yuhui; Zheng, Lemin; Xian, Xunde; Liu, George

    2018-06-01

    Lecithin cholesterol acyltransferase (LCAT) plays a pivotal role in HDL metabolism but its influence on atherosclerosis remains controversial for decades both in animal and clinical studies. Because lack of cholesteryl ester transfer protein (CETP) is a major difference between murine and humans in lipoprotein metabolism, we aimed to create a novel Syrian Golden hamster model deficient in LCAT activity, which expresses endogenous CETP, to explore its metabolic features and particularly the influence of LCAT on the development of atherosclerosis. CRISPR/CAS9 gene editing system was employed to generate mutant LCAT hamsters. The characteristics of lipid metabolism and the development of atherosclerosis in the mutant hamsters were investigated using various conventional methods in comparison with wild type control animals. Hamsters lacking LCAT activity exhibited pro-atherogenic dyslipidemia as diminished high density lipoprotein (HDL) and ApoAI, hypertriglyceridemia, Chylomicron/VLDL accumulation and significantly increased ApoB100/48. Mechanistic study for hypertriglyceridemia revealed impaired LPL-mediated lipolysis and increased very low density lipoprotein (VLDL) secretion, with upregulation of hepatic genes involved in lipid synthesis and transport. The pro-atherogenic dyslipidemia in mutant hamsters was exacerbated after high fat diet feeding, ultimately leading to near a 3- and 5-fold increase in atherosclerotic lesions by aortic en face and sinus lesion quantitation, respectively. Our findings demonstrate that LCAT deficiency in hamsters develops pro-atherogenic dyslipidemia and promotes atherosclerotic lesion formation. Published by Elsevier Inc.

  19. Imaging pathobiology of carotid atherosclerosis with ultrasmall superparamagnetic particles of iron oxide: an update.

    PubMed

    Sadat, Umar; Usman, Ammara; Gillard, Jonathan H

    2017-07-01

    To provide brief overview of the developments regarding use of ultrasmall superparamagnetic particles of iron oxide in imaging pathobiology of carotid atherosclerosis. MRI is a promising technique capable of providing morphological and functional information about atheromatous plaques. MRI using iron oxide particles, called ultrasmall superparamagnetic iron oxide (USPIO) particles, allows detection of macrophages in atherosclerotic tissue. Ferumoxytol has emerged as a new USPIO agent, which has an excellent safety profile. Based on the macrophage-selective properties of ferumoxytol, there is increasing number of recent reports suggesting its effectiveness to detect pathological inflammation. USPIO particles allow magnetic resonance detection of macrophages in atherosclerotic tissue. Ferumoxytol has emerged as a new USPIO agent, with an excellent safety profile. This has the potential to be used for MRI of the pathobiology of atherosclerosis.

  20. ApoE−/− PGC-1α−/− Mice Display Reduced IL-18 Levels and Do Not Develop Enhanced Atherosclerosis

    PubMed Central

    Stein, Sokrates; Lohmann, Christine; Handschin, Christoph; Stenfeldt, Elin; Borén, Jan; Lüscher, Thomas F.; Matter, Christian M.

    2010-01-01

    visceral fat in PGC-1α-deficient mice may explain why these mice do not develop enhanced atherosclerosis. PMID:21042583

  1. The role of T and B cells in human atherosclerosis and atherothrombosis

    PubMed Central

    Ammirati, E; Moroni, F; Magnoni, M; Camici, P G

    2015-01-01

    Far from being merely a passive cholesterol accumulation within the arterial wall, the development of atherosclerosis is currently known to imply both inflammation and immune effector mechanisms. Adaptive immunity has been implicated in the process of disease initiation and progression interwined with traditional cardiovascular risk factors. Although the body of knowledge regarding the correlation between atherosclerosis and immunity in humans is growing rapidly, a relevant proportion of it derives from studies carried out in animal models of cardiovascular disease (CVD). However, while the mouse is a well-suited model, the results obtained therein are not fully transferrable to the human setting due to intrinsic genomic and environmental differences. In the present review, we will discuss mainly human findings, obtained either by examination of post-mortem and surgical atherosclerotic material or through the analysis of the immunological profile of peripheral blood cells. In particular, we will discuss the findings supporting a pro-atherogenic role of T cell subsets, such as effector memory T cells or the potential protective function of regulatory T cells. Recent studies suggest that traditional T cell-driven B2 cell responses appear to be atherogenic, while innate B1 cells appear to exert a protective action through the secretion of naturally occurring antibodies. The insights into the immune pathogenesis of atherosclerosis can provide new targets in the quest for novel therapeutic targets to abate CVD morbidity and mortality. PMID:25352024

  2. BSN723T Prevents Atherosclerosis and Weight Gain in ApoE Knockout Mice Fed a Western Diet

    PubMed Central

    Williams, Jarrod; Ensor, Charles; Gardner, Scott; Smith, Rebecca; Lodder, Robert

    2016-01-01

    Objective This study tests the hypothesis that BSN723T can prevent the development of hyperlipidemia and atherosclerosis in ApoE-/- knockout mice fed a Western (high fat, high cholesterol, and high sucrose) diet. BSN723T is a combination drug therapy consisting of D-tagatose and dihydromyricetin (BSN723). Background D-tagatose has an antihyperglycemic effect in animal and human studies and shows promise as a treatment for type 2 diabetes and obesity. Many claims regarding BSN723's pharmacological activities have been made including anti-cancer, anti-diabetic, anti-hypertensive, anti-inflammatory, and anti-atherosclerotic effects. To our knowledge this is the first study that combines D-tagatose and BSN723 for the treatment of hyperlipidemia and the prevention of atherosclerosis. Methods ApoE-deficient mice were randomized into five groups with equivalent mean body weights. The mice were given the following diets for 8 weeks: Group 1 - Standard diet; Group 2 - Western diet; Group 3 - Western diet formulated with D-tagatose; Group 4 - Western diet formulated with BSN723; Group 5 - Western diet formulated with BSN723T. Mice were measured for weight gain, tissue and organ weights, total serum cholesterol and triglycerides and formation of atherosclerosis. Results The addition of D-tagatose, either alone or in combination with BSN723, prevented the increase in adipose tissue and weight gain brought on by the Western diet. Both D-tagatose and BSN723 alone reduced total cholesterol and the formation of atherosclerosis in the aorta compared to mice on the Western diet. Addition of BSN723 to D-tagatose (BSN723T) did not increase efficacy in prevention of increases in cholesterol or atherosclerosis compared to D-tagatose alone. Conclusion Addition of either D-tagatose or BSN723 alone to a Western diet prevented weight gain, increases in total serum cholesterol and triglycerides, and the formation of atherosclerosis. However, there was no additive or synergistic effect on the

  3. BSN723T Prevents Atherosclerosis and Weight Gain in ApoE Knockout Mice Fed a Western Diet.

    PubMed

    Williams, Jarrod; Ensor, Charles; Gardner, Scott; Smith, Rebecca; Lodder, Robert

    This study tests the hypothesis that BSN723T can prevent the development of hyperlipidemia and atherosclerosis in ApoE -/- knockout mice fed a Western (high fat, high cholesterol, and high sucrose) diet. BSN723T is a combination drug therapy consisting of D-tagatose and dihydromyricetin (BSN723). D-tagatose has an antihyperglycemic effect in animal and human studies and shows promise as a treatment for type 2 diabetes and obesity. Many claims regarding BSN723's pharmacological activities have been made including anti-cancer, anti-diabetic, anti-hypertensive, anti-inflammatory, and anti-atherosclerotic effects. To our knowledge this is the first study that combines D-tagatose and BSN723 for the treatment of hyperlipidemia and the prevention of atherosclerosis. ApoE-deficient mice were randomized into five groups with equivalent mean body weights. The mice were given the following diets for 8 weeks: Group 1 - Standard diet; Group 2 - Western diet; Group 3 - Western diet formulated with D-tagatose; Group 4 - Western diet formulated with BSN723; Group 5 - Western diet formulated with BSN723T. Mice were measured for weight gain, tissue and organ weights, total serum cholesterol and triglycerides and formation of atherosclerosis. The addition of D-tagatose, either alone or in combination with BSN723, prevented the increase in adipose tissue and weight gain brought on by the Western diet. Both D-tagatose and BSN723 alone reduced total cholesterol and the formation of atherosclerosis in the aorta compared to mice on the Western diet. Addition of BSN723 to D-tagatose (BSN723T) did not increase efficacy in prevention of increases in cholesterol or atherosclerosis compared to D-tagatose alone. Addition of either D-tagatose or BSN723 alone to a Western diet prevented weight gain, increases in total serum cholesterol and triglycerides, and the formation of atherosclerosis. However, there was no additive or synergistic effect on the measured parameters with the combination BSN

  4. Accelerating Leadership Development via Immersive Learning and Cognitive Apprenticeship

    ERIC Educational Resources Information Center

    Backus, Clark; Keegan, Kevin; Gluck, Charles; Gulick, Lisa M. V.

    2010-01-01

    The authors put forward an approach to leadership development that builds on the principle of accelerated learning. They argue that leadership development, particularly in a period of recession or slow economic growth, needs to deliver results more quickly and with fewer resources. Indeed, they raise the question of whether or not this is what is…

  5. A mechanism by which dietary trans fats cause atherosclerosis.

    PubMed

    Chen, Chun-Lin; Tetri, Laura H; Neuschwander-Tetri, Brent A; Huang, Shuan Shian; Huang, Jung San

    2011-07-01

    Dietary trans fats (TFs) have been causally linked to atherosclerosis, but the mechanism by which they cause the disease remains elusive. Suppressed transforming growth factor (TGF)-β responsiveness in aortic endothelium has been shown to play an important role in the pathogenesis of atherosclerosis in animals with hypercholesterolemia. We investigated the effects of a high TF diet on TGF-β responsiveness in aortic endothelium and integration of cholesterol in tissues. Here, we show that normal mice fed a high TF diet for 24 weeks exhibit atherosclerotic lesions and suppressed TGF-β responsiveness in aortic endothelium. The suppressed TGF-β responsiveness is evidenced by markedly reduced expression of TGF-β type I and II receptors and profoundly decreased levels of phosphorylated Smad2, an important TGF-β response indicator, in aortic endothelium. These mice exhibit greatly increased integration of cholesterol into tissue plasma membranes. These results suggest that dietary TFs cause atherosclerosis, at least in part, by suppressing TGF-β responsiveness. This effect is presumably mediated by the increased deposition of cholesterol into cellular plasma membranes in vascular tissue, as in hypercholesterolemia. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Accelerating Early Language Development with Multi-Sensory Training

    ERIC Educational Resources Information Center

    Bjorn, Piia M.; Kakkuri, Irma; Karvonen, Pirkko; Leppanen, Paavo H. T.

    2012-01-01

    This paper reports the outcome of a multi-sensory intervention on infant language skills. A programme titled "Rhyming Game and Exercise Club", which included kinaesthetic-tactile mother-child rhyming games performed in natural joint attention situations, was intended to accelerate Finnish six- to eight-month-old infants' language development. The…

  7. The Role of Vaspin in the Development of Metabolic and Glucose Tolerance Disorders and Atherosclerosis

    PubMed Central

    Dimova, Rumyana; Tankova, Tsvetalina

    2015-01-01

    In recent years, most research efforts have been focused on studying insulin-sensitizing adipokines. One of the most recently discovered adipokines is vaspin, a visceral adipose tissue-derived serine protease inhibitor. Vaspin levels have been found significantly increased in mice with obesity and insulin resistance. It has been assumed that vaspin serves as an insulin sensitizer with anti-inflammatory effects and might act as a compensatory mechanism in response to decreased insulin sensitivity. Most studies in humans have shown a positive correlation between vaspin gene expression and serum levels, and metabolic syndrome parameters. Vaspin gene expression is influenced by age and gender, and the administration of insulin sensitizers enhances it in mice, whereas the use of metformin decreases serum vaspin levels in humans, probably due to different regulatory mechanisms. Presumably vaspin plays local and endocrine role in the development of initial and advanced atherosclerosis in obese subjects and might be used as a predictor of coronary and cerebrovascular disease. It is believed that vaspin could be regarded as a new link between obesity and related metabolic disorders, including glucose intolerance. The entire understanding of vaspin intimate mechanism of action might enable the development of novel etiology-based treatment strategies, targeting metabolic and glucose tolerance disorders. PMID:25945347

  8. Endothelial cell metabolism: A novel player in atherosclerosis? Basic principles and therapeutic opportunities.

    PubMed

    Pircher, Andreas; Treps, Lucas; Bodrug, Natalia; Carmeliet, Peter

    2016-10-01

    Atherosclerosis is a leading cause of morbidity and mortality in Western society. Despite improved insight into disease pathogenesis and therapeutic options, additional treatment strategies are required. Emerging evidence highlights the relevance of endothelial cell (EC) metabolism for angiogenesis, and indicates that EC metabolism is perturbed when ECs become dysfunctional to promote atherogenesis. In this review, we overview the latest insights on EC metabolism and discuss current knowledge on how atherosclerosis deregulates EC metabolism, and how maladaptation of deregulated EC metabolism can contribute to atherosclerosis progression. We will also highlight possible therapeutic avenues, based on targeting EC metabolism. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets.

    PubMed

    Ren, Kun; Jiang, Ting; Zheng, Xi-Long; Zhao, Guo-Jun

    2017-07-01

    Furin, a member of the mammalian proprotein convertases family, can promote the proteolytic maturation of proproteins. It is known that furin is predominantly present in certain cell types of human atherosclerotic lesions and neointima in animal models, including vascular smooth muscle cells, endothelial cells and mononuclear inflammatory cells. Evidence suggests that furin participates in the initiation and progression of atherosclerosis through regulation of lipid and cholesterol metabolism, inflammatory response, blood pressure and the formation of atherosclerotic lesions. This review provides a panorama of the roles of furin in atherosclerosis and the insights into the prevention and treatment of atherosclerosis and cardiovascular disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. A Protocol for Diagnosis and Management of Aortic Atherosclerosis in Cardiac Surgery Patients

    PubMed Central

    Brandon Bravo Bruinsma, George J.; Van 't Hof, Arnoud W. J.; Grandjean, Jan G.; Nierich, Arno P.

    2017-01-01

    In patients undergoing cardiac surgery, use of perioperative screening for aortic atherosclerosis with modified TEE (A-View method) was associated with lower postoperative mortality, but not stroke, as compared to patients operated on without such screening. At the time of clinical implementation and validation, we did not yet standardize the indications for modified TEE and the changes in patient management in the presence of aortic atherosclerosis. Therefore, we designed a protocol, which combined the diagnosis of atherosclerosis of thoracic aorta and the subsequent considerations with respect to the intraoperative management and provides a systematic approach to reduce the risk of cerebral complications. PMID:28852575

  11. Cardiorespiratory Fitness and Atherosclerosis: Recent Data and Future Directions.

    PubMed

    Mehanna, Emile; Hamik, Anne; Josephson, Richard A

    2016-05-01

    Historically, the relationship between exercise and the cardiovascular system was viewed as unidirectional, with a disease resulting in exercise limitation and hazard. This article reviews and explores the bidirectional nature, delineating the effects, generally positive, on the cardiovascular system and atherosclerosis. Exercise augments eNOS, affects redox potential, and favorably affects mediators of atherosclerosis including lipids, glucose homeostasis, and inflammation. There are direct effects on the vasculature as well as indirect benefits related to exercise-induced changes in body composition and skeletal muscle. Application of aerobic exercise to specific populations is described, with the hope that this knowledge will move the science forward and improve individual patient outcome.

  12. Cardiorespiratory Fitness and Atherosclerosis: Recent Data and Future Directions

    PubMed Central

    Mehanna, Emile; Hamik, Anne; Josephson, Richard A

    2017-01-01

    Historically the relationship between exercise and the cardiovascular system was viewed as unidirectional, with disease resulting in exercise limitation and hazard. This article reviews and explores the bidirectional nature, delineating the effects, generally positive, on the cardiovascular system and atherosclerosis. Exercise augments eNOS, affects redox potential, and favorably affects mediators of atherosclerosis including lipids, glucose homeostasis, and inflammation. There are direct effects on the vasculature as well as indirect benefits related to exercises induced changes in body composition and skeletal muscle. Application of aerobic exercise to specific populations is described, with the hope that this knowledge will move the science forward and improve individual patient outcome. PMID:27005804

  13. Dietary rice protein isolate attenuates atherosclerosis in apoE-deficient mice by upregulating antioxidant enzymes

    USDA-ARS?s Scientific Manuscript database

    Rice-based diets may have been reported to protect against the development of atherosclerosis; however, the underlying mechanism(s) for this protection remains unknown. In this report, the mechanism(s) contributing to the atheroprotective effects of rice-based diet was addressed using the apolipopro...

  14. Low Levels of CD36 in Peripheral Blood Monocytes in Subclinical Atherosclerosis in Rheumatoid Arthritis: A Cross-Sectional Study in a Mexican Population

    PubMed Central

    Gómez-Bañuelos, Eduardo; Martín-Márquez, Beatriz Teresita; Martínez-García, Erika Aurora; Figueroa-Sanchez, Mauricio; Nuñez-Atahualpa, Lourdes; Rocha-Muñoz, Alberto Daniel; Sánchez-Hernández, Pedro Ernesto; Navarro-Hernandez, Rosa Elena; Madrigal-Ruiz, Perla Monserrat; Saldaña-Millan, Adan Alberto; Duran-Barragan, Sergio; Gonzalez-Lopez, Laura; Gamez-Nava, Jorge Ivan; Vázquez-Del Mercado, Mónica

    2014-01-01

    Patients with rheumatoid arthritis (RA) have a higher risk for atherosclerosis. There is no clinical information about scavenger receptor CD36 and the development of subclinical atherosclerosis in patients with RA. The aim of this study was to evaluate the association between membrane expression of CD36 in peripheral blood mononuclear cells (PBMC) and carotid intima-media thickness (cIMT) in patients with RA. Methods. We included 67 patients with RA from the Rheumatology Department of Hospital Civil “Dr. Juan I. Menchaca,” Guadalajara, Jalisco, Mexico. We evaluated the cIMT, considering subclinical atherosclerosis when >0.6 mm. Since our main objective was to associate the membrane expression of CD36 with subclinical atherosclerosis, other molecules related with cardiovascular risk such as ox-LDL, IL-6, and TNFα were tested. Results. We found low CD36 membrane expression in PBMC from RA patients with subclinical atherosclerosis (P < 0.001). CD36 mean fluorescence intensity had negative correlations with cIMT (r = −0.578, P < 0.001), ox-LDL (r = −0.427, P = 0.05), TNFα (r = −0.729, P < 0.001), and IL-6 (r = −0.822, P < 0.001). Conclusion. RA patients with subclinical atherosclerosis showed low membrane expression of CD36 in PBMC and increased serum proinflammatory cytokines. Further studies are needed to clarify the regulation of CD36 in RA. PMID:25006585

  15. Low levels of CD36 in peripheral blood monocytes in subclinical atherosclerosis in rheumatoid arthritis: a cross-sectional study in a Mexican population.

    PubMed

    Gómez-Bañuelos, Eduardo; Martín-Márquez, Beatriz Teresita; Martínez-García, Erika Aurora; Figueroa-Sanchez, Mauricio; Nuñez-Atahualpa, Lourdes; Rocha-Muñoz, Alberto Daniel; Sánchez-Hernández, Pedro Ernesto; Navarro-Hernandez, Rosa Elena; Madrigal-Ruiz, Perla Monserrat; Saldaña-Millan, Adan Alberto; Duran-Barragan, Sergio; Gonzalez-Lopez, Laura; Gamez-Nava, Jorge Ivan; Vázquez-Del Mercado, Mónica

    2014-01-01

    Patients with rheumatoid arthritis (RA) have a higher risk for atherosclerosis. There is no clinical information about scavenger receptor CD36 and the development of subclinical atherosclerosis in patients with RA. The aim of this study was to evaluate the association between membrane expression of CD36 in peripheral blood mononuclear cells (PBMC) and carotid intima-media thickness (cIMT) in patients with RA. We included 67 patients with RA from the Rheumatology Department of Hospital Civil "Dr. Juan I. Menchaca," Guadalajara, Jalisco, Mexico. We evaluated the cIMT, considering subclinical atherosclerosis when >0.6 mm. Since our main objective was to associate the membrane expression of CD36 with subclinical atherosclerosis, other molecules related with cardiovascular risk such as ox-LDL, IL-6, and TNFα were tested. We found low CD36 membrane expression in PBMC from RA patients with subclinical atherosclerosis (P < 0.001). CD36 mean fluorescence intensity had negative correlations with cIMT (r = -0.578, P < 0.001), ox-LDL (r = -0.427, P = 0.05), TNFα (r = -0.729, P < 0.001), and IL-6 (r = -0.822, P < 0.001). RA patients with subclinical atherosclerosis showed low membrane expression of CD36 in PBMC and increased serum proinflammatory cytokines. Further studies are needed to clarify the regulation of CD36 in RA.

  16. Connecting the Lines between Hypogonadism and Atherosclerosis

    PubMed Central

    Fahed, Akl C.; Gholmieh, Joanna M.; Azar, Sami T.

    2012-01-01

    Epidemiological studies show that atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality worldwide and point to gender differences with ageing males being at highest risk. Atherosclerosis is a complex process that has several risk factors and mediators. Hypogonadism is a commonly undiagnosed disease that has been associated with many of the events, and risk factors leading to atherosclerosis. The mechanistic relations between testosterone levels, atherosclerotic events, and risk factors are poorly understood in many instances, but the links are clear. In this paper, we summarize the research journey that explains the link between hypogonadism, each of the atherosclerotic events, and risk factors. We look into the different areas from which lessons could be learned, including epidemiological studies, animal and laboratory experiments, studies on androgen deprivation therapy patients, and studies on testosterone-treated patients. We finish by providing recommendations for the clinician and needs for future research. PMID:22518131

  17. Development of the Accelerator Mass Spectrometry technology at the Comenius University in Bratislava

    NASA Astrophysics Data System (ADS)

    Povinec, Pavel P.; Masarik, Jozef; Ješkovský, Miroslav; Kaizer, Jakub; Šivo, Alexander; Breier, Robert; Pánik, Ján; Staníček, Jaroslav; Richtáriková, Marta; Zahoran, Miroslav; Zeman, Jakub

    2015-10-01

    An Accelerator Mass Spectrometry (AMS) laboratory has been established at the Centre for Nuclear and Accelerator Technologies (CENTA) at the Comenius University in Bratislava comprising of a MC-SNICS ion source, 3 MV Pelletron tandem accelerator, and an analyzer of accelerated ions. The preparation of targets for 14C and 129I AMS measurements is described in detail. The development of AMS techniques for potassium, uranium and thorium analysis in radiopure materials required for ultra-low background underground experiments is briefly mentioned.

  18. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ

    PubMed Central

    Li, Andrew C.; Binder, Christoph J.; Gutierrez, Alejandra; Brown, Kathleen K.; Plotkin, Christine R.; Pattison, Jennifer W.; Valledor, Annabel F.; Davis, Roger A.; Willson, Timothy M.; Witztum, Joseph L.; Palinski, Wulf; Glass, Christopher K.

    2004-01-01

    PPARα, β/δ, and γ regulate genes involved in the control of lipid metabolism and inflammation and are expressed in all major cell types of atherosclerotic lesions. In vitro studies have suggested that PPARs exert antiatherogenic effects by inhibiting the expression of proinflammatory genes and enhancing cholesterol efflux via activation of the liver X receptor–ABCA1 (LXR-ABCA1) pathway. To investigate the potential importance of these activities in vivo, we performed a systematic analysis of the effects of PPARα, β, and γ agonists on foam-cell formation and atherosclerosis in male LDL receptor–deficient (LDLR–/–) mice. Like the PPARγ agonist, a PPARα-specific agonist strongly inhibited atherosclerosis, whereas a PPARβ-specific agonist failed to inhibit lesion formation. In concert with their effects on atherosclerosis, PPARα and PPARγ agonists, but not the PPARβ agonist, inhibited the formation of macrophage foam cells in the peritoneal cavity. Unexpectedly, PPARα and PPARγ agonists inhibited foam-cell formation in vivo through distinct ABCA1-independent pathways. While inhibition of foam-cell formation by PPARα required LXRs, activation of PPARγ reduced cholesterol esterification, induced expression of ABCG1, and stimulated HDL-dependent cholesterol efflux in an LXR-independent manner. In concert, these findings reveal receptor-specific mechanisms by which PPARs influence macrophage cholesterol homeostasis. In the future, these mechanisms may be exploited pharmacologically to inhibit the development of atherosclerosis. PMID:15578089

  19. Lactobacillus acidophilus ATCC 4356 Prevents Atherosclerosis via Inhibition of Intestinal Cholesterol Absorption in Apolipoprotein E-Knockout Mice

    PubMed Central

    Wang, Jinfeng; Quan, Guihua; Wang, Xiaojun; Yang, Longfei; Zhong, Lili

    2014-01-01

    The objective of this study was to investigate the effect of Lactobacillus acidophilus ATCC 4356 on the development of atherosclerosis in apolipoprotein E-knockout (ApoE−/−) mice. Eight-week-old ApoE−/− mice were fed a Western diet with or without L. acidophilus ATCC 4356 daily for 16 weeks. L. acidophilus ATCC 4356 protected ApoE−/− mice from atherosclerosis by reducing their plasma cholesterol levels from 923 ± 44 to 581 ± 18 mg/dl, likely via a marked decrease in cholesterol absorption caused by modulation of Niemann-Pick C1-like 1 (NPC1L1). In addition, suppression of cholesterol absorption induced reverse cholesterol transport (RCT) in macrophages through the peroxisome proliferator-activated receptor/liver X receptor (PPAR/LXR) pathway. Fecal lactobacillus and bifidobacterium counts were significantly (P < 0.05) higher in the L. acidophilus ATCC 4356 treatment groups than in the control groups. Furthermore, L. acidophilus ATCC 4356 was detected in the rat small intestine, colon, and feces during the feeding trial. The bacterial levels remained high even after the administration of lactic acid bacteria had been stopped for 2 weeks. These results suggest that administration of L. acidophilus ATCC 4356 can protect against atherosclerosis through the inhibition of intestinal cholesterol absorption. Therefore, L. acidophilus ATCC 4356 may be a potential therapeutic material for preventing the progression of atherosclerosis. PMID:25261526

  20. Smoking and atherosclerosis: mechanisms of disease and new therapeutic approaches.

    PubMed

    Siasos, Gerasimos; Tsigkou, Vasiliki; Kokkou, Eleni; Oikonomou, Evangelos; Vavuranakis, Manolis; Vlachopoulos, Charalambos; Verveniotis, Alexis; Limperi, Maria; Genimata, Vasiliki; Papavassiliou, Athanasios G; Stefanadis, Christodoulos; Tousoulis, Dimitris

    2014-01-01

    It has been clear that at least 1 billion adults worldwide are smokers and at least 700 million children are passive smokers at home. Smoking exerts a detrimental effect to many organ systems and is responsible for illnesses such as lung cancer, pneumonia, chronic obstructive pulmonary disease, cancer of head and neck, cancer of the urinary and gastrointestinal tract, periodontal disease, cataract and arthritis. Additionally, smoking is an important modifiable risk factor for the development of cardiovascular disease such as coronary artery disease, stable angina, acute coronary syndromes, sudden death, stroke, peripheral vascular disease, congestive heart failure, erectile dysfunction and aortic aneurysms via initiation and progression of atherosclerosis. A variety of studies has proved that cigarette smoking induces oxidative stress, vascular inflammation, platelet coagulation, vascular dysfunction and impairs serum lipid pro-file in both current and chronic smokers, active and passive smokers and results in detrimental effects on the cardiovascular system. The aim of this review is to depict the physical and biochemical properties of cigarette smoke and, furthermore, elucidate the main pathophysiological mechanisms of cigarette-induced atherosclerosis and overview the new therapeutic approaches for smoking cessation and augmentation of cardiovascular health.

  1. Impact of Prediabetic Status on Coronary Atherosclerosis

    PubMed Central

    Kurihara, Osamu; Takano, Masamichi; Yamamoto, Masanori; Shirakabe, Akihiro; Kimata, Nakahisa; Inami, Toru; Kobayashi, Nobuaki; Munakata, Ryo; Murakami, Daisuke; Inami, Shigenobu; Okamatsu, Kentaro; Ohba, Takayoshi; Ibuki, Chikao; Hata, Noritake; Seino, Yoshihiko; Mizuno, Kyoichi

    2013-01-01

    OBJECTIVE To determine if prediabetes is associated with atherosclerosis of coronary arteries, we evaluated the degree of coronary atherosclerosis in nondiabetic, prediabetic, and diabetic patients by using coronary angioscopy to identify plaque vulnerability based on yellow color intensity. RESEARCH DESIGN AND METHODS Sixty-seven patients with coronary artery disease (CAD) underwent angioscopic observation of multiple main-trunk coronary arteries. According to the American Diabetes Association guidelines, patients were divided into nondiabetic (n = 16), prediabetic (n = 28), and diabetic (n = 23) groups. Plaque color grade was defined as 1 (light yellow), 2 (yellow), or 3 (intense yellow) based on angioscopic findings. The number of yellow plaques (NYPs) per vessel and maximum yellow grade (MYG) were compared among the groups. RESULTS Mean NYP and MYG differed significantly between the groups (P = 0.01 and P = 0.047, respectively). These indexes were higher in prediabetic than in nondiabetic patients (P = 0.02 and P = 0.04, respectively), but similar in prediabetic and diabetic patients (P = 0.44 and P = 0.21, respectively). Diabetes and prediabetes were independent predictors of multiple yellow plaques (NYPs ≥2) in multivariate logistic regression analysis (odds ratio [OR] 10.8 [95% CI 2.09–55.6], P = 0.005; and OR 4.13 [95% CI 1.01–17.0], P = 0.049, respectively). CONCLUSIONS Coronary atherosclerosis and plaque vulnerability were more advanced in prediabetic than in nondiabetic patients and comparable between prediabetic and diabetic patients. Slight or mild disorders in glucose metabolism, such as prediabetes, could be a risk factor for CAD, as is diabetes itself. PMID:23223344

  2. Association between diabetic retinopathy and subclinical atherosclerosis in China: Results from a community-based study.

    PubMed

    Liu, Yu; Teng, Xiangyu; Zhang, Wei; Zhang, Ruifeng; Liu, Wei

    2015-09-01

    To evaluate the association of diabetic retinopathy with subclinical atherosclerosis in middle-aged and elderly Chinese with type 2 diabetes. A cross-sectional community-based study was performed among 1607 patients aged 40 years or older in Shanghai. Non-mydriatic digital fundus photography examination was used in diabetic retinopathy detection. Presence of elevated carotid intima-media thickness or carotid plaque was defined as subclinical atherosclerosis. The prevalence of diabetic retinopathy was 15.1% in total patients. Patients with diabetic retinopathy were more likely to have elevated carotid intima-media thickness, carotid plaque and subclinical atherosclerosis than those without diabetic retinopathy (37.9% vs 30.7%, 57.6% vs 49.6% and 64.6% vs 57.1%, respectively). The presence of diabetic retinopathy was significantly associated with increased odds of subclinical atherosclerosis (odds ratio = 1.93, 95% confidence interval = 1.03-3.60) after full adjustments. The presence of diabetic retinopathy was significantly associated with subclinical atherosclerosis in middle-aged and elderly patients with type 2 diabetics in China. © The Author(s) 2015.

  3. Anti-inflammatory effects of vinpocetine in atherosclerosis and ischemic stroke: a review of the literature.

    PubMed

    Zhang, Linjie; Yang, Li

    2014-12-26

    Immune responses play an important role in the pathophysiology of atherosclerosis and ischemic stroke. Atherosclerosis is a common condition that increases the risk of stroke. Hyperlipidemia damages endothelial cells, thus initiating chemokine pathways and the release of inflammatory cytokines-this represents the first step in the inflammatory response to atherosclerosis. Blocking blood flow in the brain leads to ischemic stroke, and deprives neurons of oxygen and energy. Damaged neurons release danger-associated molecular patterns, which promote the activation of innate immune cells and the release of inflammatory cytokines. The nuclear factor κ-light-chain-enhancer of activated B cells κB (NF-κB) pathway plays a key role in the pathogenesis of atherosclerosis and ischemic stroke. Vinpocetine is believed to be a potent anti-inflammatory agent and has been used to treat cerebrovascular disorders. Vinpocetine improves neuronal plasticity and reduces the release of inflammatory cytokines and chemokines from endothelial cells, vascular smooth muscle cells, macrophages, and microglia, by inhibiting the inhibitor of the NF-κB pathway. This review clarifies the anti-inflammatory role of vinpocetine in atherosclerosis and ischemic stroke.

  4. Prior renovascular hypertension does not predispose to atherosclerosis in mice.

    PubMed

    Mortensen, Martin Bødtker; Nilsson, Line; Larsen, Tore G; Espeseth, Eirild; Bek, Marie; Bjørklund, Martin M; Hagensen, Mette K; Wolff, Anne; Gunnersen, Stine; Füchtbauer, Ernst-Martin; Boedtkjer, Ebbe; Bentzon, Jacob F

    2016-06-01

    Hypertension is a major risk factor for development of atherosclerotic cardiovascular disease (ASCVD). Although lowering blood pressure with antihypertensive drugs reduces the increased risk of ASCVD, residual increased risk still remains, suggesting that hypertension may cause chronic changes that promote atherosclerosis. Thus, we tested the hypothesis that hypertension increases the susceptibility to atherosclerosis in mice even after a period of re-established normotension. We used the 2-kidney, 1-clip (2K1C) technique to induce angiotensin-driven renovascular hypertension, and overexpression of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene to cause severe hypercholesterolemia and atherosclerosis. First, we performed 2K1C (n = 8) or sham surgery (n = 9) in PCSK9 transgenic mice before they were fed a high fat diet for 14 weeks. As expected, 2K1C did not affect cholesterol levels, but induced cardiac hypertrophy and significantly increased the atherosclerotic lesion area compared to sham mice (1.8 fold, p < 0.01). Next, we performed 2K1C (n = 13) or sham surgery (n = 14) in wild-type mice but removed the clipped/sham-operated kidney after 10 weeks to eliminate hypertension, and subsequently induced hypercholesterolemia by way of adeno-associated virus-mediated hepatic gene transfer of PCSK9 combined with high-fat diet. After 14 weeks of hypercholesterolemia, atherosclerotic lesion areas were not significantly different in mice with or without prior 2K1C hypertension (0.95 fold, p = 0.35). Renovascular hypertension in mice does not induce pro-atherogenic changes that persist beyond the hypertensive phase. These results indicate that hypertension only promotes atherogenesis when coinciding temporally with hypercholesterolemia. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Monoamine oxidase A genotype, childhood trauma, and subclinical atherosclerosis: a twin study.

    PubMed

    Zhao, Jinying; Bremner, James D; Goldberg, Jack; Quyyumi, Arshed A; Vaccarino, Viola

    2013-06-01

    A functional promoter polymorphism in the monoamine oxidase A (MAOA) gene has been implicated in neuropsychiatric disorders and also moderates the association between early-life stress and mental disorders, which often co-occur with cardiovascular disease. No study has examined the relationship between MAOA genotype, childhood trauma, and subclinical atherosclerosis. The objective of this investigation was to examine whether childhood trauma moderates the association between MAOA genotype and subclinical atherosclerosis. A sample including 289 middle-aged male twin pairs was studied. Subclinical atherosclerosis was assessed by brachial flow-mediated dilation (FMD) using ultrasound. Childhood trauma, before age 18 years, was measured with the Early Trauma Inventory and included physical, emotional, and sexual abuse as well as general trauma. Generalized estimating equation models were used to test the main and interactive effects of the MAOA genotype and each domain of childhood trauma on FMD, adjusting for known risk factors. General trauma was the most prevalent childhood trauma (28.4%), followed by physical abuse (25.0%), emotional abuse (19.4%), and sexual abuse (11.6%). MAOA genotype was not associated with any domain of childhood trauma. There was no significant evidence for a main effect for the MAOA genotype (β = .02, p = .82) or childhood trauma (.005 < β < .10, p > .54) FMD. However, a significant interaction was observed between MAOA genotype and physical (β interaction = .37, p = .026) or emotional abuse (β interaction = .43, p = .025) on subclinical atherosclerosis. Childhood trauma modulates the impact of MAOA variant on subclinical atherosclerosis, independent of traditional cardiovascular risk factors.

  6. Calpain Inhibition Attenuates Angiotensin II-induced Abdominal Aortic Aneurysms and Atherosclerosis in LDL Receptor Deficient Mice

    PubMed Central

    Subramanian, Venkateswaran; Uchida, Haruhito Adam; Ijaz, Talha; Moorleghen, Jessica J.; Howatt, Deborah A.; Balakrishnan, Anju

    2011-01-01

    Chronic infusion of angiotensin II (AngII) augments atherosclerosis and abdominal aortic aneurysm (AAAs) formation in hypercholesterolemic mice. AngII-induced AAAs are associated with medial macrophage accumulation and matrix metalloproteinase (MMP) activation. Inhibition of calpain, a calcium-activated neutral cysteine protease, by overexpression of its endogenous inhibitor, calpastatin, attenuates AngII-induced leukocyte infiltration, perivascular inflammation, and MMP activation in mice. The purpose of this study was to define whether pharmacological inhibition of calpain influences AngII-induced AAAs in hypercholesterolemic mice. Male LDL receptor −/− mice were fed a fat-enriched diet and administered with either vehicle or a calpain-specific inhibitor, BDA-410 (30 mg/kg/day) for 5 weeks. After 1 week of feeding, mice were infused with AngII (1,000 ng/kg/min) for 4 weeks. AngII-infusion profoundly increased aortic calpain protein and activity. BDA-410 administration had no effect on plasma cholesterol concentrations or AngII-increased systolic blood pressure. Calpain inhibition significantly attenuated AngII-induced AAA formation and atherosclerosis development. BDA-410 administration attenuated activation of MMP12, pro-inflammatory cytokines (IL-6, MCP-1) and macrophage infiltration into the aorta. BDA-410 administration significantly attenuated thioglycollate-elicited macrophage accumulation in the peritoneal cavity. We conclude that calpain inhibition using BDA-410 attenuated AngII-induced AAA formation and atherosclerosis development in LDL receptor −/− mice. PMID:21964156

  7. The relationship of miR-146a gene polymorphism with carotid atherosclerosis in Chinese patients with type 2 diabetes mellitus.

    PubMed

    Shen, Jing; Zhang, Min; Sun, Mingfang; Tang, Kang; Zhou, Bo

    2015-12-01

    . The transcriptional coactivator p300 rs20551 polymorphism may not be a risk factor for the development or progression of atherosclerosis in type 2 diabetes mellitus. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. The "Mevalonate hypothesis": a cholesterol-independent alternative for the etiology of atherosclerosis.

    PubMed

    Keizer, Hiskias G

    2012-11-05

    The "cholesterol hypothesis" is the leading theory to explain the cause of atherosclerosis. The "cholesterol hypothesis" assumes that plasma (LDL) cholesterol is an important causal factor for atherosclerosis.However, data of at least seven placebo controlled randomized prospective trials with various cholesterol lowering drugs show that plasma cholesterol lowering does not necessarily lead to protection against cardiovascular disease. Therefore an alternative hypothesis for the etiology of cardiovascular disease is formulated. This alternative hypothesis, the "mevalonate hypothesis", assumes that after stimulation of the mevalonate pathway in endothelial cells by inflammatory factors, these cells start producing cholesterol and free radicals. In this hypothesis, only the latter play a role in the etiology of atherosclerosis by contributing to the formation of oxidized cholesterol which is a widely accepted causal factor for atherosclerosis.Regardless of how the mevalonate pathway is activated (by withdrawal of statin drugs, by inflammatory factors or indirectly by reduced intracellular cholesterol levels) in all these cases free radical production is observed as well as cardiovascular disease. Since in the "mevalonate hypothesis" cholesterol is produced at the same time as the free radicals causing atherosclerosis, this hypothesis provides an explanation for the correlation which exists between cardiovascular disease and plasma cholesterol levels. From an evolutionary perspective, concomitant cholesterol production and free radical production in response to inflammatory factors makes sense if one realizes that both activities potentially protect cells and organisms from infection by gram-negative bacteria.In conclusion, data have been collected which suggest that activation of the mevalonate pathway in endothelial cells is likely to be a causal factor for atherosclerosis. This "mevalonate hypothesis" provides a better explanation for results obtained from recent

  9. Polymer-Based Therapeutics: Nanoassemblies and Nanoparticles for Management of Atherosclerosis

    PubMed Central

    Lewis, Daniel R.; Kamisoglu, Kubra; York, Adam; Moghe, Prabhas V.

    2012-01-01

    Coronary arterial disease, one of the leading causes of adult mortality, is triggered by atherosclerosis. A disease with complex etiology, atherosclerosis results from the progressive long-term combination of atherogenesis, the accumulation of modified lipoproteins within blood vessel walls, along with vascular and systemic inflammatory processes. The management of atherosclerosis is challenged by the localized flare-up of several multipronged signaling interactions between activated monocytes, atherogenic macrophages and inflamed or dysfunctional endothelial cells. A new generation of approaches is now emerging founded on multifocal, targeted therapies that seek to reverse or ameliorate the athero-inflammatory cascade within the vascular intima. This article reviews the various classes and primary examples of bioactive configurations of nanoscale assemblies. Of specific interest are polymer-based or polymer-lipid micellar assemblies designed as multimodal receptor-targeted blockers or drug carriers whose activity can be tuned by variations in polymer hydrophobicity, charge, and architecture. Also reviewed are emerging reports on multifunctional nanoassemblies and nanoparticles for improved circulation and enhanced targeting to athero-inflammatory lesions and atherosclerotic plaques. PMID:21523920

  10. Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-β.

    PubMed

    Zhang, Cheng; Qin, Juan-Juan; Gong, Fu-Han; Tong, Jing-Jing; Cheng, Wen-Lin; Wang, Haiping; Zhang, Yan; Zhu, Xueyong; She, Zhi-Gang; Xia, Hao; Zhu, Li-Hua

    2018-06-15

    Mindin, which is a highly conserved extracellular matrix protein, has been documented to play pivotal roles in regulating angiogenesis, inflammatory processes, and immune responses. The aim of the present study was to assess whether mindin contributes to the development of atherosclerosis. A significant up-regulation of Mindin expression was observed in the serum, arteries and atheromatous plaques of ApoE -/- mice after high-fat diet treatment. Mindin -/- ApoE -/- mice and macrophage-specific mindin overexpression in ApoE -/- mice (Lyz2-mindin-TG) were generated to evaluate the effect of mindin on the development of atherosclerosis. The Mindin -/- ApoE -/- mice exhibited significantly ameliorated atherosclerotic burdens in the entire aorta and aortic root and increased atherosclerotic plaque stability. Moreover, bone marrow transplantation further demonstrated that mindin deficiency in macrophages was largely responsible for the alleviated atherogenesis. The Lyz2-mindin-TG mice exhibited the opposite phenotype. Mindin deficiency enhanced foam cell formation by increasing the expression of cholesterol effectors, including ABCA1 and ABCG1. The mechanistic study indicated that mindin ablation promoted LXR-β expression via a direct interaction. Importantly, LXR-β inhibition largely reversed the ameliorating effect of mindin deficiency on foam cell formation and ABCA1 and ABCG1 expression. The present study demonstrated that mindin deficiency serves as a novel mediator that protects against foam cell formation and atherosclerosis by directly interacting with LXR-β. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  11. Functional blockage of EMMPRIN ameliorates atherosclerosis in apolipoprotein E-deficient mice.

    PubMed

    Liu, Hong; Yang, Li-xia; Guo, Rui-wei; Zhu, Guo-Fu; Shi, Yan-Kun; Wang, Xian-mei; Qi, Feng; Guo, Chuan-ming; Ye, Jin-shan; Yang, Zhi-hua; Liang, Xing

    2013-10-09

    Extracellular matrix metalloproteinase inducer (EMMPRIN), a 58-kDa cell surface glycoprotein, has been identified as a key receptor for transmitting cellular signals mediating metalloproteinase activities, as well as inflammation and oxidative stress. Clinical evidence has revealed that EMMPRIN is expressed in human atherosclerotic plaque; however, the relationship between EMMPRIN and atherosclerosis is unclear. To evaluate the functional role of EMMPRIN in atherosclerosis, we treated apolipoprotein E-deficient (ApoE(-/-)) mice with an EMMPRIN function-blocking antibody. EMMPRIN was found to be up-regulated in ApoE(-/-) mice fed a 12-week high-fat diet in contrast to 12 weeks of normal diet. Administration of a function-blocking EMMPRIN antibody (100 μg, twice per week for 4 weeks) to ApoE(-/-) mice, starting after 12 weeks of high-fat diet feeding caused attenuated and more stable atherosclerotic lesions, less reactive oxygen stress generation on plaque, as well as down-regulation of circulating interleukin-6 and monocyte chemotactic protein-1 in ApoE(-/-) mice. The benefit of EMMPRIN functional blockage was associated with reduced metalloproteinases proteolytic activity, which delayed the circulating monocyte transmigrating into atherosclerotic lesions. EMMPRIN antibody intervention ameliorated atherosclerosis in ApoE(-/-) mice by the down-regulation of metalloproteinase activity, suggesting that EMMPRIN may be a viable therapeutic target in atherosclerosis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate-Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation.

    PubMed

    Goo, Young-Hwa; Son, Se-Hee; Yechoor, Vijay K; Paul, Antoni

    2016-04-18

    Foam cells are central to two major pathogenic processes in atherogenesis: cholesterol buildup in arteries and inflammation. The main underlying cause of cholesterol deposition in arteries is hypercholesterolemia. This study aimed to assess, in vivo, whether elevated plasma cholesterol also alters the inflammatory balance of foam cells. Apolipoprotein E-deficient mice were fed regular mouse chow through the study or were switched to a Western-type diet (WD) 2 or 14 weeks before death. Consecutive sections of the aortic sinus were used for lesion quantification or to isolate RNA from foam cells by laser-capture microdissection (LCM) for microarray and quantitative polymerase chain reaction analyses. WD feeding for 2 or 14 weeks significantly increased plasma cholesterol, but the size of atherosclerotic lesions increased only in the 14-week WD group. Expression of more genes was affected in foam cells of mice under prolonged hypercholesterolemia than in mice fed WD for 2 weeks. However, most transcripts coding for inflammatory mediators remained unchanged in both WD groups. Among the main players in inflammatory or immune responses, chemokine (C-X-C motif) ligand 13 was induced in foam cells of mice under WD for 2 weeks. The interferon-inducible GTPases, guanylate-binding proteins (GBP)3 and GBP6, were induced in the 14-week WD group, and other GBP family members were moderately increased. Our results indicate that acceleration of atherosclerosis by hypercholesterolemia is not linked to global changes in the inflammatory balance of foam cells. However, induction of GBPs uncovers a novel family of immune modulators with a potential role in atherogenesis. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  13. Co-stimulatory molecules in and beyond co-stimulation - tipping the balance in atherosclerosis?

    PubMed

    Gerdes, N; Zirlik, A

    2011-11-01

    A plethora of basic laboratory and clinical studies has uncovered the chronic inflammatory nature of atherosclerosis. The adaptive immune system with its front-runner, the T cell, drives the atherogenic process at all stages. T cell function is dependent on and controlled by a variety of either co-stimulatory or co-inhibitory signals. In addition, many of these proteins enfold T cell-independent pro-atherogenic functions on a variety of cell types. Accordingly they represent potential targets for immune-modulatory and/or anti-inflammatory therapy of atherosclerosis. This review focuses on the diverse role of co-stimulatory molecules of the B7 and tumour necrosis factor (TNF)-superfamily and their downstream signalling effectors in atherosclerosis. In particular, the contribution of CD28/CD80/CD86/CTLA4, ICOS/ICOSL, PD-1/PDL-1/2, TRAF, CD40/CD154, OX40/OX40L, CD137/CD137L, CD70/CD27, GITR/GITRL, and LIGHT to arterial disease is reviewed. Finally, the potential for a therapeutic exploitation of these molecules in the treatment of atherosclerosis is discussed.

  14. [Atherosclerosis and nutrition].

    PubMed

    Daubresse, J C

    2000-09-01

    Atherosclerosis is the main cause of mortality in industrialized countries and even in poorly developed ones. It is linked to age and gender and also to a number of well identified risk factors: lipids anomalies, arterial hypertension, diabetes, smoking and weight excess among others. Risk factors improvement significantly reduces cardiovascular events. It is evident that nutrition plays an important role as it can modulate the evolution of body weight and blood pressure. Nutrition is also able to reduce the prevalence and severity of hyperlipidemias and diabetes. Saturated fatty acids (excepted stearic acid), trans poly-unsaturated acids as well as cholesterol increase serum LDL-cholesterol. Mono- and poly-unsaturated and classical cis-mono-unsaturated acids do the opposite. N-3 poly-unsaturated acids reduce serum triglyceride levels and cardiovascular events. Carbohydrates with a low glycemic index are important determinants of serum HDL-cholesterol levels and reduce cardiovascular risk. Animal proteins bring essential amino-acids to the body but also saturated fats. It seems interesting to eat vegetal proteins among which those derived from soya look promising. Our diet will include enough fiber and phytosterols-containing margarines look interesting as well. Modest alcohol consumption improves cardiovascular mortality in the majority of the prospective studies.

  15. Is adiponectin a marker of preclinical atherosclerosis in kidney transplantation?

    PubMed

    Cañas, Laura; Bayés, Beatriz; Granada, Maria L; Ibernon, Meritxell; Porrini, Esteban; Benítez, Rosa; Díaz, Juan M; Lauzurica, Ricardo; Moreso, Francesc; Torres, Armando; Lampreabe, Ildefonso; Serra, Assumpta; Romero, Ramon

    2012-01-01

    The aim of this study was to analyze the relationship between pre-transplant adiponectin (pre-ADP), abnormalities in glucose homeostasis (AGH) at three months post-transplantation, and preclinical atherosclerosis in non-diabetic patients prior to kidney transplantation (KT). We carried out a multicenter study in 157 non-diabetic KT patients (66.5% men; age: 50±13 yr). Pre-ADP levels were analyzed using radioimmunoassay. Carotid ultrasound was performed to determine carotid intima-media thickness (c-IMT). Oral glucose tolerance test was carried out to classify patients according ADA criteria. Of the patients, 52.8% had AGH. Median pre-ADP was 19.5 (14-27) μg/mL. An inverse correlation was found between ADP and HOMA index (r=-0.432; p<0.001). Median c-IMT was 0.6 (0.48-0.71) mm. Significant inverse correlation existed between ADP and c-IMT on both sides (p<0.05). Patients with c-IMT >0.6 mm had more AGH (p=0.012) and lower ADP levels (p=0.02). We performed a logistic regression analysis using preclinical atherosclerosis (c-IMT ≥0.6 mm) as dependent variable and sex, age, BMI, ADP, AGH, and HOMA index as independent variables of altered c-IMT. Age, pre-ADP, and AGH were independent risk factors for elevated c-IMT. Patients with AGH have a greater presence of preclinical atherosclerosis. ADP has an inverse relationship with AGH and is an independent marker of preclinical atherosclerosis. © 2011 John Wiley & Sons A/S.

  16. [Psychosocial factors as predictors of atherosclerosis and cardiovascular events: contribution from animal models].

    PubMed

    Alboni, Paolo; Alboni, Marco

    2006-11-01

    Conventional risk factors (abnormal lipids, hypertension, etc.) are independent predictors of atherosclerosis and cardiovascular events; however, these factors are not specific since about half patients with acute myocardial infarction paradoxically result at low cardiovascular risk. Recent prospective studies provide convincing evidence that some psychosocial factors are independent predictors of atherosclerosis and cardiovascular events, as well. Psychosocial factors that promote atherosclerosis can be divided into two general categories: chronic stressors, including social isolation/low social support and work stress (subordination without job control) and emotional factors, including affective disorders such as depression, severe anxiety and hostility/anger. The emotional factors, such as the chronic stressors, activate the biological mechanisms of chronic stress: increased activity of the hypothalamic-pituitary-adrenal axis, sympathetic system and inflammation processes, which have atherogenic effects, and an increase in blood coagulation. In spite of the amount of published data, psychosocial factors receive little attention in the medical setting. About 30 years ago, Kuller defined the criteria for a causal relation between a risk factor and atherosclerosis and cardiac events. The first of these criteria states that experimental research should demonstrate that any new factor would increase the extent of atherosclerosis or its complications in suitable animal models. We carried out a bibliographic research in order to investigate whether the results of the studies dealing with animal examination and experimentation support the psychosocial factors as predictors of atherosclerosis. Contributions related to some of the psychosocial factors such as social isolation, subordination and hostility/anger have been found. In these studies atherosclerotic extension has been evaluated at necroscopy; however, the incidence of cardiovascular events has not been

  17. Twin-Screw Extruder and Pellet Accelerator Integration Developments for ITER

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Meitner, Steven J; Baylor, Larry R; Combs, Stephen Kirk

    The ITER pellet injection system consisting of a twinscrew frozen hydrogen isotope extruder, coupled to a combination solenoid actuated pellet cutter and pneumatic pellet accelerator, is under development at the Oak Ridge National Laboratory. A prototype extruder has been built to produce a continuous solid deuterium extrusion and will be integrated with a secondary section, where pellets are cut, chambered, and launched with a single-stage pneumatic accelerator into the plasma through a guide tube. This integrated pellet injection system is designed to provide 5 mm fueling pellets, injected at a rate up to 10 Hz, or 3 mm edge localizedmore » mode (ELM) triggering pellets, injected at higher rates up to 20 Hz. The pellet cutter, chamber mechanism, and the solenoid operated pneumatic valve for the accelerator are optimized to provide pellet velocities between 200-300 m/s to ensure high pellet survivability while traversing the inner wall fueling guide tubes, and outer wall ELMpacing guide tubes. This paper outlines the current twin-screwextruder design, pellet accelerator design, and the integrationrequired for both fueling and ELM pacing pellets.« less

  18. Residual acceleration data on IML-1: Development of a data reduction and dissemination plan

    NASA Technical Reports Server (NTRS)

    Rogers, Melissa J. B.; Alexander, J. Iwan D.; Wolf, Randy

    1992-01-01

    The main thrust of our work in the third year of contract NAG8-759 was the development and analysis of various data processing techniques that may be applicable to residual acceleration data. Our goal is the development of a data processing guide that low gravity principal investigators can use to assess their need for accelerometer data and then formulate an acceleration data analysis strategy. The work focused on the flight of the first International Microgravity Laboratory (IML-1) mission. We are also developing a data base management system to handle large quantities of residual acceleration data. This type of system should be an integral tool in the detailed analysis of accelerometer data. The system will manage a large graphics data base in the support of supervised and unsupervised pattern recognition. The goal of the pattern recognition phase is to identify specific classes of accelerations so that these classes can be easily recognized in any data base. The data base management system is being tested on the Spacelab 3 (SL3) residual acceleration data.

  19. Community Petascale Project for Accelerator Science and Simulation: Advancing Computational Science for Future Accelerators and Accelerator Technologies

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Spentzouris, P.; /Fermilab; Cary, J.

    The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessarymore » accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R&D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors. ComPASS is in the first year of executing its plan to develop the next-generation HPC accelerator modeling tools. ComPASS aims to develop an integrated simulation environment that will utilize existing and new accelerator physics modules with petascale capabilities, by employing modern computing and solver technologies. The ComPASS vision is to deliver to accelerator scientists a virtual accelerator and virtual prototyping modeling environment, with the necessary multiphysics, multiscale capabilities. The plan for this development includes delivering accelerator modeling applications appropriate for each stage of the ComPASS software evolution. Such applications are already being used to address challenging problems in accelerator design and optimization. The Com

  20. Impact of accelerated plant growth on seed variety development

    NASA Astrophysics Data System (ADS)

    Christophersen, Eric

    1998-01-01

    The commercial lives of agricultural seed products have steadily declined in recent years. The introduction of genetically engineered crop seeds in 1966 has accentuated that trend. Widespread grower demand for genetically engineered seed requires competitive response by industry followers in order to avert market share losses to the industry leaders. Limitations on plant transformation technology, regulatory requirements and patent impediments require companies to rapidly convert transformed lines into elite commercial products. Massive multigenerational backcrossing efforts are required to distribute genetically engineered traits into a broad product mix. Significant incidents of expression failures, or ``gene silencing,'' have occurred unexpectedly, requiring product substitution strategies. First-to-market strategies, competitive response, broad germplasm conversion and rescue of product failures all share the element of urgency. Technologies which reliably accelerate product development rates can expect favorable reception by commercial seed developers. A growth chamber which dramatically accelerates the rate of plant growth is described.

  1. Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains

    PubMed Central

    Bennett, Brian J.; Davis, Richard C.; Civelek, Mete; Orozco, Luz; Wu, Judy; Qi, Hannah; Pan, Calvin; Packard, René R. Sevag; Eskin, Eleazar; Yan, Mujing; Kirchgessner, Todd; Wang, Zeneng; Li, Xinmin; Gregory, Jill C.; Hazen, Stanley L.; Gargalovic, Peter S.; Lusis, Aldons J.

    2015-01-01

    Common forms of atherosclerosis involve multiple genetic and environmental factors. While human genome-wide association studies have identified numerous loci contributing to coronary artery disease and its risk factors, these studies are unable to control environmental factors or examine detailed molecular traits in relevant tissues. We now report a study of natural variations contributing to atherosclerosis and related traits in over 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). The mice were made hyperlipidemic by transgenic expression of human apolipoprotein E-Leiden (APOE-Leiden) and human cholesteryl ester transfer protein (CETP). The mice were examined for lesion size and morphology as well as plasma lipid, insulin and glucose levels, and blood cell profiles. A subset of mice was studied for plasma levels of metabolites and cytokines. We also measured global transcript levels in aorta and liver. Finally, the uptake of acetylated LDL by macrophages from HMDP mice was quantitatively examined. Loci contributing to the traits were mapped using association analysis, and relationships among traits were examined using correlation and statistical modeling. A number of conclusions emerged. First, relationships among atherosclerosis and the risk factors in mice resemble those found in humans. Second, a number of trait-loci were identified, including some overlapping with previous human and mouse studies. Third, gene expression data enabled enrichment analysis of pathways contributing to atherosclerosis and prioritization of candidate genes at associated loci in both mice and humans. Fourth, the data provided a number of mechanistic inferences; for example, we detected no association between macrophage uptake of acetylated LDL and atherosclerosis. Fifth, broad sense heritability for atherosclerosis was much larger than narrow sense heritability, indicating an important role for gene-by-gene interactions. Sixth, stepwise linear regression

  2. Therapeutic Efficacy of an ω-3-Fatty Acid-Containing 17-β Estradiol Nano-Delivery System against Experimental Atherosclerosis

    PubMed Central

    Deshpande, Dipti; Kethireddy, Sravani; Janero, David R.; Amiji, Mansoor M.

    2016-01-01

    Atherosclerosis and its consequences remain prevalent clinical challenges throughout the world. Initiation and progression of atherosclerosis involves a complex, dynamic interplay among inflammation, hyperlipidemia, and endothelial dysfunction. A multicomponent treatment approach targeted for delivery within diseased vessels could prove beneficial in treating atherosclerosis. This study was undertaken to evaluate the multimodal effects of a novel ω-3-fatty acid-rich, 17-β-estradiol (17-βE)-loaded, CREKA-peptide-modified nanoemulsion system on experimental atherosclerosis. In vitro treatment of cultured human aortic endothelial cells (ECs) with the 17-βE-loaded, CREKA-peptide-modified nanoemulsion system increased cellular nitrate/nitrite, indicating improved nitric oxide formation. In vivo, systemic administration of this nanoemulsion system to apolipoprotein-E knock out (ApoE-/-) mice fed a high-fat diet significantly improved multiple parameters related to the etiology and development of occlusive atherosclerotic vasculopathy: lesion area, circulating plasma lipid levels, and expression of aortic-wall inflammatory markers. These salutary effects were attributed selectively to the 17-βE and/or ω-3 polyunsaturated fatty acid components of the nano-delivery system. At therapeutic doses, the 17-βE-loaded, CREKA-peptide modified nanoemulsion system appeared to be biocompatible in that it elicited no apparent adverse/toxic effects, as indexed by body weight, plasma alanine aminotransferase/aspartate aminotransferase levels, and liver and kidney histopathology. The study demonstrates the therapeutic potential of a novel, 17-βE-loaded, CREKA-peptide-modified nanoemulsion system against atherosclerosis in a multimodal fashion by reducing lesion size, lowering the levels of circulating plasma lipids and decreasing the gene expression of inflammatory markers associated with the disease. PMID:26840601

  3. Multi-Ethnic Study of Atherosclerosis (MESA) - Ancillary Eye Study

    ClinicalTrials.gov

    2016-02-05

    Atherosclerosis; Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Cerebrovascular Disorders; Heart Failure, Congestive; Myocardial Infarction; Heart Diseases; Diabetes Mellitus, Non-insulin Dependent; Hypertension; Diabetic Retinopathy; Macular Degeneration; Diabetes Mellitus

  4. Metabolomic and Genomic Markers of Atherosclerosis as Related to Oxidative Stress, Inflammation, and Vascular Function in Twin Astronauts

    NASA Technical Reports Server (NTRS)

    Lee, Stuart M. C.; Rana, Brinda K.; Stenger, Michael B.; Sears, Dorothy D.; Smith, Scott M.; Zwart, Sara R.; Macias, Brandon R.; Hargans, Alan R.; Sharma, Kumar; De Vivo, Immaculata

    2017-01-01

    BACKGROUND: Future human space travel will consist primarily of long-duration missions onboard the International Space Station (ISS) or exploration-class missions to Mars, its moons, or nearby asteroids. Astronauts participating in long-duration missions may be at an increased risk of oxidative stress and inflammatory damage due to radiation, psychological stress, altered physical activity, nutritional insufficiency, and hyperoxia during extravehicular activity. By studying one identical twin during his 1-year ISS mission and his ground-based twin, this work extends a current NASA-funded investigation to determine whether these spaceflight factors contribute to an accelerated progression of atherosclerosis. This study of twins affords a unique opportunity to examine spaceflight-related atherosclerosis risk that is independent of the confounding factors associated with different genotypes. PURPOSE: The purpose of this investigation was to determine whether biomarkers of oxidative and inflammatory stress are elevated during and after long-duration spaceflight and determine if a relation exists between levels of these biomarkers and structural and functional indices of atherosclerotic risk measured in the carotid and brachial arteries. These physiological and biochemical data will be extended by using an exploratory approach to investigate the relationship between intermediate phenotypes and risk factors for atherosclerosis and the metabolomic signature from plasma and urine samples. Since metabolites are often the indirect products of gene expression, we simultaneously assessed gene expression and DNA methylation in leukocytes. HYPOTHESIS: We predict that, compared to the ground-based twin, the space-flown twin will experience elevated biomarkers of oxidative stress and inflammatory damage, altered arterial structure and function, accelerated telomere shortening, dysregulation of genes associated with oxidative stress and inflammation, and a metabolic profile shift

  5. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis

    PubMed Central

    Wang, Zeneng; Roberts, Adam B.; Buffa, Jennifer A.; Levison, Bruce S.; Zhu, Weifei; Org, Elin; Gu, Xiaodong; Huang, Ying; Zamanian-Daryoush, Maryam; Culley, Miranda K.; DiDonato, Anthony J.; Fu, Xiaoming; Hazen, Jennie E.; Krajcik, Daniel; DiDonato, Joseph A.; Lusis, Aldons J.; Hazen, Stanley L.

    2016-01-01

    SUMMARY Trimethylamine N-oxide (TMAO), a gut microbiota dependent metabolite, both enhances atherosclerosis in animal models and is associated with cardiovascular risks in clinical studies. Here we investigate the impact of targeted inhibition of the first step in TMAO generation, commensal microbial trimethylamine (TMA) production, on diet-induced atherosclerosis. A structural analogue of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases, and to both inhibit TMA production from physiologic polymicrobial cultures (eg intestinal contents, human feces) and reduce TMAO levels in mice fed a high choline or carnitine diet. DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apolipoprotein e−/− mice without alterations in circulating cholesterol levels. The present studies suggest gut microbial production of TMA specifically, and non-lethal microbial inhibitors in general, may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases. PMID:26687352

  6. Lactobacillus acidophilus ATCC 4356 prevents atherosclerosis via inhibition of intestinal cholesterol absorption in apolipoprotein E-knockout mice.

    PubMed

    Huang, Ying; Wang, Jinfeng; Quan, Guihua; Wang, Xiaojun; Yang, Longfei; Zhong, Lili

    2014-12-01

    The objective of this study was to investigate the effect of Lactobacillus acidophilus ATCC 4356 on the development of atherosclerosis in apolipoprotein E-knockout (ApoE(-/-)) mice. Eight-week-old ApoE(-/-) mice were fed a Western diet with or without L. acidophilus ATCC 4356 daily for 16 weeks. L. acidophilus ATCC 4356 protected ApoE(-/-) mice from atherosclerosis by reducing their plasma cholesterol levels from 923 ± 44 to 581 ± 18 mg/dl, likely via a marked decrease in cholesterol absorption caused by modulation of Niemann-Pick C1-like 1 (NPC1L1). In addition, suppression of cholesterol absorption induced reverse cholesterol transport (RCT) in macrophages through the peroxisome proliferator-activated receptor/liver X receptor (PPAR/LXR) pathway. Fecal lactobacillus and bifidobacterium counts were significantly (P < 0.05) higher in the L. acidophilus ATCC 4356 treatment groups than in the control groups. Furthermore, L. acidophilus ATCC 4356 was detected in the rat small intestine, colon, and feces during the feeding trial. The bacterial levels remained high even after the administration of lactic acid bacteria had been stopped for 2 weeks. These results suggest that administration of L. acidophilus ATCC 4356 can protect against atherosclerosis through the inhibition of intestinal cholesterol absorption. Therefore, L. acidophilus ATCC 4356 may be a potential therapeutic material for preventing the progression of atherosclerosis. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  7. Euterpe oleracea (açai) modifies sterol metabolism and attenuates experimentally-induced atherosclerosis.

    PubMed

    Feio, Claudine A; Izar, Maria C; Ihara, Silvia S; Kasmas, Soraia H; Martins, Celma M; Feio, Max N; Maués, Luís A; Borges, Ney C; Moreno, Ronilson A; Póvoa, Rui M; Fonseca, Francisco A

    2012-01-01

    Euterpe Oleracea (açai) is a fruit from the Amazon region whose chemical composition may be beneficial for individuals with atherosclerosis. We hypothesized that consumption of Euterpe Oleracea would reduce atherosclerosis development by decreasing cholesterol absorption and synthesis. Male New Zealand rabbits were fed a cholesterol-enriched diet (0.5%) for 12 weeks, when they were randomized to receive Euterpe Oleracea extract (n = 15) or water (n = 12) plus a 0.05% cholesterol-enriched diet for an additional 12 weeks. Plasma phytosterols and desmosterol were determined by ultra-performance liquid chromatography and mass spectrometry. Atherosclerotic lesions were estimated by computerized planimetry and histomorphometry. At sacrifice, animals treated with Euterpe Oleracea had lower levels of total cholesterol (p =0.03), non-HDL-cholesterol (p = 0.03) and triglycerides (p = 0.02) than controls. These animals had smaller atherosclerotic plaque area in their aortas (p = 0.001) and a smaller intima/media ratio (p = 0.002) than controls, without differences in plaque composition. At the end of the study, campesterol, β-sitosterol, and desmosterol plasma levels did not differ between groups; however, animals treated with Euterpe Oleracea showed lower desmosterol/campesterol (p = 0.026) and desmosterol/ β-sitosterol (p =0.006) ratios than controls. Consumption of Euterpe Oleracea extract markedly improved the lipid profile and attenuated atherosclerosis. These effects were related in part to a better balance in the synthesis and absorption of sterols.

  8. [The role of subclinical inflammation in progression of multifocal atherosclerosis during one year after myocardial infarction].

    PubMed

    Barbarash, O L; Usol'tseva, E N; Kashtalap, V V; Kolomytseva, I S; Sizova, I N; Volykova, M A; Shibanova, I A

    2014-01-01

    To elucidate role of subclinical inflammation in progression of atherosclerotic process in magistral noncoronary arteries in patients during one year after ST-elevation myocardial infarction (MI). We examined 168 men with MI (mean age 59.5 years). All patients during hospitalization underwent coronary angiography and color duplex scanning of brachiocephalic arteries. In a year ultrasound study of noncoronary vessels was repeated and progression of atherosclerosis assessed. Parameters of inflammation in blood serum were measured on days 10-14 of MI and after one year. At repeat study most patients demonstrated progression of noncoronary atherosclerosis. Some biomarkers measured during inhospital phase of MI (low concentration of anti-inflammatory interleukin 10 - IL-10, elevated N-terminal pro brain natriuretic peptide) allowed to distinguish group of patients with subsequent progression of noncoronary atherosclerosis. Elevated concentrations of C-reactive protein and 11-10 registered in a year after MI were also associated with more severe progression of atherosclerosis. Serum levels of neopterin and IL-12 remained stable in patients with and decreased in patients without pronounced progression of atherosclerosis.

  9. Salivary inflammatory cytokines may be novel markers of carotid atherosclerosis in a Japanese general population: the Suita study.

    PubMed

    Kosaka, Takayuki; Kokubo, Yoshihiro; Ono, Takahiro; Sekine, Shinichi; Kida, Momoyo; Kikui, Miki; Yamamoto, Masaaki; Watanabe, Makoto; Amano, Atsuo; Maeda, Yoshinobu; Miyamoto, Yoshihiro

    2014-11-01

    Salivary biomarkers have been recently useful of periodontal disease, which is also risk factor of atherosclerosis. However, there are few studies of the association between salivary inflammatory cytokines and carotid atherosclerosis. We aimed to clarify the association between salivary inflammatory cytokines and periodontal disease and carotid atherosclerosis in a general urban population. We studied 608 Japanese men and women (mean age: 65.4 years) in the Suita study. Carotid atherosclerosis was evaluated by high-resolution ultrasonography with atherosclerotic indexes of intima-media thickness (IMT). Periodontal status was evaluated by the Community Periodontal Index (CPI). Salivary levels of interleukin-1β, interleukin-6, tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2) were measured by enzyme linked immunosorbent assay. The risks of carotid atherosclerosis (≥75th percentiles of mean- [0.88 mm] and Max-IMT [1.50 mm]) according to the quartiles of salivary inflammatory cytokines were compared using of adjusted-logistic regression models. All salivary inflammatory cytokines were positively associated with CPI. The adjusted odds ratios for carotid atherosclerosis of mean-IMT in the highest quartile of interleukin-6 and TNF-α were higher than those in the lowest quartiles (OR = 2.32 and 2.88; 95% confidence intervals = 1.19-4.51 and 1.51-5.49, respectively). The adjusted odds ratio for carotid atherosclerosis of mean-IMT in the highest quartile of PGE2 was greater than those in the lowest quartile in women (OR = 2.78; 95% confidence intervals = 1.11-6.95). In conclusion, higher levels of salivary inflammatory cytokines were associated with both periodontal disease and carotid atherosclerosis. Selected salivary inflammatory cytokines may be useful screening markers for periodontal disease and carotid atherosclerosis. Copyright © 2014. Published by Elsevier Ireland Ltd.

  10. Kidney stones and subclinical atherosclerosis in young adults: the CARDIA study.

    PubMed

    Reiner, Alexander P; Kahn, Arnold; Eisner, Brian H; Pletcher, Mark J; Sadetsky, Natalia; Williams, O Dale; Polak, Joseph F; Jacobs, David R; Stoller, Marshall L

    2011-03-01

    Recent reports suggest that nephrolithiasis and atherosclerosis share a number of risk factors. To our knowledge there has been no previous examination of the relationship between kidney stones and subclinical atherosclerotic disease. We studied the relationship between nephrolithiasis, and carotid wall thickness and carotid stenosis assessed by B-mode ultrasound in the general community using data from the CARDIA study. The CARDIA study is a United States, population based, observational study of 5,115 white and African-American men and women between the ages of 18 and 30 years at recruitment in 1985 to 1986. By the year 20 examination 200 (3.9%) CARDIA participants had reported ever having kidney stones. Symptomatic kidney stones were associated with greater carotid wall thickness measured at the year 20 examination, particularly of the internal carotid/bulb region. Using a composite dichotomous end point of carotid stenosis and/or the upper quartile of internal carotid/bulb wall thickness, the association of kidney stones with carotid atherosclerosis was significant (OR 1.6, 95% CI 1.1-2.3, p=0.01), even after adjusting for major atherosclerotic risk factors. The association between a history of kidney stones and subclinical carotid atherosclerosis in young adults adds further support to the notion that nephrolithiasis and atherosclerosis share common systemic risk factors and/or pathophysiology. Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  11. A novel photoacoustic nanoprobe of ICG@PEG-Ag2S for atherosclerosis targeting and imaging in vivo

    NASA Astrophysics Data System (ADS)

    Wu, Chenxin; Zhang, Yejun; Li, Zhen; Li, Chunyan; Wang, Qiangbin

    2016-06-01

    Atherosclerosis is a major cause of cardiovascular and cerebrovascular diseases that have high mortality and disability rates. Because of its unclear pathogenic mechanism and heterogeneous distribution feature, it is still a big challenge to achieve precise diagnosis and therapy of atherosclerosis at its early stage in vivo. Herein, we fabricated a new ICG@PEG-Ag2S nanoprobe by a simple self-assembly of DT-Ag2S QDs, amphipathic C18/PEG polymer molecules and ICG. The ICG@PEG-Ag2S nanoprobe showed relatively long blood retention and was selectively accumulated in the region of atherosclerotic plaque due to the lipophilicity of the C18 chain to the atherosclerosis microenvironment, and thus the atherosclerosis was real-time monitored by high contrast-enhanced photoacoustic (PA) imaging of ICG. Combining the high signal-to-noise ratio (SNR) and high spatial resolution fluorescence imaging of Ag2S QDs in the second near-infrared window (NIR-II) and related histological assessment in vitro, the feasibility of this new nanoprobe for atherosclerosis targeting in an Apoe-/- mouse model was verified. Additionally, hemolysis and coagulation assays of the ICG@PEG-Ag2S revealed its decent hemocompatibility and no histological changes were observed in the main organs of the mouse. Such a simple, multifunctional nanoprobe for targeting and PA imaging of atherosclerosis will have a great potential for future clinical applications.Atherosclerosis is a major cause of cardiovascular and cerebrovascular diseases that have high mortality and disability rates. Because of its unclear pathogenic mechanism and heterogeneous distribution feature, it is still a big challenge to achieve precise diagnosis and therapy of atherosclerosis at its early stage in vivo. Herein, we fabricated a new ICG@PEG-Ag2S nanoprobe by a simple self-assembly of DT-Ag2S QDs, amphipathic C18/PEG polymer molecules and ICG. The ICG@PEG-Ag2S nanoprobe showed relatively long blood retention and was selectively

  12. Treg/Th17 balance in stable CAD patients with different stages of coronary atherosclerosis.

    PubMed

    Potekhina, Alexandra V; Pylaeva, Ekaterina; Provatorov, Sergey; Ruleva, Natalya; Masenko, Valery; Noeva, Elena; Krasnikova, Tatiana; Arefieva, Tatiana

    2015-01-01

    Objective. Immune processes play a significant role in atherosclerosis plaque progression. Regulatory T cells and T helpers 17 were shown to possess anti- and pro-atherogenic activity, respectively. We aimed to investigate the balance of circulating Treg and Th17 in stable angina patients with different stages of coronary atherosclerosis. Methods. Treg, Th17 and Th1 cell frequencies were studied in 117 patients via direct immunofluorescence staining and flow cytometry. Group 1 had intact coronary arteries. Group 2 and Group 3 had undergone previous coronary stenting; in Group 2 no coronary atherosclerosis progression was found, in Group 3 patients had disease progression in non-invaded coronary arteries. Group 4 had severe coronary atherosclerosis. Results. The frequencies of CD4+CD25highCD127low, CD4+foxp3+, and CD4+IL10 + T cells were decreased, and CD4+IL17 + T cells frequencies were increased in group 4 vs. 1. Treg/Th17 ratios were declined in groups 3 and 4 vs. groups 1 and 2. IL-10 level was lower while hsCRP and sCD25 levels were higher in group 4 vs. 1. Conclusion. We assume that the imbalance in pro- and anti-inflammatory/atherogenic lymphocyte subpopulations is associated with atherosclerosis progression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  13. Development of a wireless displacement measurement system using acceleration responses.

    PubMed

    Park, Jong-Woong; Sim, Sung-Han; Jung, Hyung-Jo; Spencer, Billie F

    2013-07-01

    Displacement measurements are useful information for various engineering applications such as structural health monitoring (SHM), earthquake engineering and system identification. Most existing displacement measurement methods are costly, labor-intensive, and have difficulties particularly when applying to full-scale civil structures because the methods require stationary reference points. Indirect estimation methods converting acceleration to displacement can be a good alternative as acceleration transducers are generally cost-effective, easy to install, and have low noise. However, the application of acceleration-based methods to full-scale civil structures such as long span bridges is challenging due to the need to install cables to connect the sensors to a base station. This article proposes a low-cost wireless displacement measurement system using acceleration. Developed with smart sensors that are low-cost, wireless, and capable of on-board computation, the wireless displacement measurement system has significant potential to impact many applications that need displacement information at multiple locations of a structure. The system implements an FIR-filter type displacement estimation algorithm that can remove low frequency drifts typically caused by numerical integration of discrete acceleration signals. To verify the accuracy and feasibility of the proposed system, laboratory tests are carried out using a shaking table and on a three storey shear building model, experimentally confirming the effectiveness of the proposed system.

  14. Development of a Wireless Displacement Measurement System Using Acceleration Responses

    PubMed Central

    Park, Jong-Woong; Sim, Sung-Han; Jung, Hyung-Jo; Spencer, Billie F.

    2013-01-01

    Displacement measurements are useful information for various engineering applications such as structural health monitoring (SHM), earthquake engineering and system identification. Most existing displacement measurement methods are costly, labor-intensive, and have difficulties particularly when applying to full-scale civil structures because the methods require stationary reference points. Indirect estimation methods converting acceleration to displacement can be a good alternative as acceleration transducers are generally cost-effective, easy to install, and have low noise. However, the application of acceleration-based methods to full-scale civil structures such as long span bridges is challenging due to the need to install cables to connect the sensors to a base station. This article proposes a low-cost wireless displacement measurement system using acceleration. Developed with smart sensors that are low-cost, wireless, and capable of on-board computation, the wireless displacement measurement system has significant potential to impact many applications that need displacement information at multiple locations of a structure. The system implements an FIR-filter type displacement estimation algorithm that can remove low frequency drifts typically caused by numerical integration of discrete acceleration signals. To verify the accuracy and feasibility of the proposed system, laboratory tests are carried out using a shaking table and on a three storey shear building model, experimentally confirming the effectiveness of the proposed system. PMID:23881123

  15. Macrophage Heterogeneity and Plasticity: Impact of Macrophage Biomarkers on Atherosclerosis

    PubMed Central

    Martínez, María Sofía; Palmar, Jim; Bautista, Jordan; Chávez-Castillo, Mervin; Gómez, Alexis; Bermúdez, Valmore

    2015-01-01

    Cardiovascular disease (CVD) is a global epidemic, currently representing the worldwide leading cause of morbidity and mortality. Atherosclerosis is the fundamental pathophysiologic component of CVD, where the immune system plays an essential role. Monocytes and macrophages are key mediators in this aspect: due to their heterogeneity and plasticity, these cells may act as either pro- or anti-inflammatory mediators. Indeed, monocytes may develop heterogeneous functional phenotypes depending on the predominating pro- or anti-inflammatory microenvironment within the lesion, resulting in classic, intermediate, and non-classic monocytes, each with strikingly differing features. Similarly, macrophages may also adopt heterogeneous profiles being mainly M1 and M2, the former showing a proinflammatory profile while the latter demonstrates anti-inflammatory traits; they are further subdivided in several subtypes with more specialized functions. Furthermore, macrophages may display plasticity by dynamically shifting between phenotypes in response to specific signals. Each of these distinct cell profiles is associated with diverse biomarkers which may be exploited for therapeutic intervention, including IL-10, IL-13, PPAR-γ, LXR, NLRP3 inflammasomes, and microRNAs. Direct modulation of the molecular pathways concerning these potential macrophage-related targets represents a promising field for new therapeutic alternatives in atherosclerosis and CVD. PMID:26491604

  16. CD8{sup +}CD25{sup +} T cells reduce atherosclerosis in apoE(−/−) mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhou, Jianchang; Dimayuga, Paul C.; Zhao, Xiaoning

    2014-01-17

    Highlights: •The role of a sub-population of CD8{sup +} T cells with suppressor functions was investigated in atherosclerosis. •CD8{sup +}CD25{sup +} T cells from adult apoE(−/−) mice had phenotype characteristics of T suppressor cells. •These CD8{sup +}CD25{sup +} T cells reduced CD4{sup +} T cell proliferation and CD8{sup +} cytotoxic activity in vitro. •Adoptive transfer of CD8{sup +}CD25{sup +} T cells significantly reduced atherosclerosis. •CD8{sup +}CD25{sup +} T cells have a suppressive function in atherosclerosis. -- Abstract: Background: It is increasingly evident that CD8{sup +} T cells are involved in atherosclerosis but the specific subtypes have yet to be defined.more » CD8{sup +}CD25{sup +} T cells exert suppressive effects on immune signaling and modulate experimental autoimmune disorders but their role in atherosclerosis remains to be determined. The phenotype and functional role of CD8{sup +}CD25{sup +} T cells in experimental atherosclerosis were investigated in this study. Methods and results: CD8{sup +}CD25{sup +} T cells were observed in atherosclerotic plaques of apoE(−/−) mice fed hypercholesterolemic diet. Characterization by flow cytometric analysis and functional evaluation using a CFSE-based proliferation assays revealed a suppressive phenotype and function of splenic CD8{sup +}CD25{sup +} T cells from apoE(−/−) mice. Depletion of CD8{sup +}CD25{sup +} from total CD8{sup +} T cells rendered higher cytolytic activity of the remaining CD8{sup +}CD25{sup −} T cells. Adoptive transfer of CD8{sup +}CD25{sup +} T cells into apoE(−/−) mice suppressed the proliferation of splenic CD4{sup +} T cells and significantly reduced atherosclerosis in recipient mice. Conclusions: Our study has identified an athero-protective role for CD8{sup +}CD25{sup +} T cells in experimental atherosclerosis.« less

  17. Subclinical atherosclerosis and history of cardiovascular events in Italian patients with rheumatoid arthritis: Results from a cross-sectional, multicenter GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) study.

    PubMed

    Ruscitti, Piero; Margiotta, Domenico Paolo Emanuele; Macaluso, Federica; Iacono, Daniela; D'Onofrio, Francesca; Emmi, Giacomo; Atzeni, Fabiola; Prete, Marcella; Perosa, Federico; Sarzi-Puttini, Piercarlo; Emmi, Lorenzo; Cantatore, Francesco Paolo; Triolo, Giovanni; Afeltra, Antonella; Giacomelli, Roberto; Valentini, Gabriele

    2017-10-01

    Several studies have pointed out a significant association between rheumatoid arthritis (RA) and accelerated atherosclerosis. At the best of our knowledge, no such study has been carried out in a large Italian series and, in this study, we aimed to investigate the prevalence of both subclinical atherosclerosis and history of cardiovascular events (CVEs), in patients consecutively admitted from January 1, 2015 to December 31, 2015 to Rheumatology Units throughout the whole Italy.Centers members of GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) were invited to enrol patients consecutively admitted from January 1, 2015 to December 31, 2015 and satisfying American College of Rheumatology/ European League Against Rheumatism criteria for RA and to investigate each of them for: traditional cardiovascular risk factors: sex, age, smoking habit, total cholesterol, triglycerides, glycaemia, high blood pressure, metabolic syndrome (MS), type 2 diabetes (T2D); RA features: disease duration as assessed from the first symptom, disease activity as evaluated by DAS28, radiographic damage as assessed by hands and feet x-ray, and previous joint surgery; prevalence of both subclinical atherosclerosis and history of CVEs.Eight centers participated to the study. From January 1, 2015 to December 31, 2015, the 1176 patients, who had been investigated for all the items, were enrolled in the study. They were mostly women (80.52%), with a median age of 60 years (range, 18-91 years), a median disease duration of 12 years (range, 0.8-25 years), seropositive in 69.21%. Nineteen percent were in remission; 17.51% presented low disease activity; 39.45% moderate disease activity; 22.61% high disease activity.Eighty-two patients (6.9%) had a history for CVEs (58 myocardial infarction, 38 heart failure, 10 ischemic transitory attack, and 7 stroke). This figure appears to be lower than that reported worldwide (8.5%). After excluding the 82 patients with a history of CV

  18. Is atherosclerosis imaging the most sensitive way to assess patients' risk and the best way to conduct future drug trials? A pros-and-cons debate.

    PubMed

    Nanchen, David; Raggi, Paolo

    2017-11-01

    Atherosclerosis imaging has been the focus of intense debate and research for several decades. Among its primary applications are risk stratification of asymptomatic individuals and follow-up of atherosclerosis progression under a variety of treatments designed to retard or regress the development of arterial disease. Although endorsed and supported by many, this approach has been fiercely opposed by several key opinion leaders over the years. Similarly, regulatory agencies have raised a number of objections to resist the approval of new drugs and devices based on surrogate imaging markers. However, there is a large body of evidence in the medical literature that shows that risk stratification is improved with implementation of atherosclerosis imaging. Additionally, numerous lipid-modifying agents have been tested as far as their ability to affect progression of atherosclerosis, and in many cases the information obtained with imaging was in line with the outcome of subsequent clinical trials. This pros-and-cons debate was staged to bring up in a fun and provoking way the main arguments in favour or against the application of atherosclerosis imaging in the main settings described above. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Echium Oil Reduces Atherosclerosis in apoB100-only LDLrKO Mice

    PubMed Central

    Forrest, Lolita M.; Boudyguina, Elena; Wilson, Martha D.; Parks, John S.

    2012-01-01

    Introduction The anti-atherogenic and hypotriglyceridemic properties of fish oil are attributed to its enrichment in eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3). Echium oil contains stearidonic acid (SDA; 18:4, n-3), which is metabolized to EPA in humans and mice, resulting in decreased plasma triglycerides. Objective We used apoB100 only, LDLrKO mice to investigate whether echium oil reduces atherosclerosis. Methods Mice were fed palm, echium, or fish oil-containing diets for 16 weeks and plasma lipids, lipoproteins, and atherosclerosis were measured. Results Compared to palm oil, echium oil feeding resulted in significantly less plasma triglyceride and cholesterol levels, and atherosclerosis, comparable to that of fish oil. Conclusion This is the first report that echium oil is anti-atherogenic, suggesting that it may be a botanical alternative to fish oil for atheroprotection. PMID:22100249

  20. Intracranial atherosclerosis is associated with progression of neurological deficit in subcortical stroke.

    PubMed

    Hallevi, Hen; Chernyshev, Oleg Y; El Khoury, Ramy; Soileau, Michael J; Walker, Kyle C; Grotta, James C; Savitz, Sean I

    2012-01-01

    Progression of neurological deficit (PND) is a frequent complication of acute subcortical ischemic stroke (SCS). The role of intracranial atherosclerosis (IAS) in PND is controversial. Our goal was to evaluate IAS on admission, as predictor of PND in SCS patients. SCS patients were identified from our prospective database from 2004 to 2008. Clinical and laboratory data were collected from charts, and radiographic data from original radiographs. The proximal intracranial arteries were graded as patent, irregular, stenotic, or occlusion. IAS was defined as irregularity or stenosis. PND was defined as a change in the National Institutes of Health Stroke Scale >1 point. Two hundred and two SCS patients were identified. In 14%, PND occurred at a median of 2 days from onset. Univariate analysis by infarct location showed the following to be associated with PND: for anterior circulation infarcts (centrum semiovale/basal ganglia), M1 atherosclerosis (p = 0.042); for posterior circulation infarcts, vertebral artery atherosclerosis (p = 0.018). For both groups, we found a non-significant association with age (p = 0.2) and HbA1c levels (p = 0.095). No association was found with admission glucose levels. Multivariate analysis showed the following association with PND: for anterior circulation infarcts, M1 atherosclerosis (OR 4.7; 95% CI 1.2-18.8; p = 0.03); for pontine infarcts, vertebral artery atherosclerosis (OR 5.8; 95% CI 1.1-29.4; p = 0.033). There was an increase in PND likelihood with an increasing number of atherosclerotic vessels. In our cohort of SCS patients, PND was associated with IAS of the responsible vessels. These results suggest a role for IAS in the pathogenesis of PNF in SCS patients. Copyright © 2011 S. Karger AG, Basel.

  1. Early accelerated senescence of circulating endothelial progenitor cells in premature coronary artery disease patients in a developing country - a case control study.

    PubMed

    Vemparala, Kranthi; Roy, Ambuj; Bahl, Vinay Kumar; Prabhakaran, Dorairaj; Nath, Neera; Sinha, Subrata; Nandi, Pradipta; Pandey, Ravindra Mohan; Reddy, Kolli Srinath; Manhapra, Ajay; Lakshmy, Ramakrishnan

    2013-11-19

    The decreased number and senescence of circulating endothelial progenitor cells (EPCs) are considered markers of vascular senescence associated with aging, atherosclerosis, and coronary artery disease (CAD) in elderly. In this study, we explore the role of vascular senescence in premature CAD (PCAD) in a developing country by comparing the numerical status and senescence of circulating EPCs in PCAD patients to controls. EPCs were measured by flow cytometry in 57 patients with angiographically documented CAD, and 57 controls without evidence of CAD, recruited from random patients ≤ 50 years of age at All India Institute of Medical Sciences. EPC senescence as determined by telomere length (EPC-TL) and telomerase activity (EPC-TA) was studied by real time polymerase chain reaction (q PCR) and PCR- ELISA respectively. The number of EPCs (0.18% Vs. 0.039% of total WBCs, p < 0.0001), and EPC-TL (3.83 Vs. 5.10 kb/genome, p = 0.009) were markedly lower in PCAD patients compared to controls. These differences persisted after adjustment for age, sex, BMI, smoking and medications. EPC-TA was reduced in PCAD patients, but was statistically significant only after adjustment for confounding factors (1.81 Vs. 2.20 IU/cell, unadjusted p = 0.057, adjusted p = 0.044). We observed an association between increased vascular cell senescence with PCAD in a sample of young patients from India. This suggests that early accelerated vascular cell senescence may play an important mechanistic role in CAD epidemic in developing countries like India where PCAD burden is markedly higher compared to developed countries.

  2. Accelerated Application Development: The ORNL Titan Experience

    DOE PAGES

    Joubert, Wayne; Archibald, Richard K.; Berrill, Mark A.; ...

    2015-05-09

    The use of computational accelerators such as NVIDIA GPUs and Intel Xeon Phi processors is now widespread in the high performance computing community, with many applications delivering impressive performance gains. However, programming these systems for high performance, performance portability and software maintainability has been a challenge. In this paper we discuss experiences porting applications to the Titan system. Titan, which began planning in 2009 and was deployed for general use in 2013, was the first multi-petaflop system based on accelerator hardware. To ready applications for accelerated computing, a preparedness effort was undertaken prior to delivery of Titan. In this papermore » we report experiences and lessons learned from this process and describe how users are currently making use of computational accelerators on Titan.« less

  3. Accelerated application development: The ORNL Titan experience

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Joubert, Wayne; Archibald, Rick; Berrill, Mark

    2015-08-01

    The use of computational accelerators such as NVIDIA GPUs and Intel Xeon Phi processors is now widespread in the high performance computing community, with many applications delivering impressive performance gains. However, programming these systems for high performance, performance portability and software maintainability has been a challenge. In this paper we discuss experiences porting applications to the Titan system. Titan, which began planning in 2009 and was deployed for general use in 2013, was the first multi-petaflop system based on accelerator hardware. To ready applications for accelerated computing, a preparedness effort was undertaken prior to delivery of Titan. In this papermore » we report experiences and lessons learned from this process and describe how users are currently making use of computational accelerators on Titan.« less

  4. Thymic stromal lymphopoietin-induced HOTAIR activation promotes endothelial cell proliferation and migration in atherosclerosis

    PubMed Central

    Peng, Yudong; Meng, Kai; Jiang, Lili; Zhong, Yucheng; Yang, Yong; Lan, Yin

    2017-01-01

    Endothelial cells’ (EC) injury is a major step for the pathological progression of atherosclerosis. Recent study demonstrated that thymic stromal lymphopoietin (TSLP) exerts a protective role in atherosclerosis. However, the effect of TSLP and the exact molecular mechanism involved in EC remains unknown. In the present study, we found that long noncoding RNA (lncRNA) HOTAIR was much lower in EC from atherosclerotic plaque. Functional assays showed that HOTAIR facilitated cell proliferation and migration, and suppressed apoptosis in EC. Moreover, we demonstrated that TSLP functions upstream of HOTAIR. We found that serum level of TSLP was decreased in atherosclerosis patients and serum TSLP level positively correlated with HOTAIR expression in EC. Further investigation demonstrated that TSLP activated HOTAIR transcription through PI3K/AKT-IRF1 pathway and then regulates the EC proliferation and migration. TSLP-HOTAIR axis also plays a protective role in low-density lipoprotein (ox-LDL)-induced EC injury. Taken together, TSLP-HOTAIR may be a potential therapy for EC dysfunction in atherosclerosis. PMID:28615347

  5. Atherosclerosis of the carotid artery: absence of evidence for CMV involvement in atheroma formation.

    PubMed

    Saetta, A; Fanourakis, G; Agapitos, E; Davaris, P S

    2000-01-01

    Several studies suggest that certain viral and bacterial pathogens may contribute to the process of atherogenesis. However, this relation between infectious agents and atherosclerosis has not yet been established with certainty. The aim of this study was to investigate the presence of CMV in carotid endarterectomies from 40 patients suffering from atherosclerosis using immunohistochemistry and the polymerase chain reaction (PCR). None of the specimens examined gave a positive result, indicating absence of CMV particles or CMV DNA sequences in the walls of carotid arteries. This finding suggests it is possible that CMV infection may not play a major role in the formation of atheroma. Therefore, further investigation is required in order to clarify the etiology of atherosclerosis.

  6. Human cells involved in atherosclerosis have a sex.

    PubMed

    Franconi, Flavia; Rosano, Giuseppe; Basili, Stefania; Montella, Andrea; Campesi, Ilaria

    2017-02-01

    The influence of sex has been largely described in cardiovascular diseases. Atherosclerosis is a complex process that involves many cell types such as vessel cells, immune cells and endothelial progenitor cells; however, many, if not all, studies do not report the sex of the cells. This review focuses on sex differences in human cells involved in the atherosclerotic process, emphasizing the role of sex hormones. Furthermore, we report sex differences and issues related to the processes that determine the fate of the cells such as apoptotic and autophagic mechanisms. The analysis of the data reveals that there are still many gaps in our knowledge regarding sex influences in atherosclerosis, largely for the cell types that have not been well studied, stressing the urgent need for a clear definition of experimental conditions and the inclusion of both sexes in preclinical studies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Amelioration of Atherosclerosis by the New Medicinal Mushroom Grifola gargal Singer

    PubMed Central

    Harada, Etsuko; D'Alessandro-Gabazza, Corina N.; Toda, Masaaki; Morizono, Toshihiro; Chelakkot-Govindalayathil, Ayshwarya-Lakshmi; Roeen, Ziaurahman; Urawa, Masahito; Yasuma, Taro; Yano, Yutaka; Sumiya, Toshimitsu

    2015-01-01

    ABSTRACT The beneficial effects of edible mushrooms for improving chronic intractable diseases have been documented. However, the antiatherogenic activity of the new medicinal mushroom Grifola gargal is unknown. Therefore, we evaluated whether Grifola gargal can prevent or delay the progression of atherosclerosis. Atherosclerosis was induced in ApoE lipoprotein-deficient mice by subcutaneous infusion of angiotensin II. Grifola gargal extract (GGE) was prepared and intraperitoneally injected. The weight of heart and vessels, dilatation/atheroma formation of thoracic and abdominal aorta, the percentage of peripheral granulocytes, and the blood concentration of MCP-1/CCL2 were significantly reduced in mice treated with GGE compared to untreated mice. By contrast, the percentage of regulatory T cells and the plasma concentration of SDF-1/CXCL12 were significantly increased in mice treated with the mushroom extract compared to untreated mice. In vitro, GGE significantly increased the secretion of SDF-1/CXCL12, VEGF, and TGF-β1 from fibroblasts compared to control. This study demonstrated for the first time that Grifola gargal therapy can enhance regulatory T cells and ameliorate atherosclerosis in mice. PMID:25799023

  8. Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice.

    PubMed

    Lambert, G; Sakai, N; Vaisman, B L; Neufeld, E B; Marteyn, B; Chan, C C; Paigen, B; Lupia, E; Thomas, A; Striker, L J; Blanchette-Mackie, J; Csako, G; Brady, J N; Costello, R; Striker, G E; Remaley, A T; Brewer, H B; Santamarina-Fojo, S

    2001-05-04

    To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice. LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (-70 to -94%) and non-HDL cholesterol (-48 to -85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (-35% to -99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.

  9. Encrustation and Atherosclerosis: The Analogy Between Early in Vivo Lesions and Deposits Which Occur in Extracorporeal Circulations

    PubMed Central

    Murphy, E. A.; Rowsell, H. C.; Downie, H. G.; Robinson, G. A.; Mustard, J. F.

    1962-01-01

    A study was made of the relation between the pattern and topography of thrombus formation in models of various vessel configurations coupled into extracorporeal shunts in swine and the development of atherosclerosis at corresponding sites on swine aortas. The pattern and distribution of deposits formed in the models were strikingly similar to the pattern and distribution of incipient atherosclerosis at comparable sites in the vascular tree. The earliest and only consistent component of the flow chamber deposits was the blood platelet. The platelet deposits would frequently stain with oil red O. The cholesterol level of washed human platelets was found to show a good correlation with that in the plasma. This evidence suggests that deposition of particulate matter (chiefly platelets), largely determined by the hydraulic factors, may be an important factor in the early, as well as later, stages of atherosclerosis. ImagesFigs. 10a and bFig. 13Fig. 21Fig. 1Fig. 3Figs. 4a and bFig. 5Fig. 6aFig. 6bFig. 7Fig. 8Fig. 9Fig. 11Fig. 12Fig. 14Fig. 15Fig. 16Fig. 17Fig. 18Fig. 19Fig. 20 PMID:14477412

  10. MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin

    PubMed Central

    Di Gregoli, Karina; Mohamad Anuar, Nur Najmi; Bianco, Rosaria; White, Stephen J.; Newby, Andrew C.; George, Sarah J.

    2017-01-01

    Rationale: Atherosclerosis and aneurysms are leading causes of mortality worldwide. MicroRNAs (miRs) are key determinants of gene and protein expression, and atypical miR expression has been associated with many cardiovascular diseases; although their contributory role to atherosclerotic plaque and abdominal aortic aneurysm stability are poorly understood. Objective: To investigate whether miR-181b regulates tissue inhibitor of metalloproteinase-3 expression and affects atherosclerosis and aneurysms. Methods and Results: Here, we demonstrate that miR-181b was overexpressed in symptomatic human atherosclerotic plaques and abdominal aortic aneurysms and correlated with decreased expression of predicted miR-181b targets, tissue inhibitor of metalloproteinase-3, and elastin. Using the well-characterized mouse atherosclerosis models of Apoe−/− and Ldlr−/−, we observed that in vivo administration of locked nucleic acid anti-miR-181b retarded both the development and the progression of atherosclerotic plaques. Systemic delivery of anti-miR-181b in angiotensin II–infused Apoe−/− and Ldlr−/− mice attenuated aneurysm formation and progression within the ascending, thoracic, and abdominal aorta. Moreover, miR-181b inhibition greatly increased elastin and collagen expression, promoting a fibrotic response and subsequent stabilization of existing plaques and aneurysms. We determined that miR-181b negatively regulates macrophage tissue inhibitor of metalloproteinase-3 expression and vascular smooth muscle cell elastin production, both important factors in maintaining atherosclerotic plaque and aneurysm stability. Validation studies in Timp3−/− mice confirmed that the beneficial effects afforded by miR-181b inhibition are largely tissue inhibitor of metalloproteinase-3 dependent, while also revealing an additional protective effect through elevating elastin synthesis. Conclusions: Our findings suggest that the management of miR-181b and its target genes

  11. MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin.

    PubMed

    Di Gregoli, Karina; Mohamad Anuar, Nur Najmi; Bianco, Rosaria; White, Stephen J; Newby, Andrew C; George, Sarah J; Johnson, Jason L

    2017-01-06

    Atherosclerosis and aneurysms are leading causes of mortality worldwide. MicroRNAs (miRs) are key determinants of gene and protein expression, and atypical miR expression has been associated with many cardiovascular diseases; although their contributory role to atherosclerotic plaque and abdominal aortic aneurysm stability are poorly understood. To investigate whether miR-181b regulates tissue inhibitor of metalloproteinase-3 expression and affects atherosclerosis and aneurysms. Here, we demonstrate that miR-181b was overexpressed in symptomatic human atherosclerotic plaques and abdominal aortic aneurysms and correlated with decreased expression of predicted miR-181b targets, tissue inhibitor of metalloproteinase-3, and elastin. Using the well-characterized mouse atherosclerosis models of Apoe - /- and Ldlr -/- , we observed that in vivo administration of locked nucleic acid anti-miR-181b retarded both the development and the progression of atherosclerotic plaques. Systemic delivery of anti-miR-181b in angiotensin II-infused Apoe -/- and Ldlr -/- mice attenuated aneurysm formation and progression within the ascending, thoracic, and abdominal aorta. Moreover, miR-181b inhibition greatly increased elastin and collagen expression, promoting a fibrotic response and subsequent stabilization of existing plaques and aneurysms. We determined that miR-181b negatively regulates macrophage tissue inhibitor of metalloproteinase-3 expression and vascular smooth muscle cell elastin production, both important factors in maintaining atherosclerotic plaque and aneurysm stability. Validation studies in Timp3 -/- mice confirmed that the beneficial effects afforded by miR-181b inhibition are largely tissue inhibitor of metalloproteinase-3 dependent, while also revealing an additional protective effect through elevating elastin synthesis. Our findings suggest that the management of miR-181b and its target genes provides therapeutic potential for limiting the progression of

  12. Imaging atherosclerosis with hybrid [18F]fluorodeoxyglucose positron emission tomography/computed tomography imaging: what Leonardo da Vinci could not see.

    PubMed

    Cocker, Myra S; Mc Ardle, Brian; Spence, J David; Lum, Cheemun; Hammond, Robert R; Ongaro, Deidre C; McDonald, Matthew A; Dekemp, Robert A; Tardif, Jean-Claude; Beanlands, Rob S B

    2012-12-01

    Prodigious efforts and landmark discoveries have led toward significant advances in our understanding of atherosclerosis. Despite significant efforts, atherosclerosis continues globally to be a leading cause of mortality and reduced quality of life. With surges in the prevalence of obesity and diabetes, atherosclerosis is expected to have an even more pronounced impact upon the global burden of disease. It is imperative to develop strategies for the early detection of disease. Positron emission tomography (PET) imaging utilizing [(18)F]fluorodeoxyglucose (FDG) may provide a non-invasive means of characterizing inflammatory activity within atherosclerotic plaque, thus serving as a surrogate biomarker for detecting vulnerable plaque. The aim of this review is to explore the rationale for performing FDG imaging, provide an overview into the mechanism of action, and summarize findings from the early application of FDG PET imaging in the clinical setting to evaluate vascular disease. Alternative imaging biomarkers and approaches are briefly discussed.

  13. The cis-9,trans-11 isomer of conjugated linoleic acid (CLA) lowers plasma triglyceride and raises HDL cholesterol concentrations but does not suppress aortic atherosclerosis in diabetic apoE-deficient mice.

    PubMed

    Nestel, Paul; Fujii, Akihiko; Allen, Terri

    2006-12-01

    Reduction in atherosclerosis has been reported in experimental animals fed mixtures of conjugated linoleic acid (CLA). In this study, the major naturally occurring CLA isomer (cis-9,trans-11) was tested in an atherosclerosis-prone mouse model. In a model of insulin deficient apoE deficient mice, 16 animals were fed for 20 weeks with supplemental CLA (09.%, w/w) and compared with a similar number of mice of this phenotype. A control comparison was made of metabolic changes in non-diabetic apoE deficient mice that develop little atherosclerosis over 20 weeks. At 20 weeks, plasma lipids were measured and aortic atherosclerosis quantified by Sudan staining in the arch, thoracic and abdominal segments. The diabetic apoE deficient mice developed marked dyslipidemia, primarily as cholesterol-enriched chylomicron and VLDL-sized lipoproteins and atherosclerosis in the aortic arch. However, there were no significant differences between CLA fed and non-CLA fed mice in either phenotype in plasma cholesterol concentration (in diabetic: 29.4+/-7.7 and 29.5+/-5.9 mmol/L, respectively) or in the area of aortic arch atherosclerosis (in diabetic: 24.8+/-10.3 and 27.6+/-7.7%, respectively). However, among diabetic mice the triglyceride concentration in triglyceride-rich lipoproteins was significantly lower in those fed CLA (for plasma 2.2+/-0.8 to 1.1+/-0.3 mmol/L; P<0.001), a significant difference that was seen also in the non-diabetic mice in which HDL cholesterol increased significantly with CLA (0.35+/-0.12-0.56+/-0.15 mmol/L). In this atherosclerosis-prone model, the diabetic apoE deficient mouse, supplemental 0.9% CLA (cis-9,trans-11) failed to reduce the severity of aortic atherosclerosis, although plasma triglyceride concentration was substantially lowered and HDL cholesterol raised.

  14. Subclinical carotid atherosclerosis and hyperuricemia in relation to renal impairment in a rural Japanese population: the Nagasaki Islands study.

    PubMed

    Shimizu, Yuji; Sato, Shimpei; Koyamatsu, Jun; Yamanashi, Hirotomo; Tamai, Mami; Kadota, Koichiro; Arima, Kazuhiko; Yamasaki, Hironori; Takamura, Noboru; Aoyagi, Kiyoshi; Maeda, Takahiro

    2014-04-01

    The influence of hyperuricemia on atherosclerosis is controversial. Subclinical carotid atherosclerosis can be defined in two ways in terms of mean and maximum carotid intima-media thickness (CIMT): one with mean CIMT≥1.1 mm and the other with maximum CIMT≥1.1 mm. However, no studies have been reported of the association between hyperuricemia and subclinical carotid atherosclerosis while taking the two different ways of classification into account. We conducted a cross-sectional study of 4133 subjects (1492 men and 2641 women) aged 30-89 years undergoing general health check-ups. For analysis of various associations, we calculated the multivariable odds ratios (ORs) for the two ways classifications of subclinical carotid atherosclerosis in relation to hyperuricemia. Hyperuricemia-related renal impairment constitutes a significant marker for subclinical carotid atherosclerosis with mean CIMT≥1.1 mm for both men and women, while hyperuricemia per se was found to be beneficially associated with risk of subclinical carotid atherosclerosis with maximum CIMT≥1.1 mm for men. The classical cardiovascular risk factors without adjustment for glomerular filtration rate (GFR) of ORs for subclinical carotid atherosclerosis (mean CIMT≥1.1 mm) and subclinical carotid atherosclerosis (maximum CIMT≥1.1 mm) were 2.20(1.10-4.22) and 0.84(0.63-1.13) for men and 2.12(1.02-4.38) and 0.92(0.66-1.27) for women. After further adjustment for GFR, the corresponding values were 1.54(0.74-3.20) and 0.67(0.49-0.92) for men and 1.32(0.61-2.88) and 0.80(0.57-1.12) for women. Hyperuricemia-related renal impairment is a significant marker for subclinical carotid atherosclerosis for both men and women, while hyperuricemia per se may be inversely associated with subclinical carotid atherosclerosis for men as seen in a rural community-dwelling Japanese population. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. Development of a tandem-electrostatic-quadrupole accelerator facility for BNCT.

    PubMed

    Kreiner, A J; Thatar Vento, V; Levinas, P; Bergueiro, J; Di Paolo, H; Burlon, A A; Kesque, J M; Valda, A A; Debray, M E; Somacal, H R; Minsky, D M; Estrada, L; Hazarabedian, A; Johann, F; Suarez Sandin, J C; Castell, W; Davidson, J; Davidson, M; Giboudot, Y; Repetto, M; Obligado, M; Nery, J P; Huck, H; Igarzabal, M; Fernandez Salares, A

    2009-07-01

    In this work we describe the present status of an ongoing project to develop a tandem-electrostatic-quadrupole (TESQ) accelerator facility for accelerator-based (AB) BNCT at the Atomic Energy Commission of Argentina in Buenos Aires. The project final goal is a machine capable of delivering 30 mA of 2.4 MeV protons to be used in conjunction with a neutron production target based on the (7)Li(p,n)(7)Be reaction slightly beyond its resonance at 2.25 MeV. These are the specifications needed to produce sufficiently intense and clean epithermal neutron beams, based on the (7)Li(p,n)(7)Be reaction, to perform BNCT treatment for deep-seated tumors in less than an hour. An electrostatic machine is the technologically simplest and cheapest solution for optimized AB-BNCT. The machine being designed and constructed is a folded TESQ with a high-voltage terminal at 1.2 MV intended to work in air. Such a machine is conceptually shown to be capable of transporting and accelerating a 30 mA proton beam to 2.4 MeV. The general geometric layout, its associated electrostatic fields, and the acceleration tube are simulated using a 3D finite element procedure. The design and construction of the ESQ modules is discussed and their electrostatic fields are investigated. Beam transport calculations through the accelerator are briefly mentioned. Likewise, work related to neutron production targets, strippers, beam shaping assembly and patient treatment room is briefly described.

  16. Prediabetes is not a risk factor for subclinical coronary atherosclerosis.

    PubMed

    Park, Gyung-Min; Cho, Young-Rak; Lee, Seung-Whan; Yun, Sung-Cheol; Won, Ki-Bum; Ann, Soe Hee; Kim, Yong-Giun; Kim, Shin-Jae; Roh, Jae-Hyung; Kim, Young-Hak; Yang, Dong Hyun; Kang, Joon-Won; Lim, Tae-Hwan; Jung, Chang Hee; Koh, Eun Hee; Lee, Woo Je; Kim, Min-Seon; Lee, Ki-Up; Park, Joong-Yeol; Kim, Hong-Kyu; Choe, Jaewon; Lee, Sang-Gon

    2017-09-15

    There are limited data regarding the influence of glycemic status on the risk of subclinical coronary atherosclerosis on coronary computed tomographic angiography (CCTA) in asymptomatic individuals. We analyzed 6434 asymptomatic individuals who underwent CCTA. The degree and extent of subclinical coronary atherosclerosis were assessed by CCTA, and ≥50% diameter stenosis was defined as significant. Of study participants, 2197 (34.1%), 3122 (48.5%), and 1115 (17.3%) were categorized as normal, prediabetic and diabetic individuals, respectively. Compared with normal individuals, there were no statistically differences in the adjusted odds ratios of prediabetic individuals for significant coronary artery stenosis (0.98, 95% confidence interval [CI] 0.80-1.22, p=0.888), any plaque (0.96, 95% CI 0.86-1.07, p=0.483), calcified plaque (0.90, 95% CI 0.79-1.01, p=0.080), non-calcified plaque (1.02, 95% CI 0.88-1.17, p=0.803), and mixed plaque (1.00, 95% CI 0.82-1.22, p=0.983). However, adjusted odds ratios for significant coronary artery stenosis (1.71, 95% CI 1.34-2.19, p<0.001), any plaque (1.45, 95% CI 1.26-1.68, p<0.001), calcified plaque (1.35, 95% CI 1.15-1.57, p<0.001), non-calcified plaque (1.33, 95% CI 1.11-1.59, p=0.002), and mixed plaque (1.64, 95% CI 1.30-2.07, p<0.001) of diabetic individuals were significantly higher than those of the normal individuals. In asymptomatic individuals, diabetic individuals had a higher risk for subclinical coronary atherosclerosis, but prediabetic individuals were not associated with an increased risk of subclinical coronary atherosclerosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Sleep duration and subclinical atherosclerosis: The Aragon Workers' Health Study.

    PubMed

    Blasco-Colmenares, Elena; Moreno-Franco, Belén; Latre, Montserrat León; Mur-Vispe, Eusebio; Pocovi, Miguel; Jarauta, Estíbaliz; Civeira, Fernando; Laclaustra, Martín; Casasnovas, José A; Guallar, Eliseo

    2018-05-03

    Few studies have evaluated the association of sleep duration with subclinical atherosclerosis, and with heterogeneous findings. We evaluated the association of sleep duration with the presence of coronary, carotid, and femoral subclinical atherosclerosis in healthy middle-age men with low prevalence of clinical comorbidities. We performed a cross-sectional analysis of 1968 men, 40-60 years of age, participating in the Aragon Workers' Health Study (AWHS). Duration of sleep during a typical work week was assessed by questionnaire. Coronary artery calcium scores (CACS) was assessed by computed tomography and the presence of carotid plaque and femoral plaque by ultrasound. In fully adjusted models, the odds ratios (95% CI) for CACS >0 comparing sleep durations of ≤5, 6, and ≥8 h with 7 h were 1.34 (0.98-1.85), 1.35 (1.08-1.69) and 1.21 (0.90-1.62), respectively (p = 0.04). A similar U-shaped association was observed for CACS ≥100 and for CACS. The corresponding odds ratios for the presence of at least one carotid plaque were ≤5, 6, and ≥8 h with 7 h were 1.23 (0.88-1.72), 1.09 (0.86-1.38), and 0.86 (0.63-1.17), respectively (p = 0.31), and for the presence of at least one femoral plaque were 1.25 (0.87-1.80), 1.19 (0.93-1.51) and 1.17 (0.86-1.61), respectively (p = 0.39). Middle-aged men reporting 7 h of sleep duration had the lowest prevalence of subclinical coronary atherosclerosis as assessed by CACs. Our results support that men with very short or very long sleep durations are at increased risk of atherosclerosis. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Atorvastatin Improves Inflammatory Response in Atherosclerosis by Upregulating the Expression of GARP.

    PubMed

    Zhao, Xiaoqi; Liu, Yuzhou; Zhong, Yucheng; Liu, Bo; Yu, Kunwu; Shi, Huairui; Zhu, Ruirui; Meng, Kai; Zhang, Wei; Wu, Bangwei; Zeng, Qiutang

    2015-01-01

    Regulatory T cells play an important role in the progression of atherosclerosis. GARP is a newly biological membrane molecule existed on activated Tregs, which is related to the release of TGF-β. The antiatherosclerosis effects of statins partly depend on their multiple immune modulatory potencies. In this paper, we present that atorvastatin could upregulate the expression of GARP and TGF-β in CD4+ T cells and increase the numbers of CD4+LAP+ and CD4+Foxp3+ regulatory T cells in ApoE-/- mice. Also, we indicate that atorvastatin promotes the aggregation of GARP+ and Foxp3+ cells and secretory of the TGF-β1 in atherosclerotic plaques. Furthermore, we prove that atorvastatin could delay the procession of atherosclerosis and improve the stability of atherosclerotic plaques. Interestingly, we report that inhibition of GARP distinctly inhibits the anti-inflammatory effects of atorvastatin. We conclude that atorvastatin improves the inflammatory response in atherosclerosis partly by upregulating the expression of GARP on regulatory T cells.

  19. Atorvastatin Improves Inflammatory Response in Atherosclerosis by Upregulating the Expression of GARP

    PubMed Central

    Zhao, Xiaoqi; Liu, Yuzhou; Zhong, Yucheng; Liu, Bo; Yu, Kunwu; Shi, Huairui; Zhu, Ruirui; Meng, Kai; Zhang, Wei; Wu, Bangwei

    2015-01-01

    Regulatory T cells play an important role in the progression of atherosclerosis. GARP is a newly biological membrane molecule existed on activated Tregs, which is related to the release of TGF-β. The antiatherosclerosis effects of statins partly depend on their multiple immune modulatory potencies. In this paper, we present that atorvastatin could upregulate the expression of GARP and TGF-β in CD4+ T cells and increase the numbers of CD4+LAP+ and CD4+Foxp3+ regulatory T cells in ApoE−/− mice. Also, we indicate that atorvastatin promotes the aggregation of GARP+ and Foxp3+ cells and secretory of the TGF-β1 in atherosclerotic plaques. Furthermore, we prove that atorvastatin could delay the procession of atherosclerosis and improve the stability of atherosclerotic plaques. Interestingly, we report that inhibition of GARP distinctly inhibits the anti-inflammatory effects of atorvastatin. We conclude that atorvastatin improves the inflammatory response in atherosclerosis partly by upregulating the expression of GARP on regulatory T cells. PMID:26063978

  20. Correlation of collagen synthesis with polarization-sensitive optical coherence tomography imaging of in vitro human atherosclerosis

    NASA Astrophysics Data System (ADS)

    Kuo, Wen-Chuan; Shyu, Jeou-Jong; Chou, Nai-Kuan; Lai, Chih-Ming; Tien, En-Kuang; Huang, Huan-Jang; Chou, Chien; Jan, Gwo-Jen

    2005-04-01

    Atherosclerosis is unquestionably the leading cause of morbidity and mortality in developed countries. In the mean time, the worldwide importance of acute vascular syndromes is increasing. Because collagen fiber is a critical component of atherosclerotic lesions; it constitutes up to 60% of the total atherosclerotic plaque protein. The uncontrolled collagen accumulation leads to arterial stenosis, whereas excessive collagen breakdown weakens plaques thereby making them prone to rupture finally. Thus, in this study, we present the first application, to our knowledge, of using polarization-sensitive optical coherence tomography (PS-OCT) in human atherosclerosis. We demonstrate this technique for imaging of intensity, birefringence, and fast-axis orientation simultaneously in atherosclerotic plaques. This in vitro study suggests that the birefringence change in plaque is due to the prominent deposition of collagen according to the correlation of PS-OCT images with histological counterpart. Moreover, we can acquire quantitative criteria based on the change of polarization of incident beam to estimate whether the collagen synthesized is "too much" or "not enough". Thus by combining of high resolution intensity imaging and birefringence detection makes PS-OCT could be a potentially powerful tool for early assessment of atherosclerosis appearance and the prediction of plaque rupture in clinic.

  1. Developments and applications of accelerator system at the Wakasa Wan Energy Research Center

    NASA Astrophysics Data System (ADS)

    Hatori, S.; Kurita, T.; Hayashi, Y.; Yamada, M.; Yamada, H.; Mori, J.; Hamachi, H.; Kimura, S.; Shimoda, T.; Hiroto, M.; Hashimoto, T.; Shimada, M.; Yamamoto, H.; Ohtani, N.; Yasuda, K.; Ishigami, R.; Sasase, M.; Ito, Y.; Hatashita, M.; Takagi, K.; Kume, K.; Fukuda, S.; Yokohama, N.; Kagiya, G.; Fukumoto, S.; Kondo, M.

    2005-12-01

    At the Wakasa Wan Energy Research Center (WERC), an accelerator system with a 5 MV tandem accelerator and a 200 MeV proton synchrotron is used for ion beam analyses and irradiation experiments. The study of cancer therapy with a proton beam is also performed. Therefore, the stable operation and efficient sharing of beam time of the system are required, based on the treatment standard. Recent developments and the operation status of the system put stress on the tandem accelerator operation, magnifying the problems.

  2. Influence of the extent of westernization of lifestyle on the progression of preclinical atherosclerosis in Japanese subjects.

    PubMed

    Egusa, Genshi; Watanabe, Hiroshi; Ohshita, Kayo; Fujikawa, Rumi; Yamane, Kiminori; Okubo, Masamichi; Kohno, Nobuoki

    2002-01-01

    To clarify the influence of a westernized lifestyle on the risk factors for atherosclerosis and preclinical atherosclerosis in Japanese subjects, we surveyed a Japanese population and Japanese immigrants in the United States. Based on the extent of westernization of their lifestyle, the subjects were classified as Japanese (J), first generation Japanese-Americans (JA-I), and second or later generation Japanese-Americans (JA-II). The consumption of animal fat and simple carbohydrates increased in the order of J, JA-I, and JA-II, while the subjects with strenuous physical activity decreased in the same order. The waist-hip ratio, fasting insulin level, serum cholesterol and triglyceride levels, and prevalence of hypertension increased in the same order as the dietary changes. The carotid intima-media wall thickness and the plaque size, which are indices of preclinical atherosclerosis, also increased in the order of J, JA-I, and JA-II. These data indicate that a westernized lifestyle aggravates the risk factors for atherosclerosis and influences the progression of preclinical atherosclerosis, in correspondence with the extent of westernization.

  3. Illinois Accelerator Research Center

    DOE PAGES

    Kroc, Thomas K.; Cooper, Charlie A.

    2017-10-26

    The Illinois Accelerator Research Center (IARC) hosts a new accelerator development program at Fermi National Accelerator Laboratory. IARC provides access to Fermi's state-of-the-art facilities and technologies for research, development and industrialization of particle accelerator technology. In addition to facilitating access to available existing Fermi infrastructure, the IARC Campus has a dedicated 36,000 ft2 heavy assembly building (HAB) with all the infrastructure needed to develop, commission and operate new accelerators. Connected to the HAB is a 47,000 ft Office, Technology and Engineering (OTE) building, paid for by the state, that has office, meeting, and light technical space. The OTE building, whichmore » contains the Accelerator Physics Center, and nearby Accelerator and Technical divisions provide IARC collaborators with unique access to world class expertise in a wide array of accelerator technologies. Finally, at IARC scientists and engineers from Fermilab and academia work side by side with industrial partners to develop breakthroughs in accelerator science and translate them into applications for the nation's health, wealth and security.« less

  4. Illinois Accelerator Research Center

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kroc, Thomas K.; Cooper, Charlie A.

    The Illinois Accelerator Research Center (IARC) hosts a new accelerator development program at Fermi National Accelerator Laboratory. IARC provides access to Fermi's state-of-the-art facilities and technologies for research, development and industrialization of particle accelerator technology. In addition to facilitating access to available existing Fermi infrastructure, the IARC Campus has a dedicated 36,000 ft2 heavy assembly building (HAB) with all the infrastructure needed to develop, commission and operate new accelerators. Connected to the HAB is a 47,000 ft Office, Technology and Engineering (OTE) building, paid for by the state, that has office, meeting, and light technical space. The OTE building, whichmore » contains the Accelerator Physics Center, and nearby Accelerator and Technical divisions provide IARC collaborators with unique access to world class expertise in a wide array of accelerator technologies. Finally, at IARC scientists and engineers from Fermilab and academia work side by side with industrial partners to develop breakthroughs in accelerator science and translate them into applications for the nation's health, wealth and security.« less

  5. Illinois Accelerator Research Center

    NASA Astrophysics Data System (ADS)

    Kroc, Thomas K.; Cooper, Charlie A.

    The Illinois Accelerator Research Center (IARC) hosts a new accelerator development program at Fermi National Accelerator Laboratory. IARC provides access to Fermi's state-of-the-art facilities and technologies for research, development and industrialization of particle accelerator technology. In addition to facilitating access to available existing Fermi infrastructure, the IARC Campus has a dedicated 36,000 ft2 Heavy Assembly Building (HAB) with all the infrastructure needed to develop, commission and operate new accelerators. Connected to the HAB is a 47,000 ft2 Office, Technology and Engineering (OTE) building, paid for by the state, that has office, meeting, and light technical space. The OTE building, which contains the Accelerator Physics Center, and nearby Accelerator and Technical divisions provide IARC collaborators with unique access to world class expertise in a wide array of accelerator technologies. At IARC scientists and engineers from Fermilab and academia work side by side with industrial partners to develop breakthroughs in accelerator science and translate them into applications for the nation's health, wealth and security.

  6. Replacement of Dietary Saturated Fat by PUFA-Rich Pumpkin Seed Oil Attenuates Non-Alcoholic Fatty Liver Disease and Atherosclerosis Development, with Additional Health Effects of Virgin over Refined Oil

    PubMed Central

    Morrison, Martine C.; Mulder, Petra; Stavro, P. Mark; Suárez, Manuel; Arola-Arnal, Anna; van Duyvenvoorde, Wim; Kooistra, Teake; Wielinga, Peter Y.; Kleemann, Robert

    2015-01-01

    Background and Aims As dietary saturated fatty acids are associated with metabolic and cardiovascular disease, a potentially interesting strategy to reduce disease risk is modification of the quality of fat consumed. Vegetable oils represent an attractive target for intervention, as they largely determine the intake of dietary fats. Furthermore, besides potential health effects conferred by the type of fatty acids in a vegetable oil, other minor components (e.g. phytochemicals) may also have health benefits. Here, we investigated the potential long-term health effects of isocaloric substitution of dietary fat (i.e. partial replacement of saturated by unsaturated fats), as well as putative additional effects of phytochemicals present in unrefined (virgin) oil on development of non-alcoholic fatty liver disease (NAFLD) and associated atherosclerosis. For this, we used pumpkin seed oil, because it is high in unsaturated fatty acids and a rich source of phytochemicals. Methods ApoE*3Leiden mice were fed a Western-type diet (CON) containing cocoa butter (15% w/w) and cholesterol (1% w/w) for 20 weeks to induce risk factors and disease endpoints. In separate groups, cocoa butter was replaced by refined (REF) or virgin (VIR) pumpkin seed oil (comparable in fatty acid composition, but different in phytochemical content). Results Both oils improved dyslipidaemia, with decreased (V)LDL-cholesterol and triglyceride levels in comparison with CON, and additional cholesterol-lowering effects of VIR over REF. While REF did not affect plasma inflammatory markers, VIR reduced circulating serum amyloid A and soluble vascular adhesion molecule-1. NAFLD and atherosclerosis development was modestly reduced in REF, and VIR strongly decreased liver steatosis and inflammation as well as atherosclerotic lesion area and severity. Conclusions Overall, we show that an isocaloric switch from a diet rich in saturated fat to a diet rich in unsaturated fat can attenuate NAFLD and atherosclerosis

  7. Replacement of Dietary Saturated Fat by PUFA-Rich Pumpkin Seed Oil Attenuates Non-Alcoholic Fatty Liver Disease and Atherosclerosis Development, with Additional Health Effects of Virgin over Refined Oil.

    PubMed

    Morrison, Martine C; Mulder, Petra; Stavro, P Mark; Suárez, Manuel; Arola-Arnal, Anna; van Duyvenvoorde, Wim; Kooistra, Teake; Wielinga, Peter Y; Kleemann, Robert

    2015-01-01

    As dietary saturated fatty acids are associated with metabolic and cardiovascular disease, a potentially interesting strategy to reduce disease risk is modification of the quality of fat consumed. Vegetable oils represent an attractive target for intervention, as they largely determine the intake of dietary fats. Furthermore, besides potential health effects conferred by the type of fatty acids in a vegetable oil, other minor components (e.g. phytochemicals) may also have health benefits. Here, we investigated the potential long-term health effects of isocaloric substitution of dietary fat (i.e. partial replacement of saturated by unsaturated fats), as well as putative additional effects of phytochemicals present in unrefined (virgin) oil on development of non-alcoholic fatty liver disease (NAFLD) and associated atherosclerosis. For this, we used pumpkin seed oil, because it is high in unsaturated fatty acids and a rich source of phytochemicals. ApoE*3Leiden mice were fed a Western-type diet (CON) containing cocoa butter (15% w/w) and cholesterol (1% w/w) for 20 weeks to induce risk factors and disease endpoints. In separate groups, cocoa butter was replaced by refined (REF) or virgin (VIR) pumpkin seed oil (comparable in fatty acid composition, but different in phytochemical content). Both oils improved dyslipidaemia, with decreased (V)LDL-cholesterol and triglyceride levels in comparison with CON, and additional cholesterol-lowering effects of VIR over REF. While REF did not affect plasma inflammatory markers, VIR reduced circulating serum amyloid A and soluble vascular adhesion molecule-1. NAFLD and atherosclerosis development was modestly reduced in REF, and VIR strongly decreased liver steatosis and inflammation as well as atherosclerotic lesion area and severity. Overall, we show that an isocaloric switch from a diet rich in saturated fat to a diet rich in unsaturated fat can attenuate NAFLD and atherosclerosis development. Phytochemical-rich virgin pumpkin

  8. Is zinc deficiency a risk factor for atherosclerosis?

    PubMed

    Beattie, John H; Kwun, In-Sook

    2004-02-01

    The development of atherosclerosis is influenced by genetic, lifestyle and nutritional risk factors. Zn and metallothionein deficiency can enhance oxidative-stress-related signalling processes in endothelial cells, and since changes in available plasma Zn may affect the Zn status of the endothelium, Zn deficiency could be a risk factor for IHD. Although the association of Zn with many proteins is essential for their function, three key signalling processes are highlighted as being principal targets for the effect of Zn deficiency: the activation of NF-kappaB, the activation of caspase enzymes and the signalling of NO. The need to develop a reliable indicator of Zn status is critical to any epidemiological approach for studying the relationship between Zn status and disease incidence. Studies using appropriate animal models and investigating how the plasma Zn pool influences endothelial intracellular labile Zn would be helpful in appreciating the importance of Zn deficiency in atherogenesis.

  9. Helicon Plasma Injector and Ion Cyclotron Acceleration Development in the VASIMR Experiment

    NASA Technical Reports Server (NTRS)

    Squire, Jared P.; Chang, Franklin R.; Jacobson, Verlin T.; McCaskill, Greg E.; Bengtson, Roger D.; Goulding, Richard H.

    2000-01-01

    In the Variable Specific Impulse Magnetoplasma Rocket (VASIMR) radio frequency (rf) waves both produce the plasma and then accelerate the ions. The plasma production is done by action of helicon waves. These waves are circular polarized waves in the direction of the electron gyromotion. The ion acceleration is performed by ion cyclotron resonant frequency (ICRF) acceleration. The Advanced Space Propulsion Laboratory (ASPL) is actively developing efficient helicon plasma production and ICRF acceleration. The VASIMR experimental device at the ASPL is called VX-10. It is configured to demonstrate the plasma production and acceleration at the 10kW level to support a space flight demonstration design. The VX-10 consists of three electromagnets integrated into a vacuum chamber that produce magnetic fields up to 0.5 Tesla. Magnetic field shaping is achieved by independent magnet current control and placement of the magnets. We have generated both helium and hydrogen high density (>10(exp 18) cu m) discharges with the helicon source. ICRF experiments are underway. This paper describes the VX-10 device, presents recent results and discusses future plans.

  10. Quantitative trait locus mapping in mice identifies phospholipase Pla2g12a as novel atherosclerosis modifier.

    PubMed

    Nicolaou, Alexandros; Northoff, Bernd H; Sass, Kristina; Ernst, Jana; Kohlmaier, Alexander; Krohn, Knut; Wolfrum, Christian; Teupser, Daniel; Holdt, Lesca M

    2017-10-01

    In a previous work, a female-specific atherosclerosis risk locus on chromosome (Chr) 3 was identified in an intercross of atherosclerosis-resistant FVB and atherosclerosis-susceptible C57BL/6 (B6) mice on the LDL-receptor deficient (Ldlr -/- ) background. It was the aim of the current study to identify causative genes at this locus. We established a congenic mouse model, where FVB.Chr3 B6/B6 mice carried an 80 Mb interval of distal Chr3 on an otherwise FVB.Ldlr -/- background, to validate the Chr3 locus. Candidate genes were identified using genome-wide expression analyses. Differentially expressed genes were validated using quantitative PCRs in F0 and F2 mice and their functions were investigated in pathophysiologically relevant cells. Fine-mapping of the Chr3 locus revealed two overlapping, yet independent subloci for female atherosclerosis susceptibility: when transmitted by grandfathers to granddaughters, the B6 risk allele increased atherosclerosis and downregulated the expression of the secreted phospholipase Pla2g12a (2.6 and 2.2 fold, respectively); when inherited by grandmothers, the B6 risk allele induced vascular cell adhesion molecule 1 (Vcam1). Down-regulation of Pla2g12a and up-regulation of Vcam1 were validated in female FVB.Chr3 B6/B6 congenic mice, which developed 2.5 greater atherosclerotic lesions compared to littermate controls (p=0.039). Pla2g12a was highly expressed in aortic endothelial cells in vivo, and knocking-down Pla2g12a expression by RNAi in cultured vascular endothelial cells or macrophages increased their adhesion to ECs in vitro. Our data establish Pla2g12a as an atheroprotective candidate gene in mice, where high expression levels in ECs and macrophages may limit the recruitment and accumulation of these cells in nascent atherosclerotic lesions. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Accelerating Vaccine Formulation Development Using Design of Experiment Stability Studies.

    PubMed

    Ahl, Patrick L; Mensch, Christopher; Hu, Binghua; Pixley, Heidi; Zhang, Lan; Dieter, Lance; Russell, Ryann; Smith, William J; Przysiecki, Craig; Kosinski, Mike; Blue, Jeffrey T

    2016-10-01

    Vaccine drug product thermal stability often depends on formulation input factors and how they interact. Scientific understanding and professional experience typically allows vaccine formulators to accurately predict the thermal stability output based on formulation input factors such as pH, ionic strength, and excipients. Thermal stability predictions, however, are not enough for regulators. Stability claims must be supported by experimental data. The Quality by Design approach of Design of Experiment (DoE) is well suited to describe formulation outputs such as thermal stability in terms of formulation input factors. A DoE approach particularly at elevated temperatures that induce accelerated degradation can provide empirical understanding of how vaccine formulation input factors and interactions affect vaccine stability output performance. This is possible even when clear scientific understanding of particular formulation stability mechanisms are lacking. A DoE approach was used in an accelerated 37(°)C stability study of an aluminum adjuvant Neisseria meningitidis serogroup B vaccine. Formulation stability differences were identified after only 15 days into the study. We believe this study demonstrates the power of combining DoE methodology with accelerated stress stability studies to accelerate and improve vaccine formulation development programs particularly during the preformulation stage. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  12. CML/CD36 accelerates atherosclerotic progression via inhibiting foam cell migration.

    PubMed

    Xu, Suining; Li, Lihua; Yan, Jinchuan; Ye, Fei; Shao, Chen; Sun, Zhen; Bao, Zhengyang; Dai, Zhiyin; Zhu, Jie; Jing, Lele; Wang, Zhongqun

    2018-01-01

    Among the various complications of type 2 diabetes mellitus, atherosclerosis causes the highest disability and morbidity. A multitude of macrophage-derived foam cells are retained in atherosclerotic plaques resulting not only from recruitment of monocytes into lesions but also from a reduced rate of macrophage migration from lesions. Nε-carboxymethyl-Lysine (CML), an advanced glycation end product, is responsible for most complications of diabetes. This study was designed to investigate the mechanism of CML/CD36 accelerating atherosclerotic progression via inhibiting foam cell migration. In vivo study and in vitro study were performed. For the in vivo investigation, CML/CD36 accelerated atherosclerotic progression via promoting the accumulation of macrophage-derived foam cells in aorta and inhibited macrophage-derived foam cells in aorta migrating to the para-aorta lymph node of diabetic apoE -/- mice. For the in vitro investigation, CML/CD36 inhibited RAW264.7-derived foam cell migration through NOX-derived ROS, FAK phosphorylation, Arp2/3 complex activation and F-actin polymerization. Thus, we concluded that CML/CD36 inhibited foam cells of plaque migrating to para-aorta lymph nodes, accelerating atherosclerotic progression. The corresponding mechanism may be via free cholesterol, ROS generation, p-FAK, Arp2/3, F-actin polymerization. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  13. ACE2 activity was increased in atherosclerotic plaque by losartan: Possible relation to anti-atherosclerosis.

    PubMed

    Zhang, Yue Hui; Hao, Qing Qing; Wang, Xiao Yu; Chen, Xu; Wang, Nan; Zhu, Li; Li, Shu Ying; Yu, Qing Tao; Dong, Bo

    2015-06-01

    Angiotensin-converting enzyme 2 (ACE2) is a new member of the renin-angiotensin system (RAS) and it has been proposed that ACE2 is a potential therapeutic target for the control of cardiovascular disease. The effect of losartan on the ACE2 activity in atherosclerosis was studied. Atherosclerosis was induced in New Zealand white rabbits by high-cholesterol diet for 3 months. An Angiotensin II (Ang II) receptor blocker (losartan, 25 mg/kg/d) was given for 3 months. ACE2 activity was measured by fluorescence assay and the extent of atherosclerosis was evaluated by H&E and Oil Red O staining. In addition, the effect of losartan on ACE2 activity in smooth muscle cells (SMCs) in vitro was also evaluated. Losartan increased ACE2 activity in atherosclerosis in vivo and SMCs in vitro. Losartan inhibited atherosclerotic evolution. Addition of losartan blocked Ang II-induced down-regulation of ACE2 activity, and blockade of extracellular signal-regulated kinase (ERK1/2) with PD98059 prevented Ang II-induced down-regulation of ACE2 activity. The results showed that ACE2 activity was regulated in atherosclerotic plaque by losartan, which may play an important role in treatment of atherosclerosis. The mechanism involves Ang II-AT1R-mediated mitogen-activated protein kinases, MAPKs (MAPKs) signaling pathway. © The Author(s) 2014.

  14. MicroRNAs and lipoproteins: a connection beyond atherosclerosis?

    PubMed Central

    Norata, Giuseppe Danilo; Sala, Federica; Catapano, Alberico Luigi; Fernández-Hernando, Carlos

    2014-01-01

    MicroRNAs (miRNAs) are involved in the pathogenesis of a number of cardiovascular diseases. In this review article, we have summarized the role of miRNAs in regulating lipid metabolism and how their therapeutical inhibition may lead to new approaches to treat cardiometabolic diseases, including atherosclerosis and metabolic syndrome. Specific miRNAs, such as miR-33a and -33b, represent one of the most interesting and attractive targets for metabolic-related disorders and anti-miR33 approaches are under intensive investigation. In addition to miR-33, other miRNAs, including miR-122, are also emerging as key players in lipid metabolism. More recently miRNAs were shown to exert their activities in a paracrine manner and also systemically. The latter is possible due to lipid-carriers, including lipoproteins, that transport and protect miRNAs from degradation. The emerging strong connection between miRNAs, lipoproteins and lipid metabolism indicates the existence of a reciprocal modulation that might go beyond atherosclerosis. PMID:23260873

  15. Recent Developments at the Accelerator Laboratory in Jyvaeskylae

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Trzaska, Wladyslaw Henryk

    Recent developments at the Accelerator Laboratory in Jyvaeskylae are described. In addition to the existing K = 130 a new cyclotron has been added. It is capable of producing of high current proton and deuteron beams at 30 and 15 MeV correspondingly. It should be fully operational in 2010. A new development in Jyvaeskylae is the growing commitment to astroparticle physics. Jyvaeskylae took the main scientific responsibility for a new cosmic-ray experiment EMMA and has joined the LAGUNA project working on the design of the next generation of very large volume detectors for underground observatories.

  16. Effects of Inorganic Arsenic, Methylated Arsenicals, and Arsenobetaine on Atherosclerosis in the apoE−/− Mouse Model and the Role of As3mt-Mediated Methylation

    PubMed Central

    Negro Silva, Luis Fernando; Lemaire, Maryse; Lemarié, Catherine A.; Plourde, Dany; Bolt, Alicia M.; Chiavatti, Christopher; Bohle, D. Scott; Slavkovich, Vesna; Graziano, Joseph H.; Lehoux, Stéphanie

    2017-01-01

    Background: Arsenic is metabolized through a series of oxidative methylation reactions by arsenic (3) methyltransferase (As3MT) to yield methylated intermediates. Although arsenic exposure is known to increase the risk of atherosclerosis, the contribution of arsenic methylation and As3MT remains undefined. Objectives: Our objective was to define whether methylated arsenic intermediates were proatherogenic and whether arsenic biotransformation by As3MT was required for arsenic-enhanced atherosclerosis. Methods: We utilized the apoE−/− mouse model to compare atherosclerotic plaque size and composition after inorganic arsenic, methylated arsenical, or arsenobetaine exposure in drinking water. We also generated apoE−/−/As3mt−/− double knockout mice to test whether As3MT-mediated biotransformation was required for the proatherogenic effects of inorganic arsenite. Furthermore, As3MT expression and function were assessed in in vitro cultures of plaque-resident cells. Finally, bone marrow transplantation studies were performed to define the contribution of As3MT-mediated methylation in different cell types to the development of atherosclerosis after inorganic arsenic exposure. Results: We found that methylated arsenicals, but not arsenobetaine, are proatherogenic and that As3MT is required for arsenic to induce reactive oxygen species and promote atherosclerosis. Importantly, As3MT was expressed and functional in multiple plaque-resident cell types, and transplant studies indicated that As3MT is required in extrahepatic tissues to promote atherosclerosis. Conclusion: Taken together, our findings indicate that As3MT acts to promote cardiovascular toxicity of arsenic and suggest that human AS3MT SNPs that correlate with enzyme function could predict those most at risk to develop atherosclerosis among the millions that are exposed to arsenic. https://doi.org/10.1289/EHP806 PMID:28728140

  17. Facilitatory effects of fetuin-A on atherosclerosis.

    PubMed

    Naito, Chisato; Hashimoto, Mio; Watanabe, Kaho; Shirai, Remina; Takahashi, Yui; Kojima, Miho; Watanabe, Rena; Sato, Kengo; Iso, Yoshitaka; Matsuyama, Taka-Aki; Suzuki, Hiroshi; Ishibashi-Ueda, Hatsue; Watanabe, Takuya

    2016-03-01

    Fetuin-A is a circulating glycoprotein that is produced by liver and adipose tissue. Fetuin-A is known to induce insulin resistance and suppress vascular calcification. There are conflicting reports that show increased or decreased serum fetuin-A levels in patients with coronary artery disease (CAD). Since the role of fetuin-A in atherosclerosis remains still controversial, we aimed to clarify it in this study. We investigated the expression of fetuin-A in atheromatous plaques in CAD patients and restenosis lesions in balloon-injured rat carotid arteries in vivo. We also assessed in vitro effects of fetuin-A on inflammatory molecules in human umbilical vein endothelial cells (HUVECs), oxidized low-density lipoprotein-induced foam cell formation in human monocyte-derived macrophages, and the migration, proliferation, and extracellular matrix expression in human aortic smooth muscle cells (HASMCs) in a serum-free culture system. Fetuin-A was abundantly expressed in cultured human monocytes, macrophages, fibroblasts, HASMCs, and human coronary artery SMCs, atheromatous plaques in human coronary arteries, and restenosis lesions in rat carotid arteries. In vitro experiments showed that fetuin-A stimulated interleukin-6, monocyte chemotactic protein-1, intercellular adhesion molecule-1, and E-selectin expression in HUVECs. Fetuin-A enhanced macrophage foam cell formation associated with scavenger receptors (CD36 and SR-A) and acyl-CoA:cholesterol acyltransferase-1 down-regulation and ATP-binding cassette transporter A1 up-regulation, and increased cell proliferation and collagen-1 and -3 expression via PI3K/AKT/c-Src/NF-κB/ERK1/2 pathways in HASMCs. Our results indicate that fetuin-A exerts the stimulatory effects on inflammatory responses in HUVECs, macrophage foam cell formation, and proliferation and collagen production in HASMCs, leading to the development of atherosclerosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Citrus Flavonoids as Regulators of Lipoprotein Metabolism and Atherosclerosis.

    PubMed

    Mulvihill, Erin E; Burke, Amy C; Huff, Murray W

    2016-07-17

    Citrus flavonoids are polyphenolic compounds with significant biological properties. This review summarizes recent advances in understanding the ability of citrus flavonoids to modulate lipid metabolism, other metabolic parameters related to the metabolic syndrome, and atherosclerosis. Citrus flavonoids, including naringenin, hesperitin, nobiletin, and tangeretin, have emerged as potential therapeutics for the treatment of metabolic dysregulation. Epidemiological studies reveal an association between the intake of citrus flavonoid-containing foods and a decreased incidence of cardiovascular disease. Studies in cell culture and animal models, as well as a limited number of clinical studies, reveal the lipid-lowering, insulin-sensitizing, antihypertensive, and anti-inflammatory properties of citrus flavonoids. In animal models, supplementation of rodent diets with citrus flavonoids prevents hepatic steatosis, dyslipidemia, and insulin resistance primarily through inhibition of hepatic fatty acid synthesis and increased fatty acid oxidation. Citrus flavonoids blunt the inflammatory response in metabolically important tissues including liver, adipose, kidney, and the aorta. The mechanisms underlying flavonoid-induced metabolic regulation have not been completely established, although several potential targets have been identified. In mouse models, citrus flavonoids show marked suppression of atherogenesis through improved metabolic parameters as well as through direct impact on the vessel wall. Recent studies support a role for citrus flavonoids in the treatment of dyslipidemia, insulin resistance, hepatic steatosis, obesity, and atherosclerosis. Larger human studies examining dose, bioavailability, efficacy, and safety are required to promote the development of these promising therapeutic agents.

  19. SMAD3 rs17228212 Gene Polymorphism Is Associated with Reduced Risk to Cerebrovascular Accidents and Subclinical Atherosclerosis in Anti-CCP Negative Spanish Rheumatoid Arthritis Patients

    PubMed Central

    Genre, Fernanda; Castañeda, Santos; González-Juanatey, Carlos; Llorca, Javier; Corrales, Alfonso; Miranda-Filloy, José A.; Rueda-Gotor, Javier; Gómez-Vaquero, Carmen; Rodríguez-Rodríguez, Luis; Fernández-Gutiérrez, Benjamín; Pascual-Salcedo, Dora; Balsa, Alejandro; López-Longo, Francisco J.; Carreira, Patricia; Blanco, Ricardo; González-Álvaro, Isidoro; Martín, Javier; González-Gay, Miguel A.

    2013-01-01

    Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased risk of cardiovascular (CV) disease. Previous genome-wide association studies have described SMAD3 rs17228212 polymorphism as an important signal associated with CV events. The aim of the present study was to evaluate for the first time the relationship between this gene polymorphism and the susceptibility to CV manifestations and its potential association with the presence of subclinical atherosclerosis assessed by the evaluation of carotid intima-media thickness (cIMT) in patients with RA. Methods One thousand eight hundred and ninety-seven patients fulfilling classification criteria for RA were genotyped for SMAD3 rs17228212 gene polymorphism through TaqMan genotyping assay. Also, subclinical atherosclerosis determined by the assessment of cIMT was analyzed in a subgroup of these patients by carotid ultrasonography. Results No statistically significant differences were observed when allele frequencies of RA patients with or without CV events were compared. Nevertheless, when RA patients were stratified according to anti-cyclic citrullinated peptide (anti-CCP) status, we found that in RA patients who were negative for anti-CCP antibodies, the presence of C allele of SMAD3 rs17228212 polymorphism conferred a protective effect against the risk of cerebrovascular accident (CVA) after adjustment for demographic and classic CV risk factors (HR [95%CI]=0.36 [0.14–0.94], p=0.038) in a Cox regression model. Additionally, correlation between the presence of C allele of SMAD3 rs17228212 polymorphism and lower values of cIMT was found after adjustment for demographic and classic CV risk factors (p-value=0.0094) in the anti-CCP negative RA patients. Conclusions Our results revealed that SMAD3 rs17228212 gene variant is associated with lower risk of CVA and less severe subclinical atherosclerosis in RA patients negative for anti-CCP antibodies

  20. SMAD3 rs17228212 gene polymorphism is associated with reduced risk to cerebrovascular accidents and subclinical atherosclerosis in anti-CCP negative Spanish rheumatoid arthritis patients.

    PubMed

    García-Bermúdez, Mercedes; López-Mejías, Raquel; Genre, Fernanda; Castañeda, Santos; González-Juanatey, Carlos; Llorca, Javier; Corrales, Alfonso; Miranda-Filloy, José A; Rueda-Gotor, Javier; Gómez-Vaquero, Carmen; Rodríguez-Rodríguez, Luis; Fernández-Gutiérrez, Benjamín; Pascual-Salcedo, Dora; Balsa, Alejandro; López-Longo, Francisco J; Carreira, Patricia; Blanco, Ricardo; González-Álvaro, Isidoro; Martín, Javier; González-Gay, Miguel A

    2013-01-01

    Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased risk of cardiovascular (CV) disease. Previous genome-wide association studies have described SMAD3 rs17228212 polymorphism as an important signal associated with CV events. The aim of the present study was to evaluate for the first time the relationship between this gene polymorphism and the susceptibility to CV manifestations and its potential association with the presence of subclinical atherosclerosis assessed by the evaluation of carotid intima-media thickness (cIMT) in patients with RA. One thousand eight hundred and ninety-seven patients fulfilling classification criteria for RA were genotyped for SMAD3 rs17228212 gene polymorphism through TaqMan genotyping assay. Also, subclinical atherosclerosis determined by the assessment of cIMT was analyzed in a subgroup of these patients by carotid ultrasonography. No statistically significant differences were observed when allele frequencies of RA patients with or without CV events were compared. Nevertheless, when RA patients were stratified according to anti-cyclic citrullinated peptide (anti-CCP) status, we found that in RA patients who were negative for anti-CCP antibodies, the presence of C allele of SMAD3 rs17228212 polymorphism conferred a protective effect against the risk of cerebrovascular accident (CVA) after adjustment for demographic and classic CV risk factors (HR [95%CI]=0.36 [0.14-0.94], p=0.038) in a Cox regression model. Additionally, correlation between the presence of C allele of SMAD3 rs17228212 polymorphism and lower values of cIMT was found after adjustment for demographic and classic CV risk factors (p-value=0.0094) in the anti-CCP negative RA patients. Our results revealed that SMAD3 rs17228212 gene variant is associated with lower risk of CVA and less severe subclinical atherosclerosis in RA patients negative for anti-CCP antibodies. These findings may have