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Sample records for irbesartan suppressing atherosclerosis

  1. Irbesartan

    MedlinePlus

    ... or in combination with other medications to treat high blood pressure. It is also used to treat kidney disease ... the amount of sugar in the blood) and high blood pressure. Irbesartan is in a class of medications called ...

  2. Irbesartan

    MedlinePlus

    ... organs may cause heart disease, a heart attack, heart failure, stroke, kidney failure, loss of vision, and other ... Irbesartan is also used sometimes to treat heart failure (condition in which the heart is unable to pump enough blood to the rest of the body). Talk to your doctor about the ...

  3. Irbesartan attenuates atherosclerosis in Watanabe heritable hyperlipidemic rabbits: noninvasive imaging of inflammation by 18F-fluorodeoxyglucose positron emission tomography.

    PubMed

    Zhao, Yan; Fukao, Keita; Zhao, Songji; Watanabe, Ayahisa; Hamada, Tadateru; Yamasaki, Kazuaki; Shimizu, Yoichi; Kubo, Naoki; Ukon, Naoyuki; Nakano, Toru; Tamaki, Nagara; Kuge, Yuji

    2015-01-01

    The purpose of this study was to assess the usefulness of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in evaluating the antiatherogenic effects of irbesartan, an angiotensin II type 1 receptor blocker. Watanabe heritable hyperlipidemic rabbits were divided into the irbesartan-treated group (75 mg/kg/d; n  =  14) and the control group (n  =  14). After a 9-month treatment, rabbits underwent 18F-FDG PET. Using the aortic lesions, autoradiography and histologic examinations were performed. PET imaging clearly visualized the thoracic lesions of control rabbits and showed a significant decrease in the 18F-FDG uptake level of irbesartan-treated rabbits (78.8% of controls; p < .05). Irbesartan treatment significantly reduced the plaque size (43.1% of controls) and intraplaque macrophage infiltration level (48.1% of controls). The 18F-FDG uptake level in plaques positively correlated with the plaque size (r  =  .65, p < .05) and macrophage infiltration level (r  =  .57, p < .05). Noninvasive imaging by 18F-FDG PET is useful for evaluating the therapeutic effects of irbesartan and reflects inflammation, a key factor involved in the therapeutic effects. PMID:25812568

  4. Suppression of atherosclerosis by synthetic REV-ERB agonist

    SciTech Connect

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

    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 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. - 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.

  5. Irbesartan Ameliorates Diabetic Nephropathy by Suppressing the RANKL-RANK-NF-κB Pathway in Type 2 Diabetic db/db Mice

    PubMed Central

    Chen, Xiao-Wen; Du, Xiao-Yan; Wang, Yu-Xian; Wang, Jian-Cheng; Liu, Wen-Ting; Chen, Wen-Jing; Li, Hong-Yu; Peng, Fen-Fen; Xu, Zhao-Zhong; Niu, Hong-Xin; Long, Hai-Bo

    2016-01-01

    The receptor activator of NF-κB ligand (RANKL) and its receptor RANK are overexpressed in focal segmental glomerular sclerosis (FSGS), IgA nephropathy (IgAN), and membranous nephropathy (MN). However, the expression and the potential roles of RANKL and RANK in diabetic nephropathy (DN) remain unclear. Irbesartan (Irb) has beneficial effects against diabetes-induced renal damage, but its mechanisms are poorly understood. Our present study investigated the effects of Irb in DN and whether the renal protective effects of Irb are mediated by RANKL/RANK and the downstream NF-κB pathway in db/db mice. Our results showed that db/db mice revealed severe metabolic abnormalities, renal dysfunction, podocyte injury, and increased MCP-1; these symptoms were reversed by Irb. At the molecular level, RANKL and RANK were overexpressed in the kidneys of db/db mice and Irb downregulated RANKL and RANK and inhibited the downstream NF-κB pathway. Our study suggests that Irb can ameliorate DN by suppressing the RANKL-RANK-NF-κB pathway. PMID:26880862

  6. Suppression of atherosclerosis by synthetic REV-ERB agonist.

    PubMed

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

    2015-05-01

    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

  7. Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice

    PubMed Central

    Han, Xinbing; Kitamoto, Shiro; Wang, Hongwei; Boisvert, William A.

    2010-01-01

    In atherogenesis, macrophage foam cell formation is modulated by pathways involving both the uptake and efflux of cholesterol. We recently showed that interleukin-10 (IL-10) modulates lipid metabolism by enhancing both uptake and efflux of cholesterol in macrophages. However, the mechanistic details of these properties in vivo have been unclear. Thus, the purpose of this study was to determine whether expression of IL-10 in macrophages would alter susceptibility to atherosclerosis and whether IL-10 exerts its antiatherosclerotic properties by modulating lipid metabolism in macrophages. We utilized a macrophage-specific retroviral vector that allows long-term in vivo expression of IL-10 in macrophages through transplantation of retrovirally transduced bone marrow cells (BMCs). IL-10 expressed by macrophages derived from transduced BMCs inhibited atherosclerosis in LDLR−/− mice by reducing cholesteryl ester accumulation in atherosclerotic sites. Experiments with primary macrophages indicated that macrophage source of IL-10 stimulated both the uptake (by up-regulating scavenger receptors) and efflux of cholesterol (by activating the PPARγ-LXR-ABCA1/ABCG1 pathway), thereby reducing inflammation and apoptosis in atherosclerosis. These findings indicate that BMC-transduced macrophage IL-10 production can act as a strong antiatherogenic agent, and they highlight a novel antiatherosclerotic therapy using a simple, yet effective, stem cell transduction system that facilitates long-term expression of IL-10 in macrophages.—Han, X., Kitamoto, S., Wang, H., Boisvert, W. A. Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice. PMID:20354139

  8. Atherosclerosis

    MedlinePlus

    ... page from the NHLBI on Twitter. What Is Atherosclerosis? Español Atherosclerosis is a disease in which plaque ... problems, including heart attack , stroke , or even death. Atherosclerosis Figure A shows a normal artery with normal ...

  9. Atherosclerosis

    MedlinePlus

    Atherosclerosis is a disease in which plaque builds up inside your arteries. Plaque is a sticky substance ... flow of oxygen-rich blood to your body. Atherosclerosis can lead to serious problems, including Coronary artery ...

  10. Atherosclerosis

    MedlinePlus

    ... Pressure High Blood Pressure Tools & Resources Stroke More Atherosclerosis Updated:Jul 6,2015 View an animation of ... the arteries as you get older. How does atherosclerosis start and progress? It's a complex process. Exactly ...

  11. Atherosclerosis

    MedlinePlus Videos and Cool Tools

    ... are smooth, allowing blood to flow unimpeded. Atherosclerosis is when harmful material collects on the wall of ... Eventually, the material builds up and a plaque is formed, narrowing the artery. When the build-up ...

  12. Apocynin suppresses the progression of atherosclerosis in apoE-deficient mice by inactivation of macrophages

    SciTech Connect

    Kinoshita, Hiroyuki; Matsumura, Takeshi; Ishii, Norio; Fukuda, Kazuki; Senokuchi, Takafumi; Motoshima, Hiroyuki; Kondo, Tatsuya; Taketa, Kayo; Kawasaki, Shuji; Hanatani, Satoko; Takeya, Motohiro; Nishikawa, Takeshi; Araki, Eiichi

    2013-02-08

    Highlights: ► We examined the anti-athrogenic effect of apocynin in atherosclerotic model mice. ► Apocynin prevented atherosclerotic lesion formation. ► Apocynin suppressed ROS production in aorta and in macrophages. ► Apocynin suppressed cytokine expression and cell proliferation in macrophages. ► Apocynin may be beneficial compound for the prevention of atherosclerosis. -- Abstract: Production of reactive oxygen species (ROS) and other proinflammatory substances by macrophages plays an important role in atherogenesis. Apocynin (4-hydroxy-3-methoxy-acetophenone), which is well known as a NADPH oxidase inhibitor, has anti-inflammatory effects including suppression of the generation of ROS. However, the suppressive effects of apocynin on the progression of atherosclerosis are not clearly understood. Thus, we investigated anti-atherosclerotic effects of apocynin using apolipoprotein E-deficient (apoE{sup –/–}) mice in vivo and in mouse peritoneal macrophages in vitro. In atherosclerosis-prone apoE{sup –/–} mice, apocynin suppressed the progression of atherosclerosis, decreased 4-hydroxynonenal-positive area in atherosclerotic lesions, and mRNA expression of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) in aorta. In mouse peritoneal macrophages, apocynin suppressed the Ox-LDL-induced ROS generation, mRNA expression of MCP-1, IL-6 and granulocyte/macrophage colony-stimulating factor, and cell proliferation. Moreover, immunohistochemical studies revealed that apocynin decreased the number of proliferating cell nuclear antigen-positive macrophages in atherosclerotic lesions of apoE{sup –/–} mice. These results suggested that apocynin suppressed the formation of atherosclerotic lesions, at least in part, by inactivation of macrophages. Therefore, apocynin may be a potential therapeutic material to prevent the progression of atherosclerosis.

  13. Niacin Suppresses Progression of Atherosclerosis by Inhibiting Vascular Inflammation and Apoptosis of Vascular Smooth Muscle Cells

    PubMed Central

    Su, Gang; Sun, Guangli; Liu, Hai; Shu, Liliang; Zhang, Jingchao; Guo, Longhui; Huang, Chen; Xu, Jing

    2015-01-01

    Background Niacin is a broad-spectrum lipid-regulating drug used for the clinical therapy of atherosclerosis; however, the mechanisms by which niacin ameliorates atherosclerosis are not clear. Material/Methods The effect of niacin on atherosclerosis was assessed by detection of atherosclerotic lesion area. Adhesion molecules in arterial endothelial cells were determined by using qRT-PCR and Western blot analysis. The levels of serum inflammatory cytokines in ApoE−/− mice were detected by using ELISA. We detected the expression levels of phosphorylated nuclear factors-κB (NF-κB) p65 in aortic endothelial cells of mice using Western blot analysis. Furthermore, we investigated the anti-inflammation effect and endothelium-protecting function of niacin and their regulatory mechanisms in vitro. Results Niacin inhibited the progress of atherosclerosis and decreased the levels of serum inflammatory cytokines and adhesion molecules in ApoE−/− mice. Niacin suppressed the activity of NF-κB and apoptosis of vascular smooth muscle cells (VSMCs). Furthermore, niacin induced phosphorylated focal adhesion kinase (FAK) and FAK inhibitor PF-573228 reduced the level of Bcl-2 and elevated the level of cleaved caspase-3 in VSMCs. Conclusions Niacin inhibits vascular inflammation and apoptosis of VSMCs via inhibiting the NF-κB signaling and the FAK signaling pathway, respectively, thus protecting ApoE−/− mice against atherosclerosis. PMID:26712802

  14. MicroRNA-16 suppresses the activation of inflammatory macrophages in atherosclerosis by targeting PDCD4

    PubMed Central

    LIANG, XUE; XU, ZHAO; YUAN, MENG; ZHANG, YUE; ZHAO, BO; WANG, JUNQIAN; ZHANG, AIXUE; LI, GUANGPING

    2016-01-01

    Programmed cell death 4 (PDCD4) is involved in a number of bioprocesses, such as apoptosis and inflammation. However, its regulatory mechanisms in atherosclerosis remain unclear. In this study, we investigated the role and mechanisms of action of PDCD4 in high-fat diet-induced atherosclerosis in mice and in foam cells (characteristic pathological cells in atherosclerotic lesions) derived from ox-LDL-stimulated macrophages. MicroRNA (miR)-16 was predicted to bind PDCD4 by bioinformatics analysis. In the mice with atherosclerosis and in the foam cells, PDCD4 protein expression (but not the mRNA expression) was enhanced, while that of miR-16 was reduced. Transfection with miR-16 mimic decreased the activity of a luciferase reporter containing the 3′ untranslated region (3′UTR) of PDCD4 in the macrophage-derived foam cells. Conversely, treatment with miR-16 inhibitor enhanced the luciferase activity. However, by introducing mutations in the predicted binding site located in the 3′UTR of PDCD4, the miR-16 mimic and inhibitor were unable to alter the level of PDCD4, suggesting that miR-16 is a direct negative regulator of PDCD4 in atherosclerosis. Furthermore, transfection wtih miR-16 mimic and siRNA targeting PDCD4 suppressed the secretion and mRNA expression of pro-inflammatory factors, such as interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), whereas it enhanced the secretion and mRNA expression of the anti-inflammatory factor, IL-10. Treatment with miR-16 inhibitor exerted the opposite effects. In addition, the phosphorylation of p38 and extracellular signal-regulated kinase (ERK), and nuclear factor-κB (NF-κB) expression were altered by miR-16. In conclusion, our data demonstrate that the targeting of PDCD4 by miR-16 may suppress the activation of inflammatory macrophages though mitogen-activated protein kinase (MAPK) and NF-κB signaling in atherosclerosis; thus, PDCD4 may prove to be a potential therapeutic target in the treatment of

  15. Suppression of diet-induced atherosclerosis in low density lipoprotein receptor knockout mice overexpressing lipoprotein lipase.

    PubMed Central

    Shimada, M; Ishibashi, S; Inaba, T; Yagyu, H; Harada, K; Osuga, J I; Ohashi, K; Yazaki, Y; Yamada, N

    1996-01-01

    Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Conflicting results have been reported concerning its role in atherogenesis. To determine the effects of the overexpressed LPL on diet-induced atherosclerosis, we have generated low density lipoprotein receptor (LDLR) knockout mice that overexpressed human LPL transgene (LPL/LDLRKO) and compared their plasma lipoproteins and atherosclerosis with those in nonexpressing LDLR-knockout mice (LDLRKO). On a normal chow diet, LPL/LDLRKO mice showed marked suppression of mean plasma triglyceride levels (32 versus 236 mg/dl) and modest decrease in mean cholesterol levels (300 versus 386 mg/dl) as compared with LDLRKO mice. Larger lipoprotein particles of intermediate density lipoprotein (IDL)/LDL were selectively reduced in LPL/LDLRKO mice. On an atherogenic diet, both mice exhibited severe hypercholesterolemia. But, mean plasma cholesterol levels in LPL/ LDLRKO mice were still suppressed as compared with that in LDLRKO mice (1357 versus 2187 mg/dl). Marked reduction in a larger subfraction of IDL/LDL, which conceivably corresponds to remnant lipoproteins, was observed in the LPL/LDLRKO mice. LDLRKO mice developed severe fatty streak lesions in the aortic sinus after feeding with the atherogenic diet for 8 weeks. In contrast, mean lesion area in the LPL/LDLRKO mice was 18-fold smaller than that in LDLRKO mice. We suggest that the altered lipoprotein profile, in particular the reduced level of remnant lipoproteins, is mainly responsible for the protection by LPL against atherosclerosis. Images Fig. 1 Fig. 3 PMID:8692976

  16. Inhibiting DNA Methylation by 5-Aza-2′-deoxycytidine Ameliorates Atherosclerosis Through Suppressing Macrophage Inflammation

    PubMed Central

    Cao, Qiang; Wang, Xianfeng; Jia, Lin; Mondal, Ashis K.; Diallo, Abdoulaye; Hawkins, Gregory A.; Das, Swapan K.; Parks, John S.; Yu, Liqing; Shi, Huidong

    2014-01-01

    Inflammation marks all stages of atherogenesis. DNA hypermethylation in the whole genome or specific genes is associated with inflammation and cardiovascular diseases. Therefore, we aimed to study whether inhibiting DNA methylation by DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) ameliorates atherosclerosis in low-density lipoprotein receptor knockout (Ldlr−/−) mice. Ldlr−/− mice were fed an atherogenic diet and adminisered saline or 5-aza-dC (0.25 mg/kg) for up to 30 weeks. 5-aza-dC treatment markedly decreased atherosclerosis development in Ldlr−/− mice without changes in body weight, plasma lipid profile, macrophage cholesterol levels and plaque lipid content. Instead, this effect was associated with decreased macrophage inflammation. Macrophages with 5-aza-dC treatment had downregulated expression of genes involved in inflammation (TNF-α, IL-6, IL-1β, and inducible nitric oxidase) and chemotaxis (CD62/L-selectin, chemokine [C-C motif] ligand 2/MCP-1 [CCL2/MCP-1], CCL5, CCL9, and CCL2 receptor CCR2). This resulted in attenuated macrophage migration and adhesion to endothelial cells and reduced macrophage infiltration into atherosclerotic plaques. 5-aza-dC also suppressed macrophage endoplasmic reticulum stress, a key upstream signal that activates macrophage inflammation and apoptotic pathways. Finally, 5-aza-dC demethylated liver X receptor α (LXRα) and peroxisome proliferator-activated receptor γ1 (PPARγ1) promoters, which are both enriched with CpG sites. This led to overexpression of LXRα and PPARγ, which may be responsible for 5-aza-dC's anti-inflammatory and atheroprotective effect. Our findings provide strong evidence that DNA methylation may play a significant role in cardiovascular diseases and serve as a therapeutic target for prevention and treatment of atherosclerosis. PMID:25251587

  17. Endothelial Dicer promotes atherosclerosis and vascular inflammation by miRNA-103-mediated suppression of KLF4

    PubMed Central

    Hartmann, Petra; Zhou, Zhe; Natarelli, Lucia; Wei, Yuanyuan; Nazari-Jahantigh, Maliheh; Zhu, Mengyu; Grommes, Jochen; Steffens, Sabine; Weber, Christian; Schober, Andreas

    2016-01-01

    MicroRNAs regulate the maladaptation of endothelial cells (ECs) to naturally occurring disturbed blood flow at arterial bifurcations resulting in arterial inflammation and atherosclerosis in response to hyperlipidemic stress. Here, we show that reduced endothelial expression of the RNAse Dicer, which generates almost all mature miRNAs, decreases monocyte adhesion, endothelial C–X–C motif chemokine 1 (CXCL1) expression, atherosclerosis and the lesional macrophage content in apolipoprotein E knockout mice (Apoe−/−) after exposure to a high-fat diet. Endothelial Dicer deficiency reduces the expression of unstable miRNAs, such as miR-103, and promotes Krüppel-like factor 4 (KLF4)-dependent gene expression in murine atherosclerotic arteries. MiR-103 mediated suppression of KLF4 increases monocyte adhesion to ECs by enhancing nuclear factor-κB-dependent CXCL1 expression. Inhibiting the interaction between miR-103 and KLF4 reduces atherosclerosis, lesional macrophage accumulation and endothelial CXCL1 expression. Overall, our study suggests that Dicer promotes endothelial maladaptation and atherosclerosis in part by miR-103-mediated suppression of KLF4. PMID:26837267

  18. Flow-dependent expression of ectonucleotide tri(di)phosphohydrolase-1 and suppression of atherosclerosis

    PubMed Central

    Kanthi, Yogendra; Hyman, Matthew C.; Liao, Hui; Baek, Amy E.; Visovatti, Scott H.; Sutton, Nadia R.; Goonewardena, Sascha N.; Neral, Mithun K.; Jo, Hanjoong; Pinsky, David J.

    2015-01-01

    The ability of cells to detect and respond to nucleotide signals in the local microenvironment is essential for vascular homeostasis. The enzyme ectonucleotide tri(di)phosphohydrolase-1 (ENTPD1, also known as CD39) on the surface of leukocytes and endothelial cells metabolizes locally released, intravascular ATP and ADP, thereby eliminating these prothrombotic and proinflammatory stimuli. Here, we evaluated the contribution of CD39 to atherogenesis in the apolipoprotein E–deficient (ApoE-deficient) mouse model of atherosclerosis. Compared with control ApoE-deficient animals, plaque burden was markedly increased along with circulating markers of platelet activation in Cd39+/–Apoe–/– mice fed a high-fat diet. Plaque analysis revealed stark regionalization of endothelial CD39 expression and function in Apoe–/– mice, with CD39 prominently expressed in atheroprotective, stable flow regions and diminished in atheroprone areas subject to disturbed flow. In mice, disturbed flow as the result of partial carotid artery ligation rapidly suppressed endothelial CD39 expression. Moreover, unidirectional laminar shear stress induced atheroprotective CD39 expression in human endothelial cells. CD39 induction was dependent upon the vascular transcription factor Krüppel-like factor 2 (KLF2) binding near the transcriptional start site of CD39. Together, these data establish CD39 as a regionalized regulator of atherogenesis that is driven by shear stress. PMID:26121751

  19. Myeloid Acyl-CoA:Cholesterol Acyltransferase 1 Deficiency Reduces Lesion Macrophage Content and Suppresses Atherosclerosis Progression.

    PubMed

    Huang, Li-Hao; Melton, Elaina M; Li, Haibo; Sohn, Paul; Rogers, Maximillian A; Mulligan-Kehoe, Mary Jo; Fiering, Steven N; Hickey, William F; Chang, Catherine C Y; Chang, Ta-Yuan

    2016-03-18

    Acyl-CoA:cholesterol acyltransferase 1 (Acat1) converts cellular cholesterol to cholesteryl esters and is considered a drug target for treating atherosclerosis. However, in mouse models for atherosclerosis, global Acat1 knockout (Acat1(-/-)) did not prevent lesion development. Acat1(-/-) increased apoptosis within lesions and led to several additional undesirable phenotypes, including hair loss, dry eye, leukocytosis, xanthomatosis, and a reduced life span. To determine the roles of Acat1 in monocytes/macrophages in atherosclerosis, we produced a myeloid-specific Acat1 knockout (Acat1(-M/-M)) mouse and showed that, in the Apoe knockout (Apoe(-/-)) mouse model for atherosclerosis, Acat1(-M/-M) decreased the plaque area and reduced lesion size without causing leukocytosis, dry eye, hair loss, or a reduced life span. Acat1(-M/-M) enhanced xanthomatosis in apoe(-/-) mice, a skin disease that is not associated with diet-induced atherosclerosis in humans. Analyses of atherosclerotic lesions showed that Acat1(-M/-M) reduced macrophage numbers and diminished the cholesterol and cholesteryl ester load without causing detectable apoptotic cell death. Leukocyte migration analysis in vivo showed that Acat1(-M/-M) caused much fewer leukocytes to appear at the activated endothelium. Studies in inflammatory (Ly6C(hi)-positive) monocytes and in cultured macrophages showed that inhibiting ACAT1 by gene knockout or by pharmacological inhibition caused a significant decrease in integrin β 1 (CD29) expression in activated monocytes/macrophages. The sparse presence of lesion macrophages without Acat1 can therefore, in part, be attributed to decreased interaction between inflammatory monocytes/macrophages lacking Acat1 and the activated endothelium. We conclude that targeting ACAT1 in a myeloid cell lineage suppresses atherosclerosis progression while avoiding many of the undesirable side effects caused by global Acat1 inhibition. PMID:26801614

  20. Ginkgo suppresses atherosclerosis through downregulating the expression of connexin 43 in rabbits

    PubMed Central

    Wang, Xin; Gong, Hui; Shi, Yi Jun; Zou, Yunzeng

    2013-01-01

    Introduction Ginkgo biloba extract (GBE) EGb761 is widely used for cardiovascular prevention. Here, we investigated the effects of GBE on atherosclerotic lesion development in rabbits with a high-fat diet. Material and methods Forty New Zealand white male rabbits were randomly divided into four groups. The first two were the normal diet group (C) and the high-fat group (HF). The remaining two groups were those who received a high cholesterol diet supplemented with either the standard drug (simvastatin 2 mg/kg/day) or GBE (3 mg/kg/day). At 12 weeks, histopathological and chemical analyses were performed. Results Plasma lipid measurement showed that GBE inhibited high-fat diet-induced increase of serum triglyceride (TG), total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C) by 59.1% (0.9 ±0.2 4 mmol/l vs. 2.2 ±0.4 mmol/l), 18.2% (31.1 ±1.4 mmol/l vs. 38.0 ±0.4 mmol/l) and 15% (28.9 ±1.3 mmol/l vs. 34.0±1.0 mmol/l), respectively, at 12 weeks (p < 0.01). The en face Sudan IV-positive lesion area of the aorta in the GBE group (51.7 ±3.1%) was significantly lower compared with that in the HF group (88.2 ±2.2%; p < 0.01). The mean atherosclerotic lesion area of the GBE group was reduced by 53.2% compared with the HF group (p < 0.01). Immunohistochemistry and western blot analysis showed that GBE markedly suppressed high-fat diet-induced upregulation of connexin 43 (Cx43) in rabbits (p < 0.01). Conclusions Thus, our study revealed that GBE prevented atherosclerosis progress through modulating plasma lipid, suppressing atherosclerotic lesion development, and attenuating the expression of Cx43 protein. PMID:23671447

  1. Suppression of coronary atherosclerosis by helix B surface Peptide, a nonerythropoietic, tissue-protective compound derived from erythropoietin.

    PubMed

    Ueba, Hiroto; Shiomi, Masashi; Brines, Michael; Yamin, Michael; Kobayashi, Tsutomu; Ako, Junya; Momomura, Shin-Ichi; Cerami, Anthony; Kawakami, Masanobu

    2013-01-01

    Erythropoietin (EPO), a type I cytokine originally identified for its critical role in hematopoiesis, has been shown to have nonhematopoietic, tissue-protective effects, including suppression of atherosclerosis. However, prothrombotic effects of EPO hinder its potential clinical use in nonanemic patients. In the present study, we investigated the antiatherosclerotic effects of helix B surface peptide (HBSP), a nonerythropoietic, tissue-protective compound derived from EPO, by using human umbilical vein endothelial cells (HUVECs) and human monocytic THP-1 cells in vitro and Watanabe heritable hyperlipidemic spontaneous myocardial infarction (WHHLMI) rabbits in vivo. In HUVECs, HBSP inhibited apoptosis (≈70%) induced by C-reactive protein (CRP), a direct mediator of atherosclerosis. By using a small interfering RNA approach, Akt was shown to be a key molecule in HBSP-mediated prevention of apoptosis. HBSP also attenuated CRP-induced production of tumor necrosis factor (TNF)-α and matrix metalloproteinase-9 in THP-1 cells. In the WHHLMI rabbit, HBSP significantly suppressed progression of coronary atherosclerotic lesions as assessed by mean cross-sectional stenosis (HBSP 21.3 ± 2.2% versus control peptide 38.0 ± 2.7%) and inhibited coronary artery endothelial cell apoptosis with increased activation of Akt. Furthermore, TNF-α expression and the number of M1 macrophages and M1/M2 macrophage ratio in coronary atherosclerotic lesions were markedly reduced in HBSP-treated animals. In conclusion, these data demonstrate that HBSP suppresses coronary atherosclerosis, in part by inhibiting endothelial cell apoptosis through activation of Akt and in association with decreased TNF-α production and modified macrophage polarization in coronary atherosclerotic lesions. Because HBSP does not have the prothrombotic effects of EPO, our study may provide a novel therapeutic strategy that prevents progression of coronary artery disease. PMID:23648638

  2. MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1

    PubMed Central

    Schober, Andreas; Nazari-Jahantigh, Maliheh; Wei, Yuanyuan; Bidzhekov, Kiril; Gremse, Felix; Grommes, Jochen; Megens, Remco T A; Heyll, Kathrin; Noels, Heidi; Hristov, Michael; Wang, Shusheng; Kiessling, Fabian; Olson, Eric N; Weber, Christian

    2015-01-01

    Atherosclerosis, a hyperlipidemia-induced chronic inflammatory process of the arterial wall, develops preferentially at sites where disturbed laminar flow compromises endothelial cell (EC) function. Here we show that endothelial miR-126-5p maintains a proliferative reserve in ECs through suppression of the Notch1 inhibitor delta-like 1 homolog (Dlk1) and thereby prevents atherosclerotic lesion formation. Endothelial recovery after denudation was impaired in Mir126−/− mice because lack of miR-126-5p, but not miR-126-3p, reduced EC proliferation by derepressing Dlk1. At nonpredilection sites, high miR-126-5p levels in endothelial cells confer a proliferative reserve that compensates for the antiproliferative effects of hyperlipidemia, such that atherosclerosis was exacerbated in Mir126−/− mice. In contrast, downregulation of miR-126-5p by disturbed flow abrogated EC proliferation at predilection sites in response to hyperlipidemic stress through upregulation of Dlk1 expression. Administration of miR-126-5p rescued EC proliferation at predilection sites and limited atherosclerosis, introducing a potential therapeutic approach. PMID:24584117

  3. MiR-129-5p-mediated Beclin-1 suppression inhibits endothelial cell autophagy in atherosclerosis

    PubMed Central

    Geng, Zhaohua; Xu, Fei; Zhang, Yiguan

    2016-01-01

    Endothelial cell injury and subsequent death play an essential role in the pathogenesis of atherosclerosis. Autophagy of endothelial cells antagonizes the development of atherosclerosis, whereas the underlying molecular mechanisms are unclear. MicroRNA-129-5p (miR-129-5p) is a well-defined tumor suppressorin some types of cancer, while it is unknown whether miR-129-5p may also play a role in the development of atherosclerosis. Here, we addressed this question in the current study. We examined the levels of endothelial cell autophagy in ApoE (-/-) mice suppled with high-fat diet (HFD), a mouse model for atherosclerosis (simplified as HFD mice). We analyzed the levels of Beclin-1 and the levels of miR-129-5p in the purified CD31+ endothelial cells from mouse aorta. Prediction of the binding between miR-129-5p and 3’-UTR of Beclin-1 mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. The effects of miR-129-5p were further analyzed in an in vitro model using oxidized low-density lipoprotein (ox-LDL)-treated human aortic endothelial cells (HAECs). We found that HFD mice developed atherosclerosisin 12 weeks, while the control ApoE (-/-) mice that had received normal diet (simplified as CTL mice) did not. Compared to CTL mice, HFD mice had significantly lower levels of endothelial cell autophagy, resulting from decreases in Beclin-1 protein, but not mRNA. The decreases in Beclin-1 in endothelial cells were due to HFD-induced increases inmiR-129-5p, which suppressed the translation of Beclin-1 mRNA via 3’-UTR binding. These in vivo findings were reproduced in vitro on ox-LDL-treated HAECs. Together, these data suggest that upregulation of miR-129-5p by HFD may impair the protective effects of endothelial cell autophagy against development of atherosclerosis through suppressing protein translation of Beclin-1. PMID:27186312

  4. Silence of NLRP3 Suppresses Atherosclerosis and Stabilizes Plaques in Apolipoprotein E-Deficient Mice

    PubMed Central

    Zheng, Fei; Xing, Shanshan; Gong, Zushun; Mu, Wei; Xing, Qichong

    2014-01-01

    Objectives. The role of the NLRP3 inflammasome in atherosclerosis remains controversial. The aim of this study was to determine whether inhibition of NLRP3 signaling by lentivirus-mediated RNA interference could reduce atherosclerosis and stabilizes plaques. We also tried to explore the mechanisms of the impact of NLRP3 inflammasome on atherosclerosis. Methods. Apolipoprotein E-deficient mice aged 8 weeks were fed a high-fat diet and were injected with NLRP3 interfering or mock viral suspension after 4 weeks. Lentivirus transfer was repeated in 2 weeks. Four weeks after the first lentivirus injection, we evaluated the effects of NLRP3 gene silencing on plaque composition and stability and on cholesterol efflux and collagen metabolism, by histopathologic analyses and real-time PCR. Results. Gene silence of NLRP3 prevented plaques progression and inhibited inductions of proinflammatory cytokines. Moreover, this RNA interference reduced plaque content of macrophages and lipid, and increased plaque content of smooth muscle cells and collagen, leading to the stabilizing of atherosclerotic plaques. Conclusions. NLRP3 inflammasomes may play a vital role in atherosclerosis, and lentivirus-mediated NLRP3 silencing would be a new strategy to inhibit plaques progression and to reduce local inflammation. PMID:24999295

  5. Protective Effect of Irisin on Atherosclerosis via Suppressing Oxidized Low Density Lipoprotein Induced Vascular Inflammation and Endothelial Dysfunction

    PubMed Central

    Zhang, Yuzhu; Mu, Qian; Zhou, Zheng; Song, Haibo; Zhang, Yuan; Wu, Fei; Jiang, Miao; Wang, Fang; Zhang, Wen; Li, Liang; Shao, Lei; Wang, Xingli; Li, Shiwu; Yang, Lijun; Wu, Qi; Zhang, Mingxiang; Tang, Dongqi

    2016-01-01

    Irisin, a newly discovered myokine, is considered as a promising candidate for the treatment of metabolic disturbances and cardiovascular diseases. In the present study, we used two animal models, apolipoprotein E-deficient mice fed on a high-cholesterol diet and a mouse carotid partial ligation model to test the anti-atherosclerotic effect of irisin. Irisin treatment (0.5 μg/g body weight/day) significantly reduced the severity of aortic atherosclerosis in apolipoprotein E-deficient mice fed on a high-cholesterol diet and suppressed carotid neointima formation in a carotid partial ligation model. It was associated with decreased inflammation and cell apoptosis in aortic tissues. In addition, in a cell culture model, irisin restored ox-LDL-induced human umbilical vein endothelial cell dysfunction by reducing the levels of inflammatory genes via inhibiting the reactive oxygen species (ROS)/ p38 MAPK/ NF-κB signaling pathway activation and inhibiting cell apoptosis via up-regulating Bcl-2 and down-regulating Bax and caspase-3 expression. Our study demonstrated that irisin significantly reduced atherosclerosis in apolipoprotein E-deficient mice via suppressing ox-LDL-induced cell inflammation and apoptosis, which might have a direct therapeutic effect on atherosclerotic diseases. PMID:27355581

  6. Effect of electrolytes on the partition coefficient of irbesartan.

    PubMed

    Mbah, C J

    2005-05-01

    The effect of various electrolytes namely monovalent, divalent and trivalent on the partition coefficient of irbesartan between n-octanol and water systems was investigated at room temperature. It was found that all the electrolytes increase the partition coefficient of irbesartan. The uptake of irbesartan by the organic phase from the aqueous phase is increased with increasing salt concentration except for potassium iodide and aluminum chloride. The effect was found to depend on the size and charge of the ions present in solution. PMID:15918582

  7. Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

    PubMed Central

    Zetterqvist, Anna V.; Berglund, Lisa M.; Blanco, Fabiana; Garcia-Vaz, Eliana; Wigren, Maria; Dunér, Pontus; Andersson, Anna-Maria Dutius; To, Fong; Spegel, Peter; Nilsson, Jan; Bengtsson, Eva; Gomez, Maria F.

    2013-01-01

    Objective of the Study Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. Methodology and Principal Findings Streptozotocin (STZ)-induced diabetes in apolipoprotein E−/− mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. Conclusions Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications. PMID:23755169

  8. Endothelial NOTCH1 is suppressed by circulating lipids and antagonizes inflammation during atherosclerosis

    PubMed Central

    Briot, Anaïs; Civelek, Mete; Seki, Atsuko; Hoi, Karen; Mack, Julia J.; Lee, Stephen D.; Kim, Jason; Hong, Cynthia; Yu, Jingjing; Fishbein, Gregory A.; Vakili, Ladan; Fogelman, Alan M.; Fishbein, Michael C.; Lusis, Aldons J.; Tontonoz, Peter; Navab, Mohamad; Berliner, Judith A.

    2015-01-01

    Although much progress has been made in identifying the mechanisms that trigger endothelial activation and inflammatory cell recruitment during atherosclerosis, less is known about the intrinsic pathways that counteract these events. Here we identified NOTCH1 as an antagonist of endothelial cell (EC) activation. NOTCH1 was constitutively expressed by adult arterial endothelium, but levels were significantly reduced by high-fat diet. Furthermore, treatment of human aortic ECs (HAECs) with inflammatory lipids (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine [Ox-PAPC]) and proinflammatory cytokines (TNF and IL1β) decreased Notch1 expression and signaling in vitro through a mechanism that requires STAT3 activation. Reduction of NOTCH1 in HAECs by siRNA, in the absence of inflammatory lipids or cytokines, increased inflammatory molecules and binding of monocytes. Conversely, some of the effects mediated by Ox-PAPC were reversed by increased NOTCH1 signaling, suggesting a link between lipid-mediated inflammation and Notch1. Interestingly, reduction of NOTCH1 by Ox-PAPC in HAECs was associated with a genetic variant previously correlated to high-density lipoprotein in a human genome-wide association study. Finally, endothelial Notch1 heterozygous mice showed higher diet-induced atherosclerosis. Based on these findings, we propose that reduction of endothelial NOTCH1 is a predisposing factor in the onset of vascular inflammation and initiation of atherosclerosis. PMID:26552708

  9. Investigation of RNA interference suppression of matrix metalloproteinase-9 in mouse model of atherosclerosis

    PubMed Central

    Jin, Zhe-Xiu; Xiong, Qiang; Jia, Fang; Sun, Chun-Ling; Zhu, Hong-Tao; Ke, Fu-Sheng

    2015-01-01

    Objective: To investigate the effect of RNA interference of matrix metalloproteinase (MMP)-9 on atherosclerosis on atherosclerosis in apolipoprotein E (ApoE)-/- mouse. Methods: ApoE-/- mouse strain and three cell lines (293T, NIH3T3 and Raw264.7) were used in the present study to investigate the effect of MMP-9 silencing by RNA interference. Thirty 10-week-old ApoE-/- mice were randomly assigned to a control group, lentiviruses with naked vector group and Lentiviruses-MMP-9 intervention group (n = 10). Aortic atherosclerotic plaques of the mice were stained with immunohistochemical techniques, the MMP-9 and high-sensitivity C-reactive protein levels of three groups were detected simultaneously. Expression of MMP-9 was significantly down-regulated in interference group. MMP-9 and high-sensitivity C-reactive protein levels in MMP-9 interference group were significantly lower than that of the control group. Conclusion: The expression of MMP-9 is closely related to vulnerability of atherosclerotic plaques. Silencing of MMP-9 expression acts as a positive role in maintenance of atherosclerotic plaque stability. The present study provides novel experimental insight for the treatment of vulnerable plaques in atherosclerosis. PMID:26131101

  10. 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. PMID:24374929

  11. Cardiac protective effects of irbesartan via the PPAR-gamma signaling pathway in angiotensin-converting enzyme 2-deficient mice

    PubMed Central

    2013-01-01

    and phosphorylated ERK1/2 were lower, and expression of PPARγ was higher in ACE2KO mice in response to irbesartan treatment, without affecting cardiac expression of PPARα, PPARδ, β-myosin heavy chain, TGFβ2 and fibronectin. Conclusions We conclude that irbesartan prevents ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in ACE2 mutant mice via activation of the PPARγ signaling and suppression of the TGFβ−CTGF−ERK signaling, resulting in attenuation of myocardial injury. Drugs targeting ACE2 and PPARγ represent potential candidates to prevent and treat myocardial injury and related cardiac disorders. PMID:24067190

  12. Beneficial effects of metformin and irbesartan on advanced glycation end products (AGEs)-RAGE-induced proximal tubular cell injury.

    PubMed

    Ishibashi, Yuji; Matsui, Takanori; Takeuchi, Masayoshi; Yamagishi, Sho-ichi

    2012-03-01

    Advanced glycation end products (AGEs) and their receptor (RAGE) axis contributes to diabetic nephropathy. An oral hypoglycemic agent, metformin may have a potential effect on the inhibition of glycation reactions. Further, since a pathophysiological crosstalk between renin-angiotensin system (RAS) and AGEs-RAGE axis is involved in diabetic nephropathy, it is conceivable that metformin and irbesartan additively could protect against the AGEs-RAGE-induced tubular cell injury. In this study, we addressed the issues. Metformin dose-dependently inhibited the formation of AGEs modification of bovine serum albumin (BSA). Compared with AGEs-modified BSA prepared without metformin (AGEs-MF0), those prepared in the presence of 30 mM or 100 mM metformin (AGEs-MF30 or AGEs-MF100) significantly reduced RAGE mRNA level, reactive oxygen species (ROS) generation, apoptosis, monocyte chemoattractant protein-1 and transforming growth factor-β mRNA level in tubular cells. Irbesartan further inhibited the harmful effects of AGEs-MF0 or AGEs-MF30 on tubular cells. Our present study suggests that combination therapy with metformin and irbesartan may have therapeutic potential in diabetic nephropathy; it could play a protective role against tubular injury in diabetes not only by inhibiting AGEs formation, but also by attenuating the deleterious effects of AGEs via down-regulating RAGE expression and subsequently suppressing ROS generation. PMID:22100460

  13. Melatonin ameliorates vascular endothelial dysfunction, inflammation, and atherosclerosis by suppressing the TLR4/NF-κB system in high-fat-fed rabbits.

    PubMed

    Hu, Ze-Ping; Fang, Xiao-Ling; Fang, Nan; Wang, Xiao-Bian; Qian, Hai-Yan; Cao, Zhong; Cheng, Yuan; Wang, Bang-Ning; Wang, Yuan

    2013-11-01

    Vascular endothelial dysfunction (VED) and inflammation contribute to the initiation and progression of atherosclerosis. Melatonin (MLT) normalizes lipid profile, improves endothelial function, and possesses anti-inflammatory properties. However, the precise mechanisms are still unclear. This study investigated whether MLT could ameliorate VED, inflammation, and atherosclerosis by suppressing the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) system in high-fat-fed rabbits. Rabbits were randomly divided into three groups that received a standard diet (control group), high-cholesterol diet (atherosclerosis group), or high-cholesterol diet plus 10 mg/kg/day MLT (MLT group) for 12 wk. After treatment, high-fat diet significantly increased serum lipid and inflammatory markers in rabbits in atherosclerosis group compared with that in control group. In addition, high-fat diet also induced VED and typical atherosclerotic plaque formation and increased intima/media thickness ratio, which were significantly improved by MLT therapy as demonstrated in MLT group. Histological and immunoblot analysis further showed that high-fat diet enhanced the expressions of TLR4, myeloid differentiation primary response protein (MyD88), and NF-κB p65, but decreased inhibitor of NF-κB (IκB) expression. By contrast, MLT therapy decreased the expressions of TLR4, MyD88, and NF-κB p65 and increased IκB expression. This study has demonstrated that MLT ameliorates lipid metabolism, VED, and inflammation and inhibits the progression of atherosclerosis in high-fat-fed rabbits. Moreover, our study indicates for the first time that suppression of the TLR4/NF-κB system in local vasculature with atherosclerotic damage is important for the protective effects of MLT. PMID:24006943

  14. The cost-effectiveness of irbesartan for hypertension.

    PubMed

    Borghi, Claudio; Urso, Riccardo; Cicero, Arrigo F G

    2015-04-01

    High blood pressure is a very common problem in the adult and elderly population, both in developed and developing countries. A relatively large number of drug classes are available to treat this condition and prevent its complications, which are not only more frequent in the aforementioned patients but also those affected by metabolic syndrome and/or Type 2 diabetes. Irbesartan is an angiotensin-receptor blocker class drug with good antihypertensive efficacy and specific pharmacological characteristics, whose efficacy has been more deeply evaluated in metabolically complex hypertensive patients. In this review, the authors will analyze its effectiveness in preventing or delaying organ damage in hypertensive patients, with a closer look at the economic implications of treating hypertension with irbesartan in the context of available antihypertensive drugs. PMID:25703678

  15. Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells

    PubMed Central

    Gruber, Sabrina; Hendrikx, Tim; Tsiantoulas, Dimitrios; Ozsvar-Kozma, Maria; Göderle, Laura; Mallat, Ziad; Witztum, Joseph L.; Shiri-Sverdlov, Ronit; Nitschke, Lars; Binder, Christoph J.

    2016-01-01

    Summary Atherosclerosis is initiated and sustained by hypercholesterolemia, which results in the generation of oxidized LDL (OxLDL) and other metabolic byproducts that trigger inflammation. Specific immune responses have been shown to modulate the inflammatory response during atherogenesis. The sialic acid-binding immunoglobulin-like lectin G (Siglec-G) is a negative regulator of the functions of several immune cells, including myeloid cells and B-1 cells. Here, we show that deficiency of Siglec-G in atherosclerosis-prone mice inhibits plaque formation and diet-induced hepatic inflammation. We further demonstrate that selective deficiency of Siglec-G in B cells alone is sufficient to mediate these effects. Levels of B-1 cell-derived natural IgM with specificity for OxLDL were significantly increased in the plasma and peritoneal cavity of Siglec-G-deficient mice. Consistent with the neutralizing functions of OxLDL-specific IgM, Siglec-G-deficient mice were protected from OxLDL-induced sterile inflammation. Thus, Siglec-G promotes atherosclerosis and hepatic inflammation by suppressing protective anti-inflammatory effector functions of B cells. PMID:26947073

  16. 77 FR 1695 - Determination That AVALIDE (Hydrochlorothiazide and Irbesartan), Oral Tablets, 25 Milligrams/300...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ...The Food and Drug Administration (FDA) has determined that AVALIDE (hydrochlorothiazide and irbesartan), oral tablets, 25 milligrams (mg)/300 mg and 12.5 mg/75 mg, were not withdrawn from sale for reasons of safety or effectiveness. This determination will allow FDA to approve abbreviated new drug applications (ANDAs) for hydrochlorothiazide and irbesartan, oral tablets, 25 mg/300 mg and 12.5......

  17. 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. PMID:25875381

  18. Anti-inflammatory effects of a Chinese herbal medicine in atherosclerosis via estrogen receptor β mediating nitric oxide production and NF-κB suppression in endothelial cells

    PubMed Central

    Wang, L; Qiu, X-M; Hao, Q; Li, D-J

    2013-01-01

    Bu-Shen-Ning-Xin Decoction (BSNXD) administration has alleviated the early pathologic damage of atherosclerosis by inhibiting the adhesion molecule expression and upregulating the estrogen receptor (ER) β expression in endothelial cells, and increasing the serum nitric oxide (NO) level without any effect on serum lipid status, endometrium and fat deposition in liver in ovariectomized rabbits. The BSNXD-derived serum increases ER β expression in the human umbilical vein endothelial cells (HUVECs), and decreases malondialdehyde (MDA) production, and upregulates eNOS expression then increases NO synthesis through ERβ-dependent pathway. NO not only suppresses the LPS-induced NF-κB transcription in HUVECs, but also decreases apoptosis of endothelial cells. The BSNXD-derived serum decreases monocyte chemoattractant protein-1 production, and suppresses cell adhesion molecules (ICAM-1, VCAM-1 and E-selectin) expression in HUVECs injured by oxidized low-density lipoproteins (ox-LDL), and these effects can be abolished by ERβ antagonist (R,RTHC) and NO synthase inhibitor (L-NAME). The BSNXD-derived serum-treated HUVECs supernatant reduces CCR2, LFA-1 and VLA-4 expression in monocytes cell line U937 cells, which in turn inhibits adherence of U937 to injured endothelial cells. NO synthesis increases, and MDA production decreases through ERβ-mediated pathway that suppresses apoptosis and NF-κB activity in endothelial cells that downregulates adhesion molecules expression on endothelial cells via ERβ/NO/NF-κB pathway, and in turn leukocyte adhesion, which suggests BSNXD potential value in prophylaxis atherosclerosis. PMID:23519120

  19. Hydrogen Sulfide Inhibits the Development of Atherosclerosis with Suppressing CX3CR1 and CX3CL1 Expression

    PubMed Central

    Wu, Duojiao; Zhang, Alian; Gu, Ting; Wang, Liansheng; Wang, Changqian

    2012-01-01

    Hydrogen sulfide, as a novel gaseous mediator, has been suggested to play a key role in atherogenesis. However, the precise mechanisms by which H2S affects atherosclerosis remain unclear. Therefore, the present study aimed to investigate the potential role of H2S in atherosclerosis and the underlying mechanism with respect to chemokines (CCL2, CCL5 and CX3CL1) and chemokine receptors (CCR2, CCR5, and CX3CR1) in macrophages. Mouse macrophage cell line RAW 264.7 or mouse peritoneal macrophages were pre-incubated with saline or NaHS (50 µM, 100 µM, 200 µM), an H2S donor, and then stimulated with interferon-γ (IFN-γ) or lipopolysaccharide (LPS). It was found that NaHS dose-dependently inhibited IFN-γ or LPS-induced CX3CR1 and CX3CL1 expression, as well as CX3CR1-mediated chemotaxis in macrophages. Overexpression of cystathionine γ-lyase (CSE), an enzyme that catalyzes H2S biosynthesis resulted in a significant reduction in CX3CR1 and CX3CL1 expression as well as CX3CR1-mediated chemotaxis in stimulated macrophages. The inhibitory effect of H2S on CX3CR1 and CX3CL1 expression was mediated by modulation of proliferators-activated receptor-γ (PPAR-γ) and NF-κB pathway. Furthermore, male apoE−/− mice were fed a high-fat diet and then randomly given NaHS (1 mg/kg, i.p., daily) or DL-propargylglycine (PAG, 10 mg/kg, i.p., daily). NaHS significantly inhibited aortic CX3CR1 and CX3CL1 expression and impeded aortic plaque development. NaHS had a better anti-atherogenic benefit when it was applied at the early stage of atherosclerosis. However, inhibition of H2S formation by PAG increased aortic CX3CR1 and CX3CL1 expression and exacerbated the extent of atherosclerosis. In addition, H2S had minimal effect on the expression of CCL2, CCL5, CCR2 and CCR5 in vitro and in vivo. In conclusion, these data indicate that H2S hampers the progression of atherosclerosis in fat-fed apoE−/− mice and downregulates CX3CR1 and CX3CL1 expression on macrophages and in lesion

  20. Tanshinol suppresses endothelial cells apoptosis in mice with atherosclerosis via lncRNA TUG1 up-regulating the expression of miR-26a

    PubMed Central

    Chen, Chao; Cheng, Guangqing; Yang, Xiaoni; Li, Changsheng; Shi, Ran; Zhao, Ningning

    2016-01-01

    Endothelial cell (EC) apoptosis is a crucial process for the development of atherosclerosis. Tanshinol is reported to protect vascular endothelia and attenuate the formation of atherosclerosis. However, the potential molecule mechanism of the protective role of tanshinol in atherosclerosis need to be further investigated. ApoE-/-mice were fed with a high-fat diet and treated with tanshinol to detect the effect of tanshinol on endothelial cells apoptosis with TUNEL staining assay. qRT-PCR and Western blot were performed to examine the expression of TUG1 and miR-26a in endothelial cells. RNA-binding protein immunoprecipitation assay was performed to verify the relationship between TUG1 and miR-26a. It has been shown that tanshinol reduced the aortic atherosclerotic lesion area in the entire aorta and aortic sinus in a concentration dependent manner, and suppressed the endothelial cells apoptosis in ApoE-/- mice. We further found that the mRNA level of TUG1 was reduced and the expression of miR-26a was up-regulated by tanshinol in endothelial cells. In addition, TUG1 down-regulated the expression of miR-26a in ECV304 cells. Finally, it was shown that overexpression of TUG1 removed the reversed effect of tanshinol on oxidized low-density lipoprotein (ox-LDL)-induced endothelial cells apoptosis. Taken together, our study reveals that tanshinol could attenuate the endothelial cells apoptosis in atherosclerotic ApoE-/- mice. Moreover, low TUG1 expression and high level of miR-26a are associated with the endothelial protecting effect of tanshinol. PMID:27508018

  1. 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.

  2. Irbesartan increased PPAR{gamma} activity in vivo in white adipose tissue of atherosclerotic mice and improved adipose tissue dysfunction

    SciTech Connect

    Iwai, Masaru; Kanno, Harumi; Senba, Izumi; Nakaoka, Hirotomo; Moritani, Tomozo; Horiuchi, Masatsugu

    2011-03-04

    Research highlights: {yields} Atherosclerotic apolipoprotein E-deficient (ApoEKO) mice were treated with irbesartan. {yields} Irbesartan decreased white adipose tissue weight without affecting body weight. {yields} DNA-binding for PPAR{gamma} was increased in white adipose tissue in vivo by irbesartan. {yields} Irbesartan increased adipocyte number in white adipose tissue. {yields} Irbesatan increased the expression of adiponectin and leptin in white adipose tissue. -- Abstract: The effect of the PPAR{gamma} agonistic action of an AT{sub 1} receptor blocker, irbesartan, on adipose tissue dysfunction was explored using atherosclerotic model mice. Adult male apolipoprotein E-deficient (ApoEKO) mice at 9 weeks of age were treated with a high-cholesterol diet (HCD) with or without irbesartan at a dose of 50 mg/kg/day for 4 weeks. The weight of epididymal and retroperitoneal adipose tissue was decreased by irbesartan without changing food intake or body weight. Treatment with irbesartan increased the expression of PPAR{gamma} in white adipose tissue and the DNA-binding activity of PPAR{gamma} in nuclear extract prepared from adipose tissue. The expression of adiponectin, leptin and insulin receptor was also increased by irbesartan. These results suggest that irbesartan induced activation of PPAR{gamma} and improved adipose tissue dysfunction including insulin resistance.

  3. MicroRNA-27 Prevents Atherosclerosis by Suppressing Lipoprotein Lipase-Induced Lipid Accumulation and Inflammatory Response in Apolipoprotein E Knockout Mice

    PubMed Central

    Cheng, Hai-Peng; Gong, Duo; Lv, Yun-Cheng; Yao, Feng; He, Ping-Ping; Ouyang, Xin-Ping; Lan, Gang; Liu, Dan; Zhao, Zhen-Wang; Tan, Yu-Lin; Zheng, Xi-Long; Yin, Wei-Dong; Tang, Chao-Ke

    2016-01-01

    Atherosclerotic lesions are lipometabolic disorder characterized by chronic progressive inflammation in arterial walls. Previous studies have shown that macrophage-derived lipoprotein lipase (LPL) might be a key factor that promotes atherosclerosis by accelerating lipid accumulation and proinflammatory cytokine secretion. Increasing evidence indicates that microRNA-27 (miR-27) has beneficial effects on lipid metabolism and inflammatory response. However, it has not been fully understood whether miR-27 affects the expression of LPL and subsequent development of atherosclerosis in apolipoprotein E knockout (apoE KO) mice. To address these questions and its potential mechanisms, oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages were transfected with the miR-27 mimics/inhibitors and apoE KO mice fed high-fat diet were given a tail vein injection with miR-27 agomir/antagomir, followed by exploring the potential roles of miR-27. MiR-27 agomir significantly down-regulated LPL expression in aorta and peritoneal macrophages by western blot and real-time PCR analyses. We performed LPL activity assay in the culture media and found that miR-27 reduced LPL activity. ELISA showed that miR-27 reduced inflammatory response as analyzed in vitro and in vivo experiments. Our results showed that miR-27 had an inhibitory effect on the levels of lipid both in plasma and in peritoneal macrophages of apoE KO mice as examined by HPLC. Consistently, miR-27 suppressed the expression of scavenger receptors associated with lipid uptake in ox-LDL-treated THP-1 macrophages. In addition, transfection with LPL siRNA inhibited the miR-27 inhibitor-induced lipid accumulation and proinflammatory cytokines secretion in ox-LDL-treated THP-1 macrophages. Finally, systemic treatment revealed that miR-27 decreased aortic plaque size and lipid content in apoE KO mice. The present results provide evidence that a novel antiatherogenic role of miR-27 was closely related to reducing lipid

  4. MicroRNA-27 Prevents Atherosclerosis by Suppressing Lipoprotein Lipase-Induced Lipid Accumulation and Inflammatory Response in Apolipoprotein E Knockout Mice.

    PubMed

    Xie, Wei; Li, Liang; Zhang, Min; Cheng, Hai-Peng; Gong, Duo; Lv, Yun-Cheng; Yao, Feng; He, Ping-Ping; Ouyang, Xin-Ping; Lan, Gang; Liu, Dan; Zhao, Zhen-Wang; Tan, Yu-Lin; Zheng, Xi-Long; Yin, Wei-Dong; Tang, Chao-Ke

    2016-01-01

    Atherosclerotic lesions are lipometabolic disorder characterized by chronic progressive inflammation in arterial walls. Previous studies have shown that macrophage-derived lipoprotein lipase (LPL) might be a key factor that promotes atherosclerosis by accelerating lipid accumulation and proinflammatory cytokine secretion. Increasing evidence indicates that microRNA-27 (miR-27) has beneficial effects on lipid metabolism and inflammatory response. However, it has not been fully understood whether miR-27 affects the expression of LPL and subsequent development of atherosclerosis in apolipoprotein E knockout (apoE KO) mice. To address these questions and its potential mechanisms, oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages were transfected with the miR-27 mimics/inhibitors and apoE KO mice fed high-fat diet were given a tail vein injection with miR-27 agomir/antagomir, followed by exploring the potential roles of miR-27. MiR-27 agomir significantly down-regulated LPL expression in aorta and peritoneal macrophages by western blot and real-time PCR analyses. We performed LPL activity assay in the culture media and found that miR-27 reduced LPL activity. ELISA showed that miR-27 reduced inflammatory response as analyzed in vitro and in vivo experiments. Our results showed that miR-27 had an inhibitory effect on the levels of lipid both in plasma and in peritoneal macrophages of apoE KO mice as examined by HPLC. Consistently, miR-27 suppressed the expression of scavenger receptors associated with lipid uptake in ox-LDL-treated THP-1 macrophages. In addition, transfection with LPL siRNA inhibited the miR-27 inhibitor-induced lipid accumulation and proinflammatory cytokines secretion in ox-LDL-treated THP-1 macrophages. Finally, systemic treatment revealed that miR-27 decreased aortic plaque size and lipid content in apoE KO mice. The present results provide evidence that a novel antiatherogenic role of miR-27 was closely related to reducing lipid

  5. Increased Expression of Chitinase 3-Like 1 in Aorta of Patients with Atherosclerosis and Suppression of Atherosclerosis in Apolipoprotein E-Knockout Mice by Chitinase 3-Like 1 Gene Silencing

    PubMed Central

    Gong, Zushun; Xing, Shanshan; Zheng, Fei; Xing, Qichong

    2014-01-01

    Introduction. The purpose of this study was to investigate the changes of chitinase 3-like 1 (CHI3L1) in the aorta of patients with coronary atherosclerosis and to determine whether inhibition of CHI3L1 by lentivirus-mediated RNA interference could stabilize atherosclerotic plaques in apolipoprotein E-knockout (ApoE−/−) mice. Methods. We collected discarded aortic specimens from patients undergoing coronary artery bypass graft surgery and renal arterial tissues from kidney donors. A lentivirus carrying small interfering RNA targeting the expression of CHI3L1 was constructed. Fifty ApoE−/− mice were divided into control group and CHI3L1 gene silenced group. A constrictive collar was placed around carotid artery to induce plaques formation. Then lentivirus was transfected into carotid plaques. Results. We found that CHI3L1 was overexpressed in aorta of patients with atherosclerosis and its expression was correlated with the atherosclerotic risk factors. After lentivirus transduction, mRNA and protein expression of CHI3L1 were attenuated in carotid plaques, leading to reduced plaque content of lipids and macrophages, and increased plaque content of collagen and smooth muscle cells. Moreover, CHI3L1 gene silencing downregulated the expression of local proinflammatory mediators. Conclusions. CHI3L1 is overexpressed in aorta from patients with atherosclerosis and the lentivirus-mediated CHI3L1 gene silencing could represent a new strategy to inhibit plaques progression. PMID:24729664

  6. Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage-Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice

    PubMed Central

    Terasaki, Michishige; Hiromura, Munenori; Mori, Yusaku; Kohashi, Kyoko; Nagashima, Masaharu; Kushima, Hideki; Watanabe, Takuya; Hirano, Tsutomu

    2015-01-01

    Direct associations between hyperglycemia and atherosclerosis remain unclear. We investigated the association between the amelioration of glycemia by sodium-glucose cotransporter 2 inhibitors (SGLT2is) and macrophage-driven atherosclerosis in diabetic mice. We administered dapagliflozin or ipragliflozin (1.0 mg/kg/day) for 4-weeks to apolipoprotein E-null (Apoe−/−) mice, streptozotocin-induced diabetic Apoe−/− mice, and diabetic db/db mice. We then determined aortic atherosclerosis, oxidized low-density lipoprotein (LDL)-induced foam cell formation, and related gene expression in exudate peritoneal macrophages. Dapagliflozin substantially decreased glycated hemoglobin (HbA1c) and glucose tolerance without affecting body weight, blood pressure, plasma insulin, and lipids in diabetic Apoe−/− mice. Aortic atherosclerotic lesions, atheromatous plaque size, and macrophage infiltration in the aortic root increased in diabetic Apoe−/− mice; dapagliflozin attenuated these changes by 33%, 27%, and 20%, respectively. Atherosclerotic lesions or foam cell formation highly correlated with HbA1c. Dapagliflozin did not affect atherosclerosis or plasma parameters in non-diabetic Apoe−/− mice. In db/db mice, foam cell formation increased by 4-fold compared with C57/BL6 mice, whereas ipragliflozin decreased it by 31%. Foam cell formation exhibited a strong correlation with HbA1c. Gene expression of lectin-like ox-LDL receptor-1 and acyl-coenzyme A:cholesterol acyltransferase 1 was upregulated, whereas that of ATP-binding cassette transporter A1 was downregulated in the peritoneal macrophages of both types of diabetic mice. SGLT2i normalized these gene expressions. Our study is the first to demonstrate that SGLT2i exerts anti-atherogenic effects by pure glucose lowering independent of insulin action in diabetic mice through suppressing macrophage foam cell formation, suggesting that foam cell formation is highly sensitive to glycemia ex vivo. PMID:26606676

  7. Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage-Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice.

    PubMed

    Terasaki, Michishige; Hiromura, Munenori; Mori, Yusaku; Kohashi, Kyoko; Nagashima, Masaharu; Kushima, Hideki; Watanabe, Takuya; Hirano, Tsutomu

    2015-01-01

    Direct associations between hyperglycemia and atherosclerosis remain unclear. We investigated the association between the amelioration of glycemia by sodium-glucose cotransporter 2 inhibitors (SGLT2is) and macrophage-driven atherosclerosis in diabetic mice. We administered dapagliflozin or ipragliflozin (1.0 mg/kg/day) for 4-weeks to apolipoprotein E-null (Apoe-/-) mice, streptozotocin-induced diabetic Apoe-/- mice, and diabetic db/db mice. We then determined aortic atherosclerosis, oxidized low-density lipoprotein (LDL)-induced foam cell formation, and related gene expression in exudate peritoneal macrophages. Dapagliflozin substantially decreased glycated hemoglobin (HbA1c) and glucose tolerance without affecting body weight, blood pressure, plasma insulin, and lipids in diabetic Apoe-/- mice. Aortic atherosclerotic lesions, atheromatous plaque size, and macrophage infiltration in the aortic root increased in diabetic Apoe-/- mice; dapagliflozin attenuated these changes by 33%, 27%, and 20%, respectively. Atherosclerotic lesions or foam cell formation highly correlated with HbA1c. Dapagliflozin did not affect atherosclerosis or plasma parameters in non-diabetic Apoe-/- mice. In db/db mice, foam cell formation increased by 4-fold compared with C57/BL6 mice, whereas ipragliflozin decreased it by 31%. Foam cell formation exhibited a strong correlation with HbA1c. Gene expression of lectin-like ox-LDL receptor-1 and acyl-coenzyme A:cholesterol acyltransferase 1 was upregulated, whereas that of ATP-binding cassette transporter A1 was downregulated in the peritoneal macrophages of both types of diabetic mice. SGLT2i normalized these gene expressions. Our study is the first to demonstrate that SGLT2i exerts anti-atherogenic effects by pure glucose lowering independent of insulin action in diabetic mice through suppressing macrophage foam cell formation, suggesting that foam cell formation is highly sensitive to glycemia ex vivo. PMID:26606676

  8. Imaging Atherosclerosis.

    PubMed

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

    2016-02-19

    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

  9. 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

  10. Nanoparticle-Mediated Delivery of Irbesartan Induces Cardioprotection from Myocardial Ischemia-Reperfusion Injury by Antagonizing Monocyte-Mediated Inflammation

    NASA Astrophysics Data System (ADS)

    Nakano, Yasuhiro; Matoba, Tetsuya; Tokutome, Masaki; Funamoto, Daiki; Katsuki, Shunsuke; Ikeda, Gentaro; Nagaoka, Kazuhiro; Ishikita, Ayako; Nakano, Kaku; Koga, Jun-Ichiro; Sunagawa, Kenji; Egashira, Kensuke

    2016-07-01

    Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effect of early reperfusion therapy for acute myocardial infarction (AMI), in which the recruitment of inflammatory monocytes plays a causative role. Here we develop bioabsorbable poly-lactic/glycolic acid (PLGA) nanoparticles incorporating irbesartan, an angiotensin II type 1 receptor blocker with a peroxisome proliferator-activated receptor (PPAR)γ agonistic effect (irbesartan-NP). In a mouse model of IR injury, intravenous PLGA nanoparticles distribute to the IR myocardium and monocytes in the blood and in the IR heart. Single intravenous treatment at the time of reperfusion with irbesartan-NP (3.0 mg kg‑1 irbesartan), but not with control nanoparticles or irbesartan solution (3.0 mg kg‑1), inhibits the recruitment of inflammatory monocytes to the IR heart, and reduces the infarct size via PPARγ-dependent anti-inflammatory mechanisms, and ameliorates left ventricular remodeling 21 days after IR. Irbesartan-NP is a novel approach to treat myocardial IR injury in patients with AMI.

  11. Nanoparticle-Mediated Delivery of Irbesartan Induces Cardioprotection from Myocardial Ischemia-Reperfusion Injury by Antagonizing Monocyte-Mediated Inflammation

    PubMed Central

    Nakano, Yasuhiro; Matoba, Tetsuya; Tokutome, Masaki; Funamoto, Daiki; Katsuki, Shunsuke; Ikeda, Gentaro; Nagaoka, Kazuhiro; Ishikita, Ayako; Nakano, Kaku; Koga, Jun-ichiro; Sunagawa, Kenji; Egashira, Kensuke

    2016-01-01

    Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effect of early reperfusion therapy for acute myocardial infarction (AMI), in which the recruitment of inflammatory monocytes plays a causative role. Here we develop bioabsorbable poly-lactic/glycolic acid (PLGA) nanoparticles incorporating irbesartan, an angiotensin II type 1 receptor blocker with a peroxisome proliferator-activated receptor (PPAR)γ agonistic effect (irbesartan-NP). In a mouse model of IR injury, intravenous PLGA nanoparticles distribute to the IR myocardium and monocytes in the blood and in the IR heart. Single intravenous treatment at the time of reperfusion with irbesartan-NP (3.0 mg kg−1 irbesartan), but not with control nanoparticles or irbesartan solution (3.0 mg kg−1), inhibits the recruitment of inflammatory monocytes to the IR heart, and reduces the infarct size via PPARγ-dependent anti-inflammatory mechanisms, and ameliorates left ventricular remodeling 21 days after IR. Irbesartan-NP is a novel approach to treat myocardial IR injury in patients with AMI. PMID:27403534

  12. Efficacy and safety of irbesartan/HCTZ combination therapy as initial treatment for rapid control of severe hypertension.

    PubMed

    Neutel, Joel M; Franklin, Stanley S; Oparil, Suzanne; Bhaumik, Amitabha; Ptaszynska, Agata; Lapuerta, Pablo

    2006-12-01

    Severe hypertension is difficult to control. This prospective, randomized, double-blind, active-controlled, multicenter trial compared efficacy and safety of once-daily irbesartan/hydrochlorothiazide (HCTZ) combination therapy with irbesartan monotherapy in severe hypertension. Patients who were untreated or uncontrolled on monotherapy (seated diastolic blood pressure [BP] > or =110 mm Hg) received fixed-dose irbesartan 150 mg/HCTZ 12.5 mg combination therapy for 7 weeks, force-titrated to irbesartan 300 mg/HCTZ 25 mg at week 1 (n=468); or irbesartan 150 mg monotherapy, force-titrated to 300 mg at week 1 (n=269). Significantly more patients on combination therapy achieved seated diastolic BP <90 mm Hg at week 5 (primary end point) compared with monotherapy recipients (47.2% vs 33.2%; P=.0005). Likewise, significantly more patients attained goals per the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) (<140/90 mm Hg) at week 5 (34.6% vs 19.2%, respectively; P<.0001), while the mean difference between combination and monotherapy in seated diastolic BP and seated systolic BP was 4.7 mm Hg and 9.7 mm Hg (P<.0001). Greater and more rapid BP reduction with irbesartan/HCTZ was achieved without additional side effects. PMID:17170610

  13. What Causes Atherosclerosis?

    MedlinePlus

    ... page from the NHLBI on Twitter. What Causes Atherosclerosis? The exact cause of atherosclerosis isn't known. ... Rate This Content: NEXT >> Featured Video What is atherosclerosis? 05/22/2014 Describes how the build-up ...

  14. How Is Atherosclerosis Treated?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Is Atherosclerosis Treated? Treatments for atherosclerosis may include heart-healthy ... Rate This Content: NEXT >> Featured Video What is atherosclerosis? 05/22/2014 Describes how the build-up ...

  15. Naringenin and atherosclerosis: a review of literature.

    PubMed

    Orhan, Ilkay E; Nabavi, Seyed F; Daglia, Maria; Tenore, Gian C; Mansouri, Kowsar; Nabavi, Seyed M

    2015-01-01

    Atherosclerosis is a multifactorial disease mainly caused by deposition of low-density lipoprotein (LD) cholesterol in macrophages of arterial walls. Atherosclerosis leads to heart attacks as well as stroke. Epidemiological studies showed that there is an inverse correlation between fruit and vegetable consumption and the risk of atherosclerosis. The promising effect of high vegetable and fruit containing diet on atherosclerosis is approved by several experimental studies on isolated phytochemicals such as flavonoids. Flavonoids are known to up-regulate endogenous antioxidant system, suppress oxidative and nitrosative stress, decrease macrophage oxidative stress through cellular oxygenase inhibition as well as interaction with several signal transduction pathways and from these ways, have therapeutic effects against atherosclerosis. Naringenin is a well known flavonoid belonging to the chemical class of flavanones. It is especially abundant in citrus fruits, especially grapefruits. A plethora of evidences ascribes to naringenin antiatherosclerotic effects. Naringenin abilities to decrease LDL and triglycerides as well as inhibit glucose uptake; increase high-density lipoprotein (HDL); co-oxidation of NADH; suppress protein oxidation; protect against intercellular adhesion molecule-1(ICAM-1); suppress macrophage inflammation; inhibit leukotriene B4, monocyte adhesion and foam cell formation; induce of HO-1 and G 0/G 1 cell cycle arrest in vascular smooth muscle cells (VSMC) and down regulate atherosclerosis related genes are believed to have crucial role in the promising role against atherosclerosis. In the present review, we have summarized the available literature data on the anti-atherosclerotic effects of naringenin and its possible mechanisms of action. PMID:25483717

  16. Bioequivalence study of two oral formulations of irbesartan 300 mg in healthy volunteers.

    PubMed

    Cánovas, M; Cabré, F; Polonio, F

    2014-01-01

    A bioequivalence study of 2 irbesartan (CAS 138402-11-6) film-coated tablet formulations was carried out in 40 healthy volunteers according to an open label, randomized, 2-period, 2-sequence, crossover, single dose and fasting conditions design. The test and reference formulations were administered in 2 treatment days, separated by a washout period of 7 days. Blood samples were drawn up to 96 h following drug administration. Plasma concentrations of irbesartan were obtained by a validated HPLC method using MS/MS detection. Log-transformed AUC0-t and Cmax values were tested for bioequivalence based on the ratios of the geometric LSmeans (test/reference). tmax was analysed nonparametrically. The 90% confidence intervals of the geometric LSmean values for the test/reference ratios for AUC0-t (98.06-109.48%, point estimator 103.61%) and Cmax (88.93-100.87%, point estimator 94.72%) were within the bioequivalence acceptance range of 80-125%. According to the European Guideline on the Investigation of Bioequivalence it may be therefore concluded that test formulation of irbesartan 300 mg film-coated tablet is bioequivalent to the reference formulation. Overall, it was judged that the study was conducted with a good tolerance of the subjects to both study drugs. PMID:24048950

  17. [Irbesartan reduces inflammatory response of central nervous system in a rat model of fluid percussion brain injury].

    PubMed

    Xing, Guoxiang; Wei, Min; Xiu, Binhua; Ma, Yinghui; Liu, Tao

    2016-07-01

    Objective To investigate the neuroprotective effect of the angiotensin II receptor 1 (AT1) antagonist irbesartan on rat models with lateral fluid percussion brain injury (FPBI). Methods FPBI models were prepared using a modified fluid percussion injury method. Before and after modeling, irbesartan was given to the rats. The regional cerebral blood flow (rCBF) was monitored by laser Doppler flowmetry. Neurologic status was evaluated before and 1, 3, 5, 7 days after FPBI surgery. Brains were removed for immunohistochemical evaluation of active microglias and macrophages. Results Compared to sham group, the rCBF and neurologic score of FPBI rats decreased significantly, while microglia and macrophage activation were confirmed. Treatment with irbesartan before FPBI surgery increased rCBF and improved neurological functions. In the peri-infarct cortex, irbesartan treatment attenuated the invasion of activated microglias and macrophages on day 7 after FPBI surgery. Conclusion Irbesartan can play a neuroprotective role through inhibiting microglia and macrophage activation in FPBI rats. PMID:27363272

  18. Atherosclerosis and Stroke

    MedlinePlus

    ... Stroke When the Beat is Off - Atrial Fibrillation Atherosclerosis and Stroke How Cardiovascular & Stroke Risks Relate Problems ... of LDL cholesterol contribute to the development of atherosclerosis as the cholesterol is deposited in artery walls, ...

  19. Postmortem Study of Validation of Low Signal on Fat-Suppressed T1-Weighted Magnetic Resonance Imaging as Marker of Lipid Core in Middle Cerebral Artery Atherosclerosis

    PubMed Central

    Yang, Wen-Jie; Zhao, Hai-Lu; Niu, Chun-Bo; Zhang, Bing; Xu, Yun; Wong, Ka-Sing; Ng, Ho-Keung

    2016-01-01

    Background and Purpose— High signal on T1-weighted fat-suppressed images in middle cerebral artery plaques on ex vivo magnetic resonance imaging was verified to be intraplaque hemorrhage histologically. However, the underlying plaque component of low signal on T1-weighted fat-suppressed images (LST1) has never been explored. Based on our experience, we hypothesized that LST1 might indicate the presence of lipid core within intracranial plaques. Methods— 1.5 T magnetic resonance imaging was performed in the postmortem brains to scan the cross sections of bilateral middle cerebral arteries. Then middle cerebral artery specimens were removed for histology processing. LST1 presence was identified on magnetic resonance images, and lipid core areas were measured on the corresponding histology sections. Results— Total 76 middle cerebral artery locations were included for analysis. LST1 showed a high specificity (96.9%; 95% confidence interval, 82.0%–99.8%) but a low sensitivity (38.6%; 95% confidence interval, 24.7%–54.5%) for detecting lipid core of all areas. However, the sensitivity increased markedly (81.2%; 95% confidence interval, 53.7%–95.0%) when only lipid cores of area ≥0.80 mm2 were included. Mean lipid core area was 5× larger in those with presence of LST1 than in those without (1.63±1.18 mm2 versus 0.32±0.31 mm2; P=0.003). Conclusions— LST1 is a promising imaging biomarker of identifying intraplaque lipid core, which may be useful to distinguish intracranial atherosclerotic disease from other intracranial vasculopathies and to assess plaque vulnerability for risk stratification of patients with intracranial atherosclerotic disease. In vivo clinical studies are required to explore the correlation between LST1 and clinical outcomes of patients with intracranial atherosclerotic disease. PMID:27462119

  20. Vinpocetine attenuates lipid accumulation and atherosclerosis formation

    SciTech Connect

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

    2013-05-10

    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-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.

  1. Atherosclerosis Prevention in Youth

    PubMed Central

    2012-01-01

    Atherosclerosis-associated circulatory disturbance is one of the most important global issues. In patients with atherosclerosis, eccentric intimal thickening and lipid deposition progress over a long period (at least 20 to 30 years). On the other hand, in patients with atherosclerosis-associated circulatory disturbance represented by myocardial infarction, the direct cause of death is thrombus formation rather than marked stenosis; wall destruction may lead to a fatal outcome. In the future, atherosclerosis susceptibility, that is, intrinsic genes, should be investigated. PMID:23641261

  2. Response to angiotensin blockade with irbesartan in a patient with metastatic colorectal cancer

    PubMed Central

    Jones, M. R.; Schrader, K. A.; Shen, Y.; Pleasance, E.; Ch'ng, C.; Dar, N.; Yip, S.; Renouf, D. J.; Schein, J. E.; Mungall, A. J.; Zhao, Y.; Moore, R.; Ma, Y.; Sheffield, B. S.; Ng, T.; Jones, S. J. M.; Marra, M. A.; Laskin, J.; Lim, H. J.

    2016-01-01

    Background A patient suffering from metastatic colorectal cancer, treatment-related toxicity and resistance to standard chemotherapy and radiation was assessed as part of a personalized oncogenomics initiative to derive potential alternative therapeutic strategies. Patients and methods Whole-genome and transcriptome sequencing was used to interrogate a metastatic tumor refractory to standard treatments of a patient with mismatch repair-deficient metastatic colorectal cancer. Results Integrative genomic analysis indicated overexpression of the AP-1 transcriptional complex suggesting experimental therapeutic rationales, including blockade of the renin–angiotensin system. This led to the repurposing of the angiotensin II receptor antagonist, irbesartan, as an anticancer therapy, resulting in the patient experiencing a dramatic and durable response. Conclusions This case highlights the utility of comprehensive integrative genomic profiling and bioinformatics analysis to provide hypothetical rationales for personalized treatment options. PMID:27022066

  3. Intracranial atherosclerosis following radiotherapy

    SciTech Connect

    Werner, M.H.; Burger, P.C.; Heinz, E.R.; Friedman, A.H.; Halperin, E.C.; Schold, S.C. Jr.

    1988-07-01

    We describe a case of severe intracranial atherosclerosis in a young man who had received therapeutic radiation for a presumed brain neoplasm. Since there was no evidence of vascular disease outside the radiation ports, we speculate that accelerated atherosclerosis was induced by radiation and that hyperlipidemia may have predisposed him to this effect.

  4. [Carotid atherosclerosis and dementia].

    PubMed

    Harlé, Louise-Marine; Plichart, Matthieu

    2015-09-01

    Over the past decade a growing interest has been devoted to exploring the role of atherosclerosis in the development of dementia. Despite a well-known association between atherosclerosis risk factors in middle-life with later cognitive decline, the pathophysiological pathways underlying this association remain unclear. The current hypothesis is that neurodegenerative and vascular lesions coexist and have a synergistic role in the development of cognitive impairment and dementia. Carotid atherosclerosis (e.g. carotid plaques and intima-media thickness as measured by carotid ultrasonography) has been associated with cognitive decline and dementia and may help to better understand the complex interaction between the vascular and neurodegenerative processes. Furthermore, carotid atherosclerosis has been used in the recent field for dementia risk prediction. In this review, we discuss the physiopathological implications from the current available data on the relationship between carotid atherosclerosis and dementia as well as the interest of carotid biomarkers for individual dementia risk prediction. PMID:26395304

  5. 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. PMID:23583194

  6. 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

  7. Animal models of atherosclerosis

    PubMed Central

    Kapourchali, Fatemeh Ramezani; Surendiran, Gangadaran; Chen, Li; Uitz, Elisabeth; Bahadori, Babak; Moghadasian, Mohammed H

    2014-01-01

    In this mini-review several commonly used animal models of atherosclerosis have been discussed. Among them, emphasis has been made on mice, rabbits, pigs and non-human primates. Although these animal models have played a significant role in our understanding of induction of atherosclerotic lesions, we still lack a reliable animal model for regression of the disease. Researchers have reported several genetically modified and transgenic animal models that replicate human atherosclerosis, however each of current animal models have some limitations. Among these animal models, the apolipoprotein (apo) E-knockout (KO) mice have been used extensively because they develop spontaneous atherosclerosis. Furthermore, atherosclerotic lesions developed in this model depending on experimental design may resemble humans’ stable and unstable atherosclerotic lesions. This mouse model of hypercholesterolemia and atherosclerosis has been also used to investigate the impact of oxidative stress and inflammation on atherogenesis. Low density lipoprotein (LDL)-r-KO mice are a model of human familial hypercholesterolemia. However, unlike apo E-KO mice, the LDL-r-KO mice do not develop spontaneous atherosclerosis. Both apo E-KO and LDL-r-KO mice have been employed to generate other relevant mouse models of cardiovascular disease through breeding strategies. In addition to mice, rabbits have been used extensively particularly to understand the mechanisms of cholesterol-induced atherosclerosis. The present review paper details the characteristics of animal models that are used in atherosclerosis research. PMID:24868511

  8. [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. PMID:26088002

  9. How Is Atherosclerosis Diagnosed?

    MedlinePlus

    ... sign that you're at risk for atherosclerosis. EKG (Electrocardiogram) An EKG is a simple, painless test that detects and ... beating and its rhythm (steady or irregular). An EKG also records the strength and timing of electrical ...

  10. 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

  11. Diet and atherosclerosis.

    PubMed Central

    Kritchevsky, D.

    1976-01-01

    Because of the statistical establishment of elevated blood lipids as a risk factor in the development of atherosclerotic heart disease, most of the attempts to regulate blood lipids by diet are centered on the fat in the diet. The levels of blood lipids and the course of experimental atherosclerosis can be affected by other dietary components such as type and amount of protein, carbohydrate, and nonnutritive fiber. Interaction among the dietary components further affects serum lipids and atherosclerosis. PMID:786036

  12. Nutrition and Atherosclerosis.

    PubMed

    Torres, Nimbe; Guevara-Cruz, Martha; Velázquez-Villegas, Laura A; Tovar, Armando R

    2015-07-01

    Cardiovascular disease (CVD) is a universal problem in modern society. Atherosclerosis is the leading cause of CVD resulting in high rate of mortality in the population. Nutrition science has focused on the role of essential nutrients in preventing deficiencies, at the present time, the nutritional strategies are crucial to promote health and intervene with these global noncommunicable diseases. In many cases, diet is a major driving force, which is much easier to change and follow than other factors. It is important to establish that the first strategy to treat atherosclerosis is to modify lifestyle habits, focusing on the beneficial properties of specific nutrients. In the last decades, epidemiological, clinical and experimental studies have demonstrated that diet plays a central role in the prevention of atherosclerosis. In this review we will focus on the effect of specific foods, nutrients and bioactive compounds, including epidemiological facts, potential mechanisms of action and dietary recommendations to reduce the risk of atherosclerosis. In particular, we include information about fiber, plant sterols and stanols, niacin, taurine, olive oil, omega 3 fatty acids, antioxidants, minerals, methyl nutrients and soy. In addition, we also show that dysbiosis of the intestinal microbiota associated with a consumption of certain animal food sources can generate some metabolites that are involved in the development of atherosclerosis and its consequences on CVD. According to the epidemiological, clinical and experimental studies we suggest a recommendation for some dietary foods, nutrients and bioactive compounds to support the complementary clinical management of patients with atherosclerosis. PMID:26031780

  13. Irbesartan, an angiotensin II receptor antagonist, with selective PPAR-gamma-modulating activity improves function and structure of chemotherapy-damaged ovaries in rats.

    PubMed

    Abdel-Raheem, Ihab T; Omran, Gamal A; Katary, Mohamed Alaa

    2015-06-01

    Cyclophosphamide (CYP) is a chemotherapeutic agent with a potent ovarian toxic effect. CYP induces granulosa cell apoptosis and oxidative stress. Irbesartan (IRB) is a unique ARB with a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonistic activity. As PPAR-ɣ activation exerts anti-inflammatory effects and reduces ROS production, IRB may further reduce inflammatory chemokine expression and suppress apoptotic cell death. Therefore, this study aimed to evaluate the effects of IRB on the development of CYP-induced ovarian damage. Rats were divided into four groups: control group, IRB group (100 mg/kg, orally), CYP group (100 mg/kg, i.p. single injection), and IRB+CYP group (IRB administered 9 days before and 6 days after CYP administration). Rats sacrificed on day 16 of experiment; estradiol (E2), FSH, and TNF-α levels were estimated in serum. Reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) and caspase-3 activities, myeloperoxidase (MPO), and IL-10 levels were determined in ovarian tissues. Protein expressions of p53, caspase-3, Ki-67, and Rad-51 were estimated by immunohistochemical and Western blot techniques. CYP produced ovarian damage as indicated from the decline in serum E2; elevation in FSH; unbalance in tissue oxidative stress parameters; increase in MPO, TNF-α levels, caspase-3 activity/expression, p53, and Rad-51 expression; and decrease in IL-10 contents, without effect on Ki-67. On the other hand, IRB, significantly reduced the toxic effects of CYP as indicted from normalization of E2, FSH, oxidative stress, apoptotic, and inflammatory mediators. These data were further supported by histopathological studies. Thus, co-administration of IRB may be promising in alleviating the ovarian toxic effects of CYP. PMID:25824615

  14. Who Is at Risk for Atherosclerosis?

    MedlinePlus

    ... NHLBI on Twitter. Who Is at Risk for Atherosclerosis? The exact cause of atherosclerosis isn't known. ... role in atherosclerosis risk. Other Factors That Affect Atherosclerosis Other factors also may raise your risk for ...

  15. Spontaneous Atherosclerosis in Pigeons

    PubMed Central

    Santerre, Robert F.; Wight, Thomas N.; Smith, Samuel C.; Brannigan, David

    1972-01-01

    The interpretation of metabolic studies related to early changes in spontaneous atherosclerosis has been hampered by the focal nature of the disease and by the lack of a well-defined model system of the disease process. Gross, histologic and ultrastructural observations of lesion development at the celiac bifurcation of the aorta in atherosclerosis-susceptible White Carneau and atherosclerosis-resistant Show Racer pigeons are compared and discussed in terms of hemodynamics, muscular aggregation and altered metabolism of smooth muscle cells. Detailed knowledge of the morphologic sequence of events in lesion localization makes the celiac bifurcation in White Carneau and Show Racer pigeons a useful model for genetic comparisons of arterial wall metabolism and for investigating metabolic alterations occurring with atherogenesis. ImagesFig 9Fig 10Fig 1Fig 2Fig 10Fig 11Fig 3Fig 4Fig 12Fig 5Fig 6Fig 7Fig 8 PMID:4261591

  16. Macrophage Autophagy in Atherosclerosis

    PubMed Central

    Maiuri, Maria Chiara; Grassia, Gianluca; Platt, Andrew M.; Carnuccio, Rosa; Ialenti, Armando; Maffia, Pasquale

    2013-01-01

    Macrophages play crucial roles in atherosclerotic immune responses. Recent investigation into macrophage autophagy (AP) in atherosclerosis has demonstrated a novel pathway through which these cells contribute to vascular inflammation. AP is a cellular catabolic process involving the delivery of cytoplasmic contents to the lysosomal machinery for ultimate degradation and recycling. Basal levels of macrophage AP play an essential role in atheroprotection during early atherosclerosis. However, AP becomes dysfunctional in the more advanced stages of the pathology and its deficiency promotes vascular inflammation, oxidative stress, and plaque necrosis. In this paper, we will discuss the role of macrophages and AP in atherosclerosis and the emerging evidence demonstrating the contribution of macrophage AP to vascular pathology. Finally, we will discuss how AP could be targeted for therapeutic utility. PMID:23401644

  17. The UPR in atherosclerosis.

    PubMed

    Zhou, Alex X; Tabas, Ira

    2013-05-01

    Multiple systemic factors and local stressors in the arterial wall can disturb the functions of endoplasmic reticulum (ER), causing ER stress in endothelial cells (ECs), smooth muscle cells (SMCs), and macrophages during the initiation and progression of atherosclerosis. As a protective response to restore ER homeostasis, the unfolded protein response (UPR) is initiated by three major ER sensors: protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α), and activating transcription factor 6 (ATF6). The activation of the various UPR signaling pathways displays a temporal pattern of activation at different stages of the disease. The ATF6 and IRE1α pathways that promote the expression of protein chaperones in ER are activated in ECs in athero-susceptible regions of pre-lesional arteries and before the appearance of foam cells. The PERK pathway that reduces ER protein client load by blocking protein translation is activated in SMCs and macrophages in early lesions. The activation of these UPR signaling pathways aims to cope with the ER stress and plays a pro-survival role in the early stage of atherosclerosis. However, with the progression of atherosclerosis, the extended duration and increased intensity of ER stress in lesions lead to prolonged and enhanced UPR signaling. Under this circumstance, the PERK pathway induces expression of death effectors, and possibly IRE1α activates apoptosis signaling pathways, leading to apoptosis of macrophages and SMCs in advanced lesions. Importantly, UPR-mediated cell death is associated with plaque instability and the clinical progression of atherosclerosis. Moreover, UPR signaling is linked to inflammation and possibly to macrophage differentiation in lesions. Therapeutic approaches targeting the UPR may have promise in the prevention and/or regression of atherosclerosis. However, more progress is needed to fully understand all of the roles of the UPR in atherosclerosis and to harness this information

  18. Molecular imaging in atherosclerosis

    PubMed Central

    Glaudemans, Andor W. J. M.; Slart, Riemer H. J. A.; Bozzao, Alessandro; Bonanno, Elena; Arca, Marcello; Dierckx, Rudi A. J. O.

    2010-01-01

    Atherosclerosis is the major cause of cardiovascular disease, which still has the leading position in morbidity and mortality in the Western world. Many risk factors and pathobiological processes are acting together in the development of atherosclerosis. This leads to different remodelling stages (positive and negative) which are both associated with plaque physiology and clinical presentation. The different remodelling stages of atherosclerosis are explained with their clinical relevance. Recent advances in basic science have established that atherosclerosis is not only a lipid storage disease, but that also inflammation has a fundamental role in all stages of the disease. The molecular events leading to atherosclerosis will be extensively reviewed and described. Further on in this review different modalities and their role in the different stages of atherosclerosis will be discussed. Non-nuclear invasive imaging techniques (intravascular ultrasound, intravascular MRI, intracoronary angioscopy and intravascular optical coherence tomography) and non-nuclear non-invasive imaging techniques (ultrasound with Doppler flow, electron-bean computed tomography, coronary computed tomography angiography, MRI and coronary artery MR angiography) will be reviewed. After that we focus on nuclear imaging techniques for detecting atherosclerotic plaques, divided into three groups: atherosclerotic lesion components, inflammation and thrombosis. This emerging area of nuclear imaging techniques can provide measures of biological activity of atherosclerotic plaques, thereby improving the prediction of clinical events. As we will see in the future perspectives, at present, there is no special tracer that can be called the diagnostic tool to diagnose prospective stroke or infarction in patients. Nevertheless, we expect such a tracer to be developed in the next few years and maybe, theoretically, it could even be used for targeted therapy (in the form of a beta-emitter) to combat

  19. [Lipoproteins, free radicals and atherosclerosis].

    PubMed

    Manso, C

    1990-10-01

    The Author reviews vascular, lipidic and oxidative factors in the genesis of atherosclerosis. He admits the possibility that an alteration in the arterial wall, an increase in circulating lipids or an oxidative stress may influence the precocity of atherosclerosis. The transport of lipoperoxides or of oxidized cholesterol by lipoproteins renders them toxic and susceptible to aggravate atherosclerosis. PMID:2291852

  20. 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. PMID:26438419

  1. Blood Pressure Response to Zofenopril or Irbesartan Each Combined with Hydrochlorothiazide in High-Risk Hypertensives Uncontrolled by Monotherapy: A Randomized, Double-Blind, Controlled, Parallel Group, Noninferiority Trial

    PubMed Central

    Malacco, Ettore; Omboni, Stefano; Parati, Gianfranco

    2015-01-01

    In this randomized, double-blind, controlled, parallel group study (ZENITH), 434 essential hypertensives with additional cardiovascular risk factors, uncontrolled by a previous monotherapy, were treated for 18 weeks with zofenopril 30 or 60 mg plus hydrochlorothiazide (HCTZ) 12.5 mg or irbesartan 150 or 300 mg plus HCTZ. Rate of office blood pressure (BP) response (zofenopril: 68% versus irbesartan: 70%; p = 0.778) and 24-hour BP response (zofenopril: 85% versus irbesartan: 84%; p = 0.781) was similar between the two treatment groups. Cardiac and renal damage was equally reduced by both treatments, whereas the rate of carotid plaque regression was significantly larger with zofenopril. In conclusion, uncontrolled monotherapy treated hypertensives effectively respond to a combination of zofenopril or irbesartan plus a thiazide diuretic, in terms of either BP response or target organ damage progression. PMID:26347187

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

    SciTech Connect

    Cheng, Tain-Junn; Chuu, Jiunn-Jye; Chang, Chia-Yu; Tsai, Wan-Chen; Chen, Kuan-Jung; Guo, How-Ran

    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 lipoprotein 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 increase in HSP

  3. Macrophage phenotypes in atherosclerosis.

    PubMed

    Colin, Sophie; Chinetti-Gbaguidi, Giulia; Staels, Bart

    2014-11-01

    Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype. PMID:25319333

  4. Ectasia and Severe Atherosclerosis

    PubMed Central

    Adiloglu, Ali K.; Can, Rabia; Nazli, Cem; Ocal, Ahmet; Ergene, Oktay; Tinaz, Gulgun; Kisioglu, Nesimi

    2005-01-01

    To date, there has been no convincing evidence for an association between Chlamydia pneumoniae or Helicobacter pylori and ectasia. In this case-control study, we have investigated the association of H. pylori and C. pneumoniae seropositivity with ectasia, severe coronary atherosclerosis, and normal vessels, which were so classified by coronary angiography. We have also evaluated the influence of these infections on inflammatory markers such as high-sensitive C-reactive protein (hsCRP) and interleukin 6 (IL-6). Of the 796 patients undergoing coronary angiography for suspected ischemic heart disease, 244 patients were recruited. Of these, 91 had normal vessels, 88 had 3 or more obstructed vessels, and 65 had ectatic vessels without atherosclerosis. Eighty-seven atherosclerotic patients (98.9%) were positive for C. pneumoniae IgG, as were 64 ectatic patients (98.5%) and 76 controls (83.5%) (P < 0.001). Forty-two atherosclerotic patients (47.7%) were positive for C. pneumoniae IgM, as were 43 ectatic patients (66.2%) and 43 controls (47.3%) (P = 0.036). Seventy-two atherosclerotic patients (81.8%) were positive for H. pylori IgA, as were 26 ectatic patients (40.0%) and 44 controls (48.4%) (P < 0.001). High-sensitive CRP levels were significantly higher in ectatic patients (5.639 mg/L) than in controls (4.390 mg/L) (P = 0.032), and IL-6 levels were significantly higher in atherosclerotic patients (33.92 U/L) than in controls (14.01 U/L) (P < 0.001). Interleukin-6 levels were higher in H. pylori seropositive patients, and hsCRP levels were higher in C. pneumoniae seropositive patients, when compared with seronegatives. We suggest that, as in atherosclerosis, C. pneumoniae infection is related to ectasia, with raised CRP levels. PMID:15902817

  5. Effect of combination tablets containing amlodipine 10 mg and irbesartan 100 mg on blood pressure and cardiovascular risk factors in patients with hypertension

    PubMed Central

    Yagi, Shusuke; Takashima, Akira; Mitsugi, Minoru; Wada, Toshihiro; Hotchi, Junko; Aihara, Ken-ichi; Hara, Tomoya; Ishida, Masayoshi; Fukuda, Daiju; Ise, Takayuki; Yamaguchi, Koji; Tobiume, Takeshi; Iwase, Takashi; Yamada, Hirotsugu; Soeki, Takeshi; Wakatsuki, Tetsuzo; Shimabukuro, Michio; Akaike, Masashi; Sata, Masataka

    2015-01-01

    Background Hypertension is one of the major risk factors for cardiovascular and cerebrovascular disease and mortality. Patients who receive insufficient doses of antihypertensive agents or who are poorly adherent to multidrug treatment regimens often fail to achieve adequate blood pressure (BP) control. The aim of this study was to determine the efficacy of an angiotensin II receptor blocker (ARB) and calcium channel blocker (CCB) combination tablet containing a regular dose of irbesartan (100 mg) and a high dose of amlodipine (10 mg) with regard to lowering BP and other risk factors for cardiovascular disease. Methods We retrospectively evaluated data from 68 patients with essential hypertension whose treatment regimen was changed either from combination treatment with an independent ARB and a low-dose or regular-dose CCB or from a combination tablet of ARB and a low-dose or regular-dose CCB to a combination tablet containing amlodipine 10 mg and irbesartan 100 mg, because of incomplete BP control. Previous treatments did not include irbesartan as the ARB. Results The combination tablet decreased systolic and diastolic BP. In addition, it significantly decreased serum uric acid, low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol levels, independent of the BP-lowering effect. Treatment with the combination tablet did not affect serum triglycerides, plasma glucose, glycated hemoglobin, serum potassium or creatinine levels, or the urinary albumin excretion rate. Conclusion The combination tablet containing amlodipine 10 mg and irbesartan 100 mg had a greater BP-lowering effect than an ARB and a low-dose or regular-dose CCB. In addition, the combination tablet had more favorable effects on serum uric acid, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels in patients with hypertension. PMID:25624765

  6. Neutrophil's weapons in atherosclerosis.

    PubMed

    Chistiakov, Dimitry A; Bobryshev, Yuri V; Orekhov, Alexander N

    2015-12-01

    Neutrophils are important components of immunity associated with inflammatory responses against a broad spectrum of pathogens. These cells could be rapidly activated by proinflammatory stimuli and migrate to the inflamed and infected sites where they release a variety of cytotoxic molecules with antimicrobial activity. Neutrophil antibacterial factors include extracellular proteases, redox enzymes, antimicrobial peptides, and small bioactive molecules. In resting neutrophils, these factors are stored in granules and released upon activation during degranulation. These factors could be also secreted in a neutrophil-derived microparticle-dependent fashion. Neutrophils exhibit a unique property to produce neutrophil extracellular traps (NETs) composed of decondensed chromatin and granular proteins to catch and kill bacteria. Neutrophil-released factors are efficient in inactivation and elimination of pathogens through oxidation-dependent or independent damage of bacterial cells, inactivation and neutralization of virulence factors and other mechanisms. However, in chronic atherosclerosis-associated inflammation, protective function of neutrophils could be impaired and misdirected against own cells. This could lead to deleterious effects and progressive vascular injury. In atherogenesis, a pathogenic role of neutrophils could be especially seen in early stages associated with endothelial dysfunction and induction of vascular inflammation and in late atherosclerosis associated with plaque rupture and atherothrombosis. Assuming a prominent impact of neutrophils in cardiovascular pathology, developing therapeutic strategies targeting neutrophil-specific antigens could have a promising clinical potential. PMID:26551083

  7. Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice.

    PubMed

    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

  8. Immunometabolism of AMPK in insulin resistance and atherosclerosis.

    PubMed

    Fullerton, Morgan D; Steinberg, Gregory R; Schertzer, Jonathan D

    2013-02-25

    Obesity leads to insulin resistance and atherosclerosis, which precede Type 2 diabetes and cardiovascular disease. Immunometabolism addresses how metabolic and inflammatory pathways converge to maintain health and a contemporary problem is determining how obesity-induced inflammation precipitates chronic diseases such as insulin resistance and atherosclerosis. AMP-activated protein kinase (AMPK) is an important serine/threonine kinase well known for regulating metabolic processes and maintaining energy homeostasis. However, both metabolic and immunological AMPK-mediated effects play a role in disease. Pro-inflammatory mediators suppress AMPK activity and hinder lipid oxidation. In addition, AMPK activation curbs inflammation by directly inhibiting pro-inflammatory signaling pathways and limiting the build-up of specific lipid intermediates that elicit immune responses. In the context of obesity and chronic disease, these reciprocal responses involve both immune and metabolic cells. Therefore, the immunometabolism of AMPK-mediated processes and therapeutics should be considered in atherosclerosis and insulin resistance. PMID:22361321

  9. [Major pathogenic links of atherosclerosis].

    PubMed

    Antelava, N A; Pachkoriia, K Z; Kezeli, T D; Nikuradze, N S; Shamkulashvili, G G

    2005-11-01

    The experimental and clinical data concerning pathogenesis of the atherosclerosis are summarized and analyzed in this article. Major concepts that explain initiation and progressive growth of atherosclerosis such as lipid infiltrations, response to disturbing factors, "response on the keeping of particles" and inflammatory processes are discussed. These concepts are considered as base for integral theory of atherosclerosis according which the inflammatory process in atherosclerosis are the result of the universal response reaction of endothelium to the various disturbing risk factors. Chronic inflammation leads to complex cellular and molecular interactions among cells derived from the endothelium, smooth muscle and several blood cell components and causes oxidative stress, proliferation of smooth muscle cells, oxidative modification of LDL, uptake and macrophage foam cell formation, endothelium dysfunction. Major pathogenic links of atherosclerosis, such as inflammation, oxidative stress, oxidative modification of LDL, lipid infiltration, endothelial dysfunction closely interact, forming close vicious circles which leads to metabolic and morphological disturbances, re-modulation of blood vessels, cardiovascular diseases and such complication as cardiac infarction and stroke. Pathogenic peculiarities of atherosclerosis are the theoretic base to the elaboration of therapeutic strategy. Endothelium may be discussed as a new therapeutic target in atherosclerosis. So far as the leukotrienes play an important role in inflammatory processes, it is suggested that the leukotrienes may be as a potential therapeutic target in cardiovascular diseases. PMID:16369071

  10. Hyperhomocysteinemia and atherosclerosis.

    PubMed

    Yang, Fan; Tan, Hong-Mei; Wang, Hong

    2005-04-25

    Arteriosclerosis and its complications, such as heart attack and stroke, are the major causes of death in developed countries. It was believed that age, hyperlipidemia, hypertension, diabetes and smoking are common risk factors for cardiovascular disease. In addition, overwhelming clinical and epidemiological studies have identified homocysteine (Hcy) as a significant and independent risk factor for cardiovascular disease. In healthy individuals, plasma Hcy is between 5 and 10 micromol/L. One cause of severe hypehomocys- teinemia (HHcy) is the deficiency of cystathionine beta-synthase (CBS), which converts Hcy to cystathionine. CBS homozygous deficiency results in severe HHcy with Hcy levels up to 100 to 500 micromol/L. Patients with severe HHcy usually present with neurological abnormalities, premature arteriosclerosis. It has been reported that lowering plasma Hcy improved endothelial dysfunction and reduced incidence of major adverse events after percutaneous coronary intervention. The mechanisms by which Hcy induces atherosclerosis are largely unknown. Several biological mechanisms have been proposed to explain cardiovascular pathological changes associated with HHcy. These include: (1) endothelial cell damage and impaired endothelial function; (2) dysregulation of cholesterol and triglyceride biosynthesis; (3) stimulation of vascular smooth muscle cell proliferation; (4) thrombosis activation and (5) activation of monocytes. Four major biochemical mechanisms have been proposed to explain the vascular pathology of Hcy. These include: (1) autooxidation through the production of reactive oxygen species; (2) hypomethylation by forming SAH, a potent inhibitor of biological transmethylations; (3) nitrosylation by binding to nitric oxide or (4) protein homocysteinylation by incorporating into protein. In summary, our studies, as well as data from other laboratories support the concept that Hcy is causally linked to atherosclerosis, and is not merely associated with

  11. Recent Highlights of ATVB Atherosclerosis

    PubMed Central

    Lu, Hong; Daugherty, Alan

    2015-01-01

    Summary Mechanistic studies over the past decades using in vitro systems, animal models, and human tissues have highlighted the complexity of pathophysiological processes of atherosclerosis. Hypercholesterolemia, as one of the major risk factors for the development and progression of atherosclerosis, is still the focus of many mechanistic studies and the major therapeutic target of atherosclerosis. Although there is a dire need to validate many experimental findings in humans, there is a large number of approaches that have been showing promise for contributing to future therapeutic strategies. PMID:25717174

  12. [PREDICTORS OF ATHEROSCLEROSIS: NEW DEVELOPMENTS].

    PubMed

    Gozhenko, A I; Kotyuzhinskaya, S G; Kovalevskaya, L A

    2014-12-01

    The article describes known atherosclerosis predictors of endothelial origin, which are diagnostic criteria for identifying's early stages of atherosclerosis, and can prevent the development of this disease and are used to monitor the effectiveness of the therapy The authors analyzed the possibility of using heparin as an early marker of atherosclerosis, based on the fact that the inhibition of lipoprotein lipase activity due hyperheparinemia resulting from depletion of mast cells due to endothelial dysfunction, leads to the disorders of lipid transporting system in the form of the resistant hyperlipidemia with the phenomena of dyslipidemia. PMID:26638463

  13. MicroRNAs and atherosclerosis

    PubMed Central

    Madrigal-Matute, Julio; Rotllan, Noemi; Aranda, Juan F.; Fernández-Hernando, Carlos

    2014-01-01

    MicroRNAs (miRNAs) are small (~22nucleotide) sequences of RNA that regulate gene expression at posttranscriptional level. MiRNA/mRNA base pairing complementarity provokes mRNA decay and consequent gene silencing. These endogenous gene expression inhibitors were primarily described in cancer but recent exciting findings have also demonstrated a key role in cardiovascular diseases (CVDs) including atherosclerosis. MiRNAs controls endothelial cell (EC), vascular smooth muscle cell (VSMC) and macrophage functions, and thereby regulate the progression of atherosclerosis. MiRNAs expression is modulated by different stimuli involved in every stage of atherosclerosis and conversely miRNAs modulates several pathways implicated in plaque development such as cholesterol metabolism. In the present review, we focus on the importance of miRNAs in atherosclerosis and we further discuss their potential use as biomarkers and therapeutic targets in CVDs. PMID:23512606

  14. Knockdown of mTOR by lentivirus‑mediated RNA interference suppresses atherosclerosis and stabilizes plaques via a decrease of macrophages by autophagy in apolipoprotein E‑deficient mice.

    PubMed

    Wang, Xiaochuang; Li, Lingxia; Li, Manxiang; Dang, Xiaoyan; Wan, Lin; Wang, Ni; Bi, Xiaoju; Gu, Changwei; Qiu, Suijuan; Niu, Xiaolin; Zhu, Xinye; Wang, Lina

    2013-11-01

    Atherosclerotic plaque destabilization and rupture leads to acute coronary syndromes which cause serious damage to human health worldwide. However, there is currently a lack of efficient therapeutic methods. Mammalian target of rapamycin (mTOR) has been suggested to be involved in the development of atherosclerotic plaques and serves as a therapeutic target. The present study was performed to determine whether RNA interference (RNAi) of mTOR in vivo by LV‑mediated small hairpin RNA (shRNA) was capable of inhibiting the progression of atherosclerotic plaques. LV‑mediated shRNA against mTOR (LV‑shmTOR) was designed and obtained. Male apolipoprotein E‑deficient mice were fed a high‑fat diet and a constrictive collar was placed around the right carotid arteries of these mice to induce plaque formation. Eight weeks after surgery, mice were randomly divided into the mTOR RNA interference (LV‑shmTOR) group, receiving treatment with LV‑mTOR‑shRNA; the LV‑shCON group, receiving treatment with LV‑non‑specific‑shRNA; and the control group, receiving treatment with phosphate‑buffered saline. Following transfection, the mice were sacrificed to evaluate the effects of mTOR expression silencing on atherosclerosis. Transfection of LV‑mTOR‑shRNA markedly inhibited the mRNA and protein expression levels. Knockdown of mTOR ameliorated dysregulated blood lipid metabolism and stabilized aortic atherosclerotic plaques by decreasing the plaque area and increasing the fibrous cap and cap‑to‑core ratio. Furthermore, macrophages were decreased by silencing mTOR in atherosclerotic plaques. In addition, western blot analysis revealed that the knockdown of mTOR increased autophagy‑related protein 13 (Atg13) dephosphorylation and light chain 3‑I/light chain 3‑II (LC3‑I/LC3‑II) ratios, both of which were associated with a high activity of autophagy, suggesting an increase of autophagy in atherosclerotic plaques. Moreover, genes including matrix

  15. Targeting hydrogen sulfide as a promising therapeutic strategy for atherosclerosis.

    PubMed

    Xu, Suowen; Liu, Zhiping; Liu, Peiqing

    2014-03-15

    Physiological concentrations of nitric oxide (NO) and carbon monoxide (CO) have multiple protective effects in the cardiovascular system. Recent studies have implicated hydrogen sulfide (H2S) as a new member of vasculoprotective gasotransmitter family, behaving similarly to NO and CO. H2S has been demonstrated to inhibit multiple key aspects of atherosclerosis, including atherogenic modification of LDL, monocytes adhesion to the endothelial cells, macrophage-derived foam cell formation and inflammation, smooth muscle cell proliferation, neointimal hyperplasia, vascular calcification, and thrombogenesis. H2S also decreases plasma homocysteine levels in experimental animal models. In the human body, H2S production is predominantly catalyzed by cystathionine-β-synthase (CBS) and cystathionine γ-lyase (CSE). CSE is the primary H2S-producing enzyme in the vasculature. Growing evidence suggests that atherosclerosis is associated with vascular CSE/H2S deficiency and that H2S supplementation by exogenous H2S donors (such as NaHS and GYY4137) attenuates, and H2S synthesis suppression by inhibitors (such as D, L-propargylglycine) aggravates the development of atherosclerotic plaques. However, it remains elusive whether CSE deficiency plays a causative role in atherosclerosis. A recent study (Circulation. 2013; 127: 2523-2534) demonstrates that decreased endogenous H2S production by CSE genetic deletion accelerates atherosclerosis in athero-prone ApoE-/- mice, pinpointing that endogenously produced H2S by CSE activation may be of benefit in the prevention and treatment of atherosclerosis. This study will facilitate the development of H2S-based pharmaceuticals with therapeutic applications in atherosclerosis-related cardiovascular diseases. PMID:24491853

  16. Microdomains, Inflammation, and Atherosclerosis.

    PubMed

    Sorci-Thomas, Mary G; Thomas, Michael J

    2016-02-19

    Elevated levels of cholesteryl ester (CE)-enriched apoB containing plasma lipoproteins lead to increased foam cell formation, the first step in the development of atherosclerosis. Unregulated uptake of low-density lipoprotein cholesterol by circulating monocytes and other peripheral blood cells takes place through scavenger receptors and over time causes disruption in cellular cholesterol homeostasis. As lipoproteins are taken up, their CE core is hydrolyzed by liposomal lipases to generate free cholesterol (FC). FC can be either re-esterified and stored as CE droplets or shuttled to the plasma membrane for ATP-binding cassette transporter A1-mediated efflux. Because cholesterol is an essential component of all cellular membranes, some FC may be incorporated into microdomains or lipid rafts. These platforms are essential for receptor signaling and transduction, requiring rapid assembly and disassembly. ATP-binding cassette transporter A1 plays a major role in regulating microdomain cholesterol and is most efficient when lipid-poor apolipoprotein AI (apoAI) packages raft cholesterol into soluble particles that are eventually catabolized by the liver. If FC is not effluxed from the cell, it becomes esterified, CE droplets accumulate and microdomain cholesterol content becomes poorly regulated. This dysregulation leads to prolonged activation of immune cell signaling pathways, resulting in receptor oversensitization. The availability of apoAI or other amphipathic α-helix-rich apoproteins relieves the burden of excess microdomain cholesterol in immune cells allowing a reduction in immune cell proliferation and infiltration, thereby stimulating regression of foam cells in the artery. Therefore, cellular balance between FC and CE is essential for proper immune cell function and prevents chronic immune cell overstimulation and proliferation. PMID:26892966

  17. Atherosclerosis in parrots. A review.

    PubMed

    Bavelaar, F J; Beynen, A C

    2004-06-01

    Atherosclerosis is a common disease in parrots. The disease is found in all common parrot species, but especially in African Grey parrots and Amazons. It is a disease of older birds that is seen in both males and females. The most common sign is sudden death, but clinical symptoms that can be found include dyspnea, lethargy and nervous signs, such as paresis and collapses. Because the clinical signs are seldomly seen, it is difficult to diagnose atherosclerosis and therefore it is mostly an unexpected finding at necropsy. Age and species are determinants of atherosclerosis in parrots. Suggested risk factors include an elevated plasma cholesterol level, diet composition, social stress and inactivity, but research is needed to confirm this. PMID:15230050

  18. How Can Atherosclerosis Be Prevented or Delayed?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Can Atherosclerosis Be Prevented or Delayed? Taking action to control ... Rate This Content: NEXT >> Featured Video What is atherosclerosis? 05/22/2014 Describes how the build-up ...

  19. Endoplasmic reticulum stress and atherosclerosis

    PubMed Central

    Hotamisligil, Gökhan S

    2010-01-01

    Atherosclerosis and related cardiovascular diseases represent one of the greatest threats to human health worldwide. Despite important progress in prevention and treatment, these conditions still account for one third of all deaths annually. Often presented together with obesity, insulin resistance and type 2 diabetes, these chronic diseases are strongly influenced by pathways that lie at the interface of chronic inflammation and nutrient metabolism. Here I discuss recent advances in the study of endoplasmic reticulum stress as one mechanism that links immune response with nutrient sensing in the pathogenesis of atherosclerosis and its complications. PMID:20376052

  20. Spectroscopic and spectrofluorimetric studies on the interaction of irbesartan with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and iodine.

    PubMed

    Ganesh, K; Balraj, C; Elango, K P

    2011-09-01

    Raman, UV-vis, 1H NMR, FT-IR, mass and fluorescence spectral techniques were employed to investigate the mechanism of interaction of irbesartan (IRB) drug with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and iodine. Interaction of IRB with iodine yields triiodide ion and its formation was confirmed by electronic and Raman spectra. The peaks appeared in Raman spectrum of the isolated product at 143, 113 and 76 cm(-1) are assigned to νas(I-I), νs(I-I) and δ(I3-) respectively, confirmed the presence of I3- ion. The interaction of DDQ with irbesartan was found to proceed through the formation of outer complex and its conversion to the CT complex. Formation constant (K), molar extinction coefficient (ɛ) and thermodynamic properties ΔH#, ΔS# and ΔG# were determined and discussed. Fluorescence quenching studies indicated that the interaction between the IRB and the acceptors are spontaneous and the IRB-DDQ interaction is found to be stronger than that the other system. Solvent variation studies indicated that the binding constant increased with an increase in polarity of the medium. PMID:21684193

  1. [The infection theory in atherosclerosis].

    PubMed

    Capron, L; Wyplosz, B

    1998-10-01

    Atherosclerosis displays all the features of a chronic inflammatory process. Aggressions that ignite and fuel atherosclerotic inflammation warrant keen attention. Infection is a potential clue, implying microbes with certain discrete characteristics: a wide epidemiologic distribution, a tropism for the arterial wall, and an aptitude for persistence, latency and recurrence. The infectious theory has built up from the pioneering observations of Fabricant et al. (1978) on the arterial lesions provoked by Marek's disease herpesvirus in chicken. So far one virus (cytomegalovirus) and two bacteria (Chlamydia pneumoniae and Helicobacter pylori) have been implicated in human atherosclerosis, based upon experimental, sero-epidemiologic, or pathologic evidence. None of these potential contributions has yet been established beyond reasonable doubt. However, grounded on the suspicion about C. pneumoniae, provocative therapeutic evidence has added recently: according to two pilot studies, treatment with macrolide antibiotics appear to improve the prognosis of coronary artery disease in both its chronic and acute forms. If ongoing larger-scale studies confirm these preliminary results, a novel era will open in our capacity for explaining, treating and preventing atherosclerosis. An infectious aetiology of atherosclerosis is now to be considered earnestly, and is already being submitted to more intensive clinical and experimental investigation. PMID:9833076

  2. Vitamin K Intake and Atherosclerosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It has been hypothesized that insufficient intake of vitamin K may increase soft tissue calcification due to impaired gamma-carboxylation of the vitamin K-dependent protein, matrix gamma-carboxyglutamic acid (MGP). The evidence to support this putative role of vitamin K intake in atherosclerosis is ...

  3. Pathway analysis of coronary atherosclerosis.

    PubMed

    King, Jennifer Y; Ferrara, Rossella; Tabibiazar, Raymond; Spin, Joshua M; Chen, Mary M; Kuchinsky, Allan; Vailaya, Aditya; Kincaid, Robert; Tsalenko, Anya; Deng, David Xing-Fei; Connolly, Andrew; Zhang, Peng; Yang, Eugene; Watt, Clifton; Yakhini, Zohar; Ben-Dor, Amir; Adler, Annette; Bruhn, Laurakay; Tsao, Philip; Quertermous, Thomas; Ashley, Euan A

    2005-09-21

    Large-scale gene expression studies provide significant insight into genes differentially regulated in disease processes such as cancer. However, these investigations offer limited understanding of multisystem, multicellular diseases such as atherosclerosis. A systems biology approach that accounts for gene interactions, incorporates nontranscriptionally regulated genes, and integrates prior knowledge offers many advantages. We performed a comprehensive gene level assessment of coronary atherosclerosis using 51 coronary artery segments isolated from the explanted hearts of 22 cardiac transplant patients. After histological grading of vascular segments according to American Heart Association guidelines, isolated RNA was hybridized onto a customized 22-K oligonucleotide microarray, and significance analysis of microarrays and gene ontology analyses were performed to identify significant gene expression profiles. Our studies revealed that loss of differentiated smooth muscle cell gene expression is the primary expression signature of disease progression in atherosclerosis. Furthermore, we provide insight into the severe form of coronary artery disease associated with diabetes, reporting an overabundance of immune and inflammatory signals in diabetics. We present a novel approach to pathway development based on connectivity, determined by language parsing of the published literature, and ranking, determined by the significance of differentially regulated genes in the network. In doing this, we identify highly connected "nexus" genes that are attractive candidates for therapeutic targeting and followup studies. Our use of pathway techniques to study atherosclerosis as an integrated network of gene interactions expands on traditional microarray analysis methods and emphasizes the significant advantages of a systems-based approach to analyzing complex disease. PMID:15942018

  4. ATP-binding cassette transporters, atherosclerosis, and inflammation.

    PubMed

    Westerterp, Marit; Bochem, Andrea E; Yvan-Charvet, Laurent; Murphy, Andrew J; Wang, Nan; Tall, Alan R

    2014-01-01

    Although recent genome-wide association studies have called into question the causal relationship between high-density lipoprotein (HDL) cholesterol levels and cardiovascular disease, ongoing research in animals and cells has produced increasing evidence that cholesterol efflux pathways mediated by ATP-binding cassette (ABC) transporters and HDL suppress atherosclerosis. These differing perspectives may be reconciled by a modified HDL theory that emphasizes the antiatherogenic role of cholesterol flux pathways, initiated in cells by ABC transporters. ABCA1 and ABCG1 control the proliferation of hematopoietic stem and multipotential progenitor cells in the bone marrow and hematopoietic stem and multipotential progenitor cell mobilization and extramedullary hematopoiesis in the spleen. Thus, activation of cholesterol efflux pathways by HDL infusions or liver X receptor activation results in suppression of hematopoietic stem and multipotential progenitor cell mobilization and extramedullary hematopoiesis, leading to decreased production of monocytes and neutrophils and suppression of atherosclerosis. In addition, macrophage-specific knockout of transporters has confirmed their role in suppression of inflammatory responses in the arterial wall. Recent studies have also shown that ABCG4, a close relative of ABCG1, controls platelet production, atherosclerosis, and thrombosis. ABCG4 is highly expressed in megakaryocyte progenitors, where it promotes cholesterol efflux to HDL and controls the proliferative responses to thrombopoietin. Reconstituted HDL infusions act in an ABCG4-dependent fashion to limit hypercholesterolemia-driven excessive platelet production, thrombosis, and atherogenesis, as occurs in human myeloproliferative syndromes. Activation of ABC transporter-dependent cholesterol efflux pathways in macrophages, hematopoietic stem and multipotential progenitor cells, or platelet progenitors by reconstituted HDL infusion or liver X receptor activation remain

  5. CD8{sup +}CD25{sup +} T cells reduce atherosclerosis in apoE(−/−) mice

    SciTech Connect

    Zhou, Jianchang; Dimayuga, Paul C.; Zhao, Xiaoning; Yano, Juliana; Lio, Wai Man; Trinidad, Portia; Honjo, Tomoyuki; Cercek, Bojan; Shah, Prediman K.; Chyu, Kuang-Yuh

    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. 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.

  6. Plasmacytoid Dendritic Cells in Atherosclerosis

    PubMed Central

    Döring, Yvonne; Zernecke, Alma

    2012-01-01

    Atherosclerosis, a chronic inflammatory disease of the vessel wall and the underlying cause of cardiovascular disease, is initiated and maintained by innate and adaptive immunity. Accumulating evidence suggests an important contribution of autoimmune responses to this disease. Plasmacytoid dendritic cells (pDCs), a specialized cell type known to produce large amounts of type I interferons (IFNs) in response to bacterial and viral infections, have recently been revealed to play important roles in atherosclerosis. For example, the development of autoimmune complexes consisting of self-DNA and antimicrobial peptides, which trigger chronic type I IFN production by pDCs, promote early atherosclerotic lesion formation. pDCs and pDC-derived type I IFNs can also induce the maturation of conventional DCs and macrophages, and the development of autoreactive B cells and antibody production. These mechanisms, known to play a role in the pathogenesis of other autoimmune diseases such as systemic lupus erythematosus and psoriasis, may also affect the development and progression of atherosclerotic lesion formation. This review discusses emerging evidence showing a contribution of pDCs in the onset and progression of atherosclerosis. PMID:22754539

  7. Immunity, atherosclerosis and cardiovascular disease

    PubMed Central

    2013-01-01

    Atherosclerosis, the major cause of cardiovascular disease (CVD), is a chronic inflammatory condition with immune competent cells in lesions producing mainly pro-inflammatory cytokines. Dead cells and oxidized forms of low density lipoproteins (oxLDL) are abundant. The major direct cause of CVD appears to be rupture of atherosclerotic plaques. oxLDL has proinflammatory and immune-stimulatory properties, causes cell death at higher concentrations and contains inflammatory phospholipids with phosphorylcholine (PC) as an interesting epitope. Antibodies against PC (anti-PC) may be atheroprotective, one mechanism being anti-inflammatory. Bacteria and virus have been discussed, but it has been difficult to find direct evidence, and antibiotic trials have not been successful. Heat shock proteins could be one major target for atherogenic immune reactions. More direct causes of plaque rupture include pro-inflammatory cytokines, chemokines, and lipid mediators. To prove that inflammation is a cause of atherosclerosis and CVD, clinical studies with anti-inflammatory and/or immune-modulatory treatment are needed. The potential causes of immune reactions and inflammation in atherosclerosis and how inflammation can be targeted therapeutically to provide novel treatments for CVD are reviewed. PMID:23635324

  8. Intestinal Microbiota Metabolism and Atherosclerosis

    PubMed Central

    Liu, Tian-Xing; Niu, Hai-Tao; Zhang, Shu-Yang

    2015-01-01

    Objective: This review aimed to summarize the relationship between intestinal microbiota metabolism and cardiovascular disease (CVD) and to propose a novel CVD therapeutic target. Data Sources: This study was based on data obtained from PubMed and EMBASE up to June 30, 2015. Articles were selected using the following search terms: “Intestinal microbiota”, “trimethylamine N-oxide (TMAO)”, “trimethylamine (TMA)”, “cardiovascular”, and “atherosclerosis”. Study Selection: Studies were eligible if they present information on intestinal microbiota metabolism and atherosclerosis. Studies on TMA-containing nutrients were also included. Results: A new CVD risk factor, TMAO, was recently identified. It has been observed that several TMA-containing compounds may be catabolized by specific intestinal microbiota, resulting in TMA release. TMA is subsequently converted to TMAO in the liver. Several preliminary studies have linked TMAO to CVD, particularly atherosclerosis; however, the details of this relationship remain unclear. Conclusions: Intestinal microbiota metabolism is associated with atherosclerosis and may represent a promising therapeutic target with respect to CVD management. PMID:26481750

  9. 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. PMID:26518635

  10. SIRT1 improves VSMC functions in atherosclerosis.

    PubMed

    Zhang, Ming-Jie; Zhou, Yi; Chen, Lei; Wang, Xu; Long, Chun-Yan; Pi, Yan; Gao, Chang-Yue; Li, Jing-Cheng; Zhang, Li-Li

    2016-05-01

    Despite advancements in diagnosis and treatment of cardiovascular diseases (CVDs), the morbidity and mortality of CVDs are still rising. Atherosclerosis is a chronic inflammatory disease contributing to multiple CVDs. Considering the complexity and severity of atherosclerosis, it is apparent that exploring the mechanisms of atherosclerotic formation and seeking new therapies for patients with atherosclerosis are required to overcome the heavy burden of CVDs on the quality and length of life of the global population. Vascular smooth muscle cells (VSMCs) play a dominant role in functional and structural changes of the arterial walls in response to atherogenic factors. Therefore, improvement of VSMC functions will slow down the development of atherosclerosis to a large extent. Given its protective performances on regulation of cholesterol metabolism and inflammatory responses, SIRT1 has long been known as an anti-atherosclerosis factor. In this review, we focus on the effects of SIRT1 on VSMC functions and thereby the development of atherosclerosis. PMID:27080738

  11. Sex Differences in Inflammation During Atherosclerosis

    PubMed Central

    Fairweather, DeLisa

    2014-01-01

    Atherosclerosis is the leading cause of death in the United States and worldwide, yet more men die from atherosclerosis than women, and at a younger age. Women, on the other hand, mainly develop atherosclerosis following menopause, and particularly if they have one or more autoimmune diseases, suggesting that the immune mechanisms that increase disease in men are different from those in women. The key processes in the pathogenesis of atherosclerosis are vascular inflammation, lipid accumulation, intimal thickening and fibrosis, remodeling, and plaque rupture or erosion leading to myocardial infarction and ischemia. Evidence indicates that sex hormones alter the immune response during atherosclerosis, resulting in different disease phenotypes according to sex. Women, for example, respond to infection and damage with increased antibody and autoantibody responses, while men have elevated innate immune activation. This review describes current knowledge regarding sex differences in the inflammatory immune response during atherosclerosis. Understanding sex differences is critical for improving individualized medicine. PMID:25983559

  12. A multimodal Darwinian strategy for alleviating the atherosclerosis pandemic.

    PubMed

    Mathew, Geetha; Thambi, Magith; Unnikrishnan, M K

    2014-02-01

    The conflict between our 'primitive' genes and 'modern' lifestyle probably lies at the root of several disorders that afflict modern man. Atherosclerosis, which is relatively unknown among contemporary hunter-gatherer populations, has reached pandemic proportions in recent times. Being an evolutionary problem with several inter-related pathologies, current therapeutic strategy for treating atherosclerosis has inherent limitations. Reviewing evolution-linked risk factors suggests that there are four aspects to the etiology of atherosclerosis namely, decreased intestinal parasitism, oversensitivity of evolutionarily redundant mast cells, chronic underactivation of AMPK (cellular energy sensor) and a deficiency of vitamin D. A combination of these four causes appear to have precipitated the atherosclerosis pandemic in modern times. Man and worms co-existed symbiotically in the past. Massive de-worming campaigns could have disrupted this symbiosis, increasing nutritional availability to man (pro-obesity) at the cost of decreased immunotolerance (pro-atherogenicity). A reduction in helminth-induced chronic TH2 activation could also have enhanced TH1 polarization, eventually disrupting the reciprocal regulation of TH1/TH2 balance and resulting in atherosclerosis. The riddance of helminth infestations may have rendered mast cells immunologically redundant, making them oversensitive to inflammatory stimuli, thereby playing a pro-atherogenic role. AMPK activation exerts pleiotropic anti-atherogenic effects, such as suppression of fatty acid, cholesterol, protein synthesis, reduction of vascular smooth muscle proliferation, etc. As energy deficit is the chief stimulus for AMPK activation, the over-nourished modern man appears to be suffering from chronic underactivation of AMPK, legitimising the unrivalled supremacy of metformin, the oldest prescribed antidiabetic drug. The fact that humans evolved in the sunny tropics suggests that humans are selected for high vitamin D

  13. 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

  14. Cholesterol-Lowering Atherosclerosis Study (CLAS)

    ClinicalTrials.gov

    2013-12-12

    Arterial Occlusive Diseases; Cardiovascular Diseases; Carotid Artery Diseases; Cerebral Arteriosclerosis; Cerebrovascular Disorders; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Myocardial Ischemia; Atherosclerosis

  15. Production of β -cyclodextrin from pH and thermo stable Cyclodextrin Glycosyl Transferase, obtained from Arthrobacter mysorens and its evaluation as a drug carrier for Irbesartan.

    PubMed

    Rajesh, Y; Narayanan, K; Reddy, M Sreenivasa; Bhaskar, Vijaya K; Shenoy, G Gautham; Subrahmanyam, V M; Rao, J Venkata

    2015-01-01

    Cyclodextrins (CDs) are carrier molecules produced by cyclization of α-1,4-glucans by Cyclodextrin Glycosyl Transferase (CGTase). These torus shaped molecules have hydrophobic cavity and hydrophilic shell making them useful in pharmaceutical, food, textile, pesticide and cosmetic industries. In this study, culture conditions for the production of CGTase by organism belonging to Arthrobacter genus obtained from a paddy field soil were optimized by single parameter mode. Soluble starch, yeast extract and magnesium sulphate played an important role in CGTase production. Percentage increase in CGTase yield under optimized conditions was 396.77%. The enzyme precipitated by 60% ammonium sulphate was purified using DEAE-sepharose. The molecular weight of the purified protein as determined by SDS-PAGE was 75 kDa. Purified CGTase was thermostable and stable over a wide pH range. Dissolution studies on β -cyclodextrin-Irbesartan complex revealed that β -CDs formed were useful in preparing immediate release oral dosage forms. PMID:25901452

  16. Cathepsin G activity lowers plasma LDL and reduces atherosclerosis

    PubMed Central

    Wang, Jing; Sjöberg, Sara; Tang, Ting-Ting; Öörni, Katariina; Wu, Wenxue; Liu, Conglin; Secco, Blandine; Tia, Viviane; Sukhova, Galina K.; Fernandes, Cleverson; Lesner, Adam; Kovanen, Petri T.; Libby, Peter; Cheng, Xiang; Shi, Guo-Ping

    2014-01-01

    Cathepsin G (CatG), a serine protease present in mast cells and neutrophils, can produce angiotensin-II (Ang-II) and degrade elastin. Here we demonstrate increased CatG expression in smooth muscle cells (SMCs), endothelial cells (ECs), macrophages, and T cells from human atherosclerotic lesions. In low-density lipoprotein (LDL) receptor-deficient (Ldlr−/−) mice, the absence of CatG reduces arterial wall elastin degradation and attenuates early atherosclerosis when mice consume a Western diet for 3 months. When mice consume this diet for 6 months, however, CatG deficiency exacerbates atherosclerosis in aortic arch without affecting lesion inflammatory cell content or extracellular matrix accumulation, but raises plasma total cholesterol and LDL levels without affecting high-density lipoprotein (HDL) or triglyceride levels. Patients with atherosclerosis also have significantly reduced plasma CatG levels that correlate inversely with total cholesterol (r= −0.535, P<0.0001) and LDL cholesterol (r= −0.559, P<0.0001), but not with HDL cholesterol (P=0.901) or triglycerides (P=0.186). Such inverse correlations with total cholesterol (r= −0.504, P<0.0001) and LDL cholesterol (r= −0.502, P<0.0001) remain significant after adjusting for lipid lowering treatments among this patient population. Human CatG degrades purified human LDL, but not HDL. This study suggests that CatG promotes early atherogenesis through its elastinolytic activity, but suppresses late progression of atherosclerosis by degrading LDL without affecting HDL or triglycerides. PMID:25092171

  17. What Are the Signs and Symptoms of Atherosclerosis?

    MedlinePlus

    ... Twitter. What Are the Signs and Symptoms of Atherosclerosis? Atherosclerosis usually doesn't cause signs and symptoms ... Rate This Content: NEXT >> Featured Video What is atherosclerosis? 05/22/2014 Describes how the build-up ...

  18. Oxyradical Stress, Endocannabinoids, and Atherosclerosis

    PubMed Central

    Matthews, Anberitha T.; Ross, Matthew K.

    2015-01-01

    Atherosclerosis is responsible for most cardiovascular disease (CVD) and is caused by several factors including hypertension, hypercholesterolemia, and chronic inflammation. Oxidants and electrophiles have roles in the pathophysiology of atherosclerosis and the concentrations of these reactive molecules are an important factor in disease initiation and progression. Overactive NADPH oxidase (Nox) produces excess superoxide resulting in oxidized macromolecules, which is an important factor in atherogenesis. Although superoxide and reactive oxygen species (ROS) have obvious toxic properties, they also have fundamental roles in signaling pathways that enable cells to adapt to stress. In addition to inflammation and ROS, the endocannabinoid system (eCB) is also important in atherogenesis. Linkages have been postulated between the eCB system, Nox, oxidative stress, and atherosclerosis. For instance, CB2 receptor-evoked signaling has been shown to upregulate anti-inflammatory and anti-oxidative pathways, whereas CB1 signaling appears to induce opposite effects. The second messenger lipid molecule diacylglycerol is implicated in the regulation of Nox activity and diacylglycerol lipase β (DAGLβ) is a key biosynthetic enzyme in the biosynthesis eCB ligand 2-arachidonylglycerol (2-AG). Furthermore, Nrf2 is a vital transcription factor that protects against the cytotoxic effects of both oxidant and electrophile stress. This review will highlight the role of reactive oxygen species (ROS) in intracellular signaling and the impact of deregulated ROS-mediated signaling in atherogenesis. In addition, there is also emerging knowledge that the eCB system has an important role in atherogenesis. We will attempt to integrate oxidative stress and the eCB system into a conceptual framework that provides insights into this pathology. PMID:26702404

  19. Therapeutic approaches to drug targets in atherosclerosis.

    PubMed

    Jamkhande, Prasad G; Chandak, Prakash G; Dhawale, Shashikant C; Barde, Sonal R; Tidke, Priti S; Sakhare, Ram S

    2014-07-01

    Non-communicable diseases such as cancer, atherosclerosis and diabetes are responsible for major social and health burden as millions of people are dying every year. Out of which, atherosclerosis is the leading cause of deaths worldwide. The lipid abnormality is one of the major modifiable risk factors for atherosclerosis. Both genetic and environmental components are associated with the development of atherosclerotic plaques. Immune and inflammatory mediators have a complex role in the initiation and progression of atherosclerosis. Understanding of all these processes will help to invent a range of new biomarkers and novel treatment modalities targeting various cellular events in acute and chronic inflammation that are accountable for atherosclerosis. Several biochemical pathways, receptors and enzymes are involved in the development of atherosclerosis that would be possible targets for improving strategies for disease diagnosis and management. Earlier anti-inflammatory or lipid-lowering treatments could be useful for alleviating morbidity and mortality of atherosclerotic cardiovascular diseases. However, novel drug targets like endoglin receptor, PPARα, squalene synthase, thyroid hormone analogues, scavenger receptor and thyroid hormone analogues are more powerful to control the process of atherosclerosis. Therefore, the review briefly focuses on different novel targets that act at the starting stage of the plaque form to the thrombus formation in the atherosclerosis. PMID:25061401

  20. Rapid Progression of Coronary Atherosclerosis: A Review

    PubMed Central

    Shah, Priyank; Bajaj, Sharad; Virk, Hartaj; Bikkina, Mahesh; Shamoon, Fayez

    2015-01-01

    Atherosclerosis is chronic disease, the prevalence of which has increased steadily as the population ages. Vascular injury is believed to be critical initiating event in pathogenesis of spontaneous atherosclerosis. Syndrome of accelerated atherosclerosis has been classically described in patients undergoing heart transplantation, coronary artery bypass graft, and percutaneous transluminal coronary angioplasty. In contrast to spontaneous atherosclerosis, denuding endothelial injury followed by thrombus formation and initial predominant smooth muscle cell proliferation is believed to be playing a significant role in accelerated atherosclerosis. There is no universal definition of rapid progression of atherosclerosis. However most studies describing the phenomenon have used the following definition: (i) > or = 10% diameter reduction of at least one preexisting stenosis > or = 50%, (ii) > or = 30% diameter reduction of a preexisting stenosis <50%, and (iii) progression of a lesion to total occlusion within few months. Recent studies have described the role of coronary vasospasm, human immunodeficiency virus, various inflammatory markers, and some genetic mutations as predictors of rapid progression of atherosclerosis. As research in the field of vascular biology continues, more factors are likely to be implicated in the pathogenesis of rapid progression of atherosclerosis. PMID:26823982

  1. 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.

  2. Quantification of carotid vessel atherosclerosis

    NASA Astrophysics Data System (ADS)

    Chiu, Bernard; Egger, Micaela; Spence, J. D.; Parraga, Grace; Fenster, Aaron

    2006-03-01

    Atherosclerosis is characterized by the development of plaques in the arterial wall, which ultimately leads to heart attacks and stroke. 3D ultrasound (US) has been used to screen patients' carotid arteries. Plaque measurements obtained from these images may aid in the management and monitoring of patients, and in evaluating the effect of new treatment options. Different types of measures for ultrasound phenotypes of atherosclerosis have been proposed. Here, we report on the development and application of a method used to analyze changes in carotid plaque morphology from 3D US images obtained at two different time points. We evaluated our technique using manual segmentations of the wall and lumen of the carotid artery from images acquired in two US scanning sessions. To incorporate the effect of intraobserver variability in our evaluation, manual segmentation was performed five times each for the arterial wall and lumen. From this set of five segmentations, the mean wall and lumen surfaces were reconstructed, with the standard deviation at each point mapped onto the surfaces. A correspondence map between the mean wall and lumen surfaces was then established, and the thickness of the atherosclerotic plaque at each point in the vessel was estimated to be the distance between each correspondence pairs. The two-sample Student's t-test was used to judge whether the difference between the thickness values at each pair corresponding points of the arteries in the two 3D US images was statistically significant.

  3. Role of LCAT in Atherosclerosis.

    PubMed

    Ossoli, Alice; Simonelli, Sara; Vitali, Cecilia; Franceschini, Guido; Calabresi, Laura

    2016-01-01

    Lecithin:cholesterol acyltransferase (LCAT) is the only enzyme capable of esterifying cholesterol in plasma, thus determining the maturation of high-density lipoproteins. Because it maintains an unesterified cholesterol gradient between peripheral cells and extracellular acceptors, for a long time, LCAT has been considered as a key enzyme in reverse cholesterol transport. However, despite the fact that it has been more than 50 years since the identification of LCAT, the role of this enzyme in the pathogenesis of atherosclerosis is still debated. A number of studies have been conducted in different animal models, with contradictory results. Studies in humans, in particular in the general population, in subjects at high cardiovascular risk, and in carriers of genetic LCAT deficiency in an excellent model to evaluate the correlation between the reduction of LCAT activity and atherosclerosis also gave conflicting results. This review provides a comprehensive overview of the controversial findings obtained in animals and humans, strengthening the necessity of further investigation to establish how LCAT could be regulated in a promising therapeutic strategy to reduce cardiovascular risk. PMID:26607351

  4. The roles of macrophage autophagy in atherosclerosis

    PubMed Central

    Shao, Bo-zong; Han, Bin-ze; Zeng, Yan-xia; Su, Ding-feng; Liu, Chong

    2016-01-01

    Although various types of drugs and therapies are available to treat atherosclerosis, it remains a major cause of mortality throughout the world. Macrophages are the major source of foam cells, which are hallmarks of atherosclerotic lesions. Consequently, the roles of macrophages in the pathophysiology of atherosclerosis are increasingly investigated. Autophagy is a self-protecting cellular catabolic pathway. Since its discovery, autophagy has been found to be associated with a variety of diseases, including cardiovascular diseases, malignant tumors, neurodegenerative diseases, and immune system disorders. Accumulating evidence demonstrates that autophagy plays an important role in inhibiting inflammation and apoptosis, and in promoting efferocytosis and cholesterol efflux. These facts suggest the induction of autophagy may be exploited as a potential strategy for the treatment of atherosclerosis. In this review we mainly discuss the relationship between macrophage autophagy and atherosclerosis and the molecular mechanisms, as well as the recent advances in targeting the process of autophagy to treat atherosclerosis. PMID:26750103

  5. Vasa Vasorum in Atherosclerosis and Clinical Significance

    PubMed Central

    Xu, Junyan; Lu, Xiaotong; Shi, Guo-Ping

    2015-01-01

    Atherosclerosis is a chronic inflammatory disease that leads to several acute cardiovascular complications with poor prognosis. For decades, the role of the adventitial vasa vasorum (VV) in the initiation and progression of atherosclerosis has received broad attention. The presence of VV neovascularization precedes the apparent symptoms of clinical atherosclerosis. VV also mediates inflammatory cell infiltration, intimal thickening, intraplaque hemorrhage, and subsequent atherothrombosis that results in stroke or myocardial infarction. Intraplaque neovessels originating from VV can be immature and hence susceptible to leakage, and are thus regarded as the leading cause of intraplaque hemorrhage. Evidence supports VV as a new surrogate target of atherosclerosis evaluation and treatment. This review provides an overview into the relationship between VV and atherosclerosis, including the anatomy and function of VV, the stimuli of VV neovascularization, and the available underlying mechanisms that lead to poor prognosis. We also summarize translational researches on VV imaging modalities and potential therapies that target VV neovascularization or its stimuli. PMID:26006236

  6. Atherosclerosis

    MedlinePlus

    ... disease in which plaque builds up inside your arteries. Plaque is a sticky substance made up of ... blood. Over time, plaque hardens and narrows your arteries. That limits the flow of oxygen-rich blood ...

  7. Atherosclerosis

    MedlinePlus

    ... heart health as EPA and DHA. Red yeast rice. A common seasoning in Asian countries, red yeast rice may help reduce the amount of cholesterol your ... Talk to your doctor before taking red yeast rice, especially if you take another cholesterol-lowering medicine ...

  8. Platelets and the complement cascade in atherosclerosis

    PubMed Central

    Patzelt, Johannes; Verschoor, Admar; Langer, Harald F.

    2015-01-01

    Atherosclerosis and its late sequels are still the number one cause of death in western societies. Platelets are a driving force not only during the genesis of atherosclerosis, but especially in its late stages, as evidenced by complications such as arterial thrombosis, myocardial infarction, and ischemic stroke. Atherosclerosis is increasingly recognized as an inflammatory disease, influenced by various immune mechanisms. The complement system is part of our innate immune system, and its diverse roles in atherosclerosis have become evident over the past years. In this review we identify points of intersection between platelets and the complement system and discuss their relevance for atherosclerosis. Specifically, we will focus on roles for platelets in the onset as well as progression of the disease, a possible dual role for complement in the genesis and development of atherosclerosis, and review emerging literature revealing previously unrecognized cross-talk between platelets and the complement system and discuss its possible impact for atherosclerosis. Finally, we identify limitations of current research approaches and discuss perspectives of complement modulation in the control of the disease. PMID:25784879

  9. Hypercholesterolemia links hematopoiesis with atherosclerosis.

    PubMed

    Soehnlein, Oliver; Swirski, Filip K

    2013-03-01

    Atherosclerosis is characterized by the progressive accumulation of lipids and leukocytes in the arterial wall. Leukocytes such as macrophages accumulate oxidized lipoproteins in the growing atheromata and give rise to foam cells, which can then contribute to the necrotic core of lesions. Lipids and leukocytes also interact in other important ways. In experimental models, systemic hypercholesterolemia is associated with severe neutrophilia and monocytosis. Recent evidence indicates that cholesterol-sensing pathways control the proliferation of hematopoietic stem-cell progenitors. Here we review some of the studies that are forging this particular link between metabolism and inflammation, and propose several strategies that could target this axis for the treatment of cardiovascular disease. PMID:23228326

  10. Vasoprotective Effects of Urocortin 1 against Atherosclerosis In Vitro and In Vivo

    PubMed Central

    Shirai, Remina; Watanabe, Rena; Yamamoto, Keigo; Watanabe, Kaho; Nohtomi, Kyoko; Hirano, Tsutomu; Watanabe, Takuya

    2014-01-01

    Aim Atherosclerosis is the complex lesion that consists of endothelial inflammation, macrophage foam cell formation, vascular smooth muscle cell (VSMC) migration and proliferation, and extracellular matrix production. Human urocortin 1 (Ucn1), a 40-amino acid peptide member of the corticotrophin-releasing factor/urotensin I family, has potent cardiovascular protective effects. This peptide induces potent and long-lasting hypotension and coronary vasodilation. However, the relationship of Ucn1 with atherosclerosis remains unclear. The present study was performed to clarify the effects of Ucn1 on atherosclerosis. Methods We assessed the effects of Ucn1 on the inflammatory response and proliferation of human endothelial cells (ECs), human macrophage foam cell formation, migration and proliferation of human VSMCs, extracellular matrix expression in VSMCs, and the development of atherosclerosis in apolipoprotein E-deficient (Apoe−/−) mice. Results Ucn1 significantly suppressed cell proliferation without inducing apoptosis, and lipopolysaccharide-induced up-regulation of monocyte chemoattractant protein-1 and intercellular adhesion molecule-1 in human ECs. Ucn1 significantly reduced oxidized low-density lipoprotein-induced foam cell formation with a significant down-regulation of CD36 and acyl-CoA:cholesterol acyltransferase 1 in human monocyte-derived macrophages. Ucn1 significantly suppressed the migration and proliferation of human VSMCs and increased the activities of matrix metalloproteinase-2 (MMP2) and MMP9 in human VSMCs. Intraperitoneal injection of Ucn1 into Apoe−/− mice for 4 weeks significantly retarded the development of aortic atherosclerotic lesions. Conclusions This study provided the first evidence that Ucn1 prevents the development of atherosclerosis by suppressing EC inflammatory response and proliferation, macrophage foam cell formation, and VSMC migration and proliferation. Thus, Ucn1 could serve as a novel therapeutic target for

  11. CLI-095 decreases atherosclerosis by modulating foam cell formation in apolipoprotein E-deficient mice

    PubMed Central

    WANG, XIAO-QING; WAN, HUI-QING; WEI, XIAN-JING; ZHANG, YING; QU, PENG

    2016-01-01

    Toll-like receptor 4 (TLR4) is considered to have a critical role in the occurrence and development of atherosclerosis in atherosclerosis-prone mice; however, it remains uncertain whether treatment with a TLR4 inhibitor may attenuate atherosclerosis. The present study aimed to determine the vascular protective effects of the TLR4 inhibitor CLI-095 on apolipoprotein E-deficient (ApoE−/−) mice. ApoE−/− mice were fed either chow or a high-fat diet, and were treated with or without CLI-095 for 10 weeks. The mean atherosclerotic plaque area in the aortic sections of CLI-095-treated mice was 54.3% smaller than in the vehicle-treated mice (P=0.0051). In vitro, murine peritoneal macrophages were treated with or without CLI-095, and were subsequently stimulated with oxidized low-density lipoprotein. Treatment with CLI-095 markedly reduced the expression levels of lectin-like oxidized low-density lipoprotein receptor-1 and acyl-coenzyme A:cholesterol acyltransferase-1, and significantly upregulated the expression levels of ATP-binding cassette transporter A1, predominantly via suppressing activation of the TLR4/nuclear factor-κB signaling pathway. The results of the present study indicated that the TLR4 inhibitor CLI-095 has the ability to suppress the progression of atherosclerosis in an in vivo model by reducing macrophage foam cell formation. PMID:27176130

  12. History of Discovery: Inflammation in Atherosclerosis

    PubMed Central

    Libby, Peter

    2012-01-01

    Experimental work has elucidated molecular and cellular pathways of inflammation that promote atherosclerosis. Unraveling the roles of cytokines as inflammatory messengers provided a mechanism whereby risk factors for atherosclerosis can alter arterial biology, and produce a systemic milieu that favors atherothrombotic events. The discovery of the immune basis of allograft arteriosclerosis demonstrated that inflammation per se can drive arterial hyperplasia, even in the absence of traditional risk factors. Inflammation regulates aspects of plaque biology that trigger the thrombotic complications of atherosclerosis. Translation of these discoveries to humans has enabled both novel mechanistic insights and practical clinical advances. PMID:22895665

  13. Aorta Atherosclerosis Lesion Analysis in Hyperlipidemic Mice

    PubMed Central

    Mohanta, Sarajo; Yin, Changjun; Weber, Christian; Hu, Desheng; Habenicht, Andreas JR

    2016-01-01

    Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries. Apolipoprotein E-deficient (ApoE-/-) mice are used as experimental models to study human atherosclerosis. ApoE-/- mice are constitutively hyperlipidemic and develop intima plaques that resemble human plaques. Various issues including experimental design for lesion analysis, dietary conditions, isolation of the aorta, staining methods, morphometry, group size, age, the location within the arterial tree, and statistical analyses are important parameters that need to be addressed to obtain robust data. Here, we provide detailed methods to quantify aorta atherosclerosis. PMID:27366759

  14. Methylarginines in Mice with Experimental Atherosclerosis.

    PubMed

    Gilinsky, M A; Sukhovershin, R A; Cherkanova, M S

    2015-11-01

    We studied the dynamics of indexes for the system of endogenous regulation of NO bioavailability. The content of NO synthase inhibitors (monomethylarginine and asymmetric dimethylarginine) in the blood of mice was measured after intraperitoneal injections of a nonionic surfactant poloxamer 407 for 2 and 14 weeks. The concentrations of both methylarginines in animals with atherosclerosis due to 14-week administration of poloxamer were much higher than in control specimens. The amount of arginine and symmetric dimethylarginine practically did not differ from the control. Poloxamer-induced model of atherosclerosis is characterized by increased content of NO synthase inhibitors. These changes contribute to the development of endothelial dysfunction and atherosclerosis. PMID:26601840

  15. Atherosclerosis and the internal mammary arteries

    SciTech Connect

    Singh, R.N.

    1983-06-01

    One hundred and fifty patients with coronary artery disease (CAD), 14 (9.3%) of whom had coexisting peripheral vascular disease, underwent bilateral internal mammary arteriography to study the incidence and extent of atherosclerosis in these vessels. Significant atherosclerosis of the internal mammary arteries (IMAs) was present in three patients (2%), of whom one had coexisting peripheral vascular disease. Lesions in the IMAs were found either proximally, close to the origin or distally, around the terminal bifurcation. Six of the 14 patients with peripheral vascular disease (4% of total subjects) had significant atherosclerosis of the brachiocephalic arteries. Atherosclerotic involvement of the IMA is very unusual and rarely interferes with the use of these vessels for coronary bypass. More common, however, is atherosclerosis of the subclavian arteries, a contraindication for IMA grafting if the lesion is proximal to the IMA origin.

  16. Innate and Adaptive Immunity in Atherosclerosis

    PubMed Central

    Packard, René R. S.; Lichtman, Andrew H.; Libby, Peter

    2010-01-01

    Atherosclerosis, a chronic inflammatory disorder, involves both the innate and adaptive arms of the immune response that mediate the initiation, progression, and ultimate thrombotic complications of atherosclerosis. Most fatal thromboses, which may manifest as acute myocardial infarction or ischemic stroke, result from frank rupture or superficial erosion of the fibrous cap overlying the atheroma, processes that occur in inflammatorily active, rupture-prone plaques. Appreciation of the inflammatory character of atherosclerosis has led to the application of C-reactive protein as a biomarker of cardiovascular risk, and the characterization of the anti-inflammatory and immunomodulatory actions of the statin class of drugs. An improved understanding of the pathobiology of atherosclerosis and further studies of its immune mechanisms provide avenues for the development of future strategies directed toward better risk stratification of patients as well as the identification of novel anti-inflammatory therapies. This review retraces leukocyte subsets involved in innate and adaptive immunity and their contributions to atherogenesis. PMID:19449008

  17. Atherosclerosis is an inflammatory disorder after all.

    PubMed

    Meng, Charles Q

    2006-01-01

    Inflammation has been increasingly recognized as an important player in the pathophysiology of numerous human disorders. Accumulating evidence has led to the conclusion that atherosclerosis is an inflammatory disease, although it was believed to be a disorder of high cholesterol levels in the bloodstream for over a century. Cholesterol does contribute to the pathogenesis of atherosclerosis, but through inflammatory mechanisms. Statins lower cholesterol levels and hence reduce inflammation in the vasculature and prevent heart disease. Statins may also exert anti-inflammatory effects through mechanisms independent of cholesterol lowering. Adhesion molecules, cytokines, oxidative stress, etc. appear to contribute to the inflammatory state of atherosclerosis and therapeutic approaches directed toward these markers or targets have the potential to be effective in reducing inflammation and treating atherosclerosis. PMID:16454761

  18. Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis.

    PubMed

    Miao, Ji; Ling, Alisha V; Manthena, Praveen V; Gearing, Mary E; Graham, Mark J; Crooke, Rosanne M; Croce, Kevin J; Esquejo, Ryan M; Clish, Clary B; Vicent, David; Biddinger, Sudha B

    2015-01-01

    Despite the well-documented association between insulin resistance and cardiovascular disease, the key targets of insulin relevant to the development of cardiovascular disease are not known. Here, using non-biased profiling methods, we identify the enzyme flavin-containing monooxygenase 3 (Fmo3) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans. We show that FMO3 is suppressed by insulin in vitro, increased in obese/insulin resistant male mice and increased in obese/insulin-resistant humans. Knockdown of FMO3 in insulin-resistant mice suppresses FoxO1, a central node for metabolic control, and entirely prevents the development of hyperglycaemia, hyperlipidemia and atherosclerosis. Taken together, these data indicate that FMO3 is required for FoxO1 expression and the development of metabolic dysfunction. PMID:25849138

  19. Environmental carcinogens and mutational pathways in atherosclerosis.

    PubMed

    Pulliero, A; Godschalk, R; Andreassi, M G; Curfs, D; Van Schooten, F J; Izzotti, A

    2015-05-01

    Atherosclerosis is associated with DNA damage in both circulating and vessel-wall cells and DNA adducts derived from exposure to environmental mutagens are abundant in atherosclerotic vessels. Environmental chemical carcinogens identified as risk factor for atherosclerosis include polycyclic aromatic hydrocarbons (benzo(a)pyrene, dimethylbenz(a)anthracene, beta-naphthoflavone, pyrene, 3-methylcolanthrene), arsenic, cadmium, 1,3-butadiene, cigarette smoke. Accordingly, polymorphisms of genes encoding for phase I/II metabolic reaction and DNA repair are risk factor for cardiovascular diseases, although their role is negligible as compared to other risk factors. The pathogenic relevance of mutation-related molecular damage in atherosclerosis has been demonstrated in experimental animal models involving the exposure to chemical mutagens. The relevance of mutation-related events in worsening atherosclerosis prognosis has been demonstrated in human clinical studies mainly as referred to mitochondrial DNA damage. Atherosclerosis is characterized by the occurrence of high level of oxidative damage in blood vessel resulting from both endogenous and exogenous sources. Mitochondrial damage is a main endogenous source of oxidative stress whose accumulation causes activation of intrinsic apoptosis through BIRC2 inhibition and cell loss contributing to plaque development and instability. Environmental physical mutagens, including ionizing radiation, are a risk factor for atherosclerosis even at the low exposure dose occurring in case of occupational exposure or the high exposure doses occurring during radiotherapy. Conversely, the role of exciting UV radiation in atherosclerosis is still uncertain. This review summarizes the experimental and clinical evidence supporting the pathogenic role of mutation-related pathway in atherosclerosis examining the underlying molecular mechanisms. PMID:25704189

  20. Vascular Smooth Muscle Cells in Atherosclerosis.

    PubMed

    Bennett, Martin R; Sinha, Sanjay; Owens, Gary K

    2016-02-19

    The historical view of vascular smooth muscle cells (VSMCs) in atherosclerosis is that aberrant proliferation of VSMCs promotes plaque formation, but that VSMCs in advanced plaques are entirely beneficial, for example preventing rupture of the fibrous cap. However, this view has been based on ideas that there is a homogenous population of VSMCs within the plaque, that can be identified separate from other plaque cells (particularly macrophages) using standard VSMC and macrophage immunohistochemical markers. More recent genetic lineage tracing studies have shown that VSMC phenotypic switching results in less-differentiated forms that lack VSMC markers including macrophage-like cells, and this switching directly promotes atherosclerosis. In addition, VSMC proliferation may be beneficial throughout atherogenesis, and not just in advanced lesions, whereas VSMC apoptosis, cell senescence, and VSMC-derived macrophage-like cells may promote inflammation. We review the effect of embryological origin on VSMC behavior in atherosclerosis, the role, regulation and consequences of phenotypic switching, the evidence for different origins of VSMCs, and the role of individual processes that VSMCs undergo in atherosclerosis in regard to plaque formation and the structure of advanced lesions. We think there is now compelling evidence that a full understanding of VSMC behavior in atherosclerosis is critical to identify therapeutic targets to both prevent and treat atherosclerosis. PMID:26892967

  1. Positron Emission Tomography Imaging of Atherosclerosis

    PubMed Central

    Orbay, Hakan; Hong, Hao; Zhang, Yin; Cai, Weibo

    2013-01-01

    Atherosclerosis-related cardiovascular events are the leading causes of death in the industrialized world. Atherosclerosis develops insidiously and the initial manifestation is usually sudden cardiac death, stroke, or myocardial infarction. Molecular imaging is a valuable tool to identify the disease at an early stage before fatal manifestations occur. Among the various molecular imaging techniques, this review mainly focuses on positron emission tomography (PET) imaging of atherosclerosis. The targets and pathways that have been investigated to date for PET imaging of atherosclerosis include: glycolysis, cell membrane metabolism (phosphatidylcholine synthesis), integrin αvβ3, low density lipoprotein (LDL) receptors (LDLr), natriuretic peptide clearance receptors (NPCRs), fatty acid synthesis, vascular cell adhesion molecule-1 (VCAM-1), macrophages, platelets, etc. Many PET tracers have been investigated clinically for imaging of atherosclerosis. Early diagnosis of atherosclerotic lesions by PET imaging can help to prevent the premature death caused by atherosclerosis, and smooth translation of promising PET tracers into the clinic is critical to the benefit of patients. PMID:24312158

  2. Smooth muscle FGF/TGFβ cross talk regulates atherosclerosis progression.

    PubMed

    Chen, Pei-Yu; Qin, Lingfeng; Li, Guangxin; Tellides, George; Simons, Michael

    2016-01-01

    The conversion of vascular smooth muscle cells (SMCs) from contractile to proliferative phenotype is thought to play an important role in atherosclerosis. However, the contribution of this process to plaque growth has never been fully defined. In this study, we show that activation of SMC TGFβ signaling, achieved by suppression of SMC fibroblast growth factor (FGF) signaling input, induces their conversion to a contractile phenotype and dramatically reduces atherosclerotic plaque size. The FGF/TGFβ signaling cross talk was observed in vitro and in vivo In vitro, inhibition of FGF signaling increased TGFβ activity, thereby promoting smooth muscle differentiation and decreasing proliferation. In vivo, smooth muscle-specific knockout of an FGF receptor adaptor Frs2α led to a profound inhibition of atherosclerotic plaque growth when these animals were crossed on Apoe(-/-) background and subjected to a high-fat diet. In particular, there was a significant reduction in plaque cellularity, increase in fibrous cap area, and decrease in necrotic core size. In agreement with these findings, examination of human coronary arteries with various degrees of atherosclerosis revealed a strong correlation between the activation of FGF signaling, loss of TGFβ activity, and increased disease severity. These results identify SMC FGF/TGFβ signaling cross talk as an important regulator of SMC phenotype switch and document a major contribution of medial SMC proliferation to atherosclerotic plaque growth. PMID:27189169

  3. 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. PMID:27146015

  4. Nitric oxide function in atherosclerosis

    PubMed Central

    Matthys, K. E.

    1997-01-01

    Atherosclerosis is a chronic inflammatory process in the intima of conduit arteries, which disturbs the endothelium-dependent regulation of the vascular tone by the labile liposoluble radical nitric oxide (NO) formed by the constitutive endothelial nitric oxide synthase (eNOS). This defect predisposes to coronary vasospasm and cardiac ischaemia, with anginal pain as the typical clinical manifestation. It is now appreciated that endothelial dysfunction is an early event in atherogenesis and that it may also involve the microcirculation, in which atherosclerotic lesions do not develop. On the other hand, the inflammatory environment in atherosclerotic plaques may result in the expression of the inducible NO synthase (iNOS) isozyme. Whether the dysfunction in endothelial NO production is causal to, or the result of, atherosclerotic lesion formation is still highly debated. Most evidence supports the hypothesis that constitutive endothelial NO release protects against atherogenesis e.g. by preventing smooth muscle cell proliferation and leukocyte adhesion. Nitric oxide generated by the inducible isozyme may be beneficial by replacing the failing endothelial production but excessive release may damage the vascular wall cells, especially in combination with reactive oxygen intermediates. PMID:18472828

  5. [Is atherosclerosis an autoimmunological process?].

    PubMed

    Partyka, Ł; Hartwich, J; Kieć-Wilk, B; Polus, A; Wybrańska, I; Dembińska-Kieć, A

    2001-01-01

    The theories formulated to explain atherogenesis evolved from simple vessel wall lipid accumulation assumption to endothelial dysfunction with adverse vascular wall remodelling hypothesis. The theory that has been accepted lately integrates the former hypotheses and allows for introducing the local immunological activation concept. This immunological activation is initiated by negatively charged and oxidatively modified lipids (e.g. oxPAPC) and their complexes with proteins (like beta 2-GP I). Antibodies and cellular response against chaperonins: HSP 60 and their analogues from bacterial pathogens such as HSP 65, GroEi etc.) as well as release of cytokines, adhesion molecules and inflammatory mediators (CD 40/CD 40-L, IL 15, IFN gamma, IL 1 beta, TNF alpha) also take part in the process. Another important element of atherogenesis is the pathological angiogenic response within the plaque connected with the expression of angiogenic growth factors (such as VEGF, bFGF and PDGF), metallo-proteinases and local hemostasis regulators. This complex activation of local inflammatory and immunological process initiates such phenomena as development of unstable plaque, vascular remodelling, vessel lumen constriction and ischemic, thromboembolic complications of atherosclerosis. PMID:12041024

  6. Role of infections in atherosclerosis.

    PubMed

    Valtonen, V V

    1999-11-01

    A growing amount of epidemiologic, experimental, and clinical evidence has linked infection as a risk factor to variousatherosclerotic diseases including acute myocardial infarction and cerebral infarction. Bacteremic infections with and without endocarditis carry a high risk for both stroke and acute myocardial infarction. During the last decade, chronic bacterial infections such as Chlamydia pneumoniae and dental infections have been associated as risk factors for various atherosclerotic diseases. These chronic bacterial infections are risk factors for acute cardiovascular events, but they may also have some role in the etiopathogenesis of atherosclerotic process itself. There are many known mechanisms that might explain the observed association of infection and atherosclerotic diseases, but it is probable that these mechanisms are complex and multifactorial and probably differ from infection to infection and from patient to patient. Infection theory is by no means against classic risk factor theory in the etiopathogenesis of atherosclerosis. Infection may also act as a synergistic risk factor together with classic risk factors in the development of various atherosclerotic diseases. PMID:10539842

  7. Superoxide and peroxynitrite in atherosclerosis.

    PubMed Central

    White, C R; Brock, T A; Chang, L Y; Crapo, J; Briscoe, P; Ku, D; Bradley, W A; Gianturco, S H; Gore, J; Freeman, B A

    1994-01-01

    The role of reactive oxygen species in the vascular pathology associated with atherosclerosis was examined by testing the hypothesis that impaired vascular reactivity results from the reaction of nitric oxide (.NO) with superoxide (O2-), yielding the oxidant peroxynitrite (ONOO-). Contractility studies were performed on femoral arteries from rabbits fed a cholesterol-supplemented diet. Cholesterol feeding shifted the EC50 for acetylcholine (ACh)-induced relaxation and impaired the maximal response to ACh. We used pH-sensitive liposomes to deliver CuZn superoxide dismutase (SOD; superoxide:superoxide oxidoreductase, EC 1.15.1.1) to critical sites of .NO reaction with O2-. Intravenously injected liposomes (3000 units of SOD per ml) augmented ACh-induced relaxation in the cholesterol-fed group to a greater extent than in controls. Quantitative immunocytochemistry demonstrated enhanced distribution of SOD in both endothelial and vascular smooth muscle cells as well as in the extracellular matrix. SOD activity in vessel homogenates of liposome-treated rabbits was also increased. Incubation of beta very low density lipoprotein with ONOO- resulted in the rapid formation of conjugated dienes and thiobarbituric acid-reactive substances. Our results suggest that the reaction of O2- with .NO is involved in the development of atherosclerotic disease by yielding a potent mediator of lipoprotein oxidation, as well as by limiting .NO stimulation of vascular smooth muscle guanylate cyclase activity. Images PMID:8302829

  8. The chylomicron: relationship to atherosclerosis.

    PubMed

    Tomkin, Gerald H; Owens, Daphne

    2012-01-01

    The B-containing lipoproteins are the transporters of cholesterol, and the evidence suggests that the apo B48-containing postprandial chylomicron particles and the triglyceride-rich very low density lipoprotein (VLDL) particles play an important part in the development of the plaque both directly and indirectly by their impact on LDL composition. The ratio of dietary to synthesised cholesterol is variable but tightly regulated: hence intervention with diet at best reduces serum cholesterol by <20% andusually <10%. Statins are the mainstay of cholesterol reduction therapy, but they increase cholesterol absorption, an example of the relationship between synthesis and absorption. Inhibition of cholesterol absorption with Ezetimibe, an inhibitor of Niemann Pick C1-like 1 (NPC1-L1), the major regulator of cholesterol absorption, increases cholesterol synthesis and hence the value of adding an inhibitor of cholesterol absorption to an inhibitor of cholesterol synthesis. Apo B48, the structural protein of the chylomicron particle, is synthesised in abundance so that the release of these particles is dependent on the amount of cholesterol and triglyceride available in the intestine. This paper will discuss cholesterol absorption and synthesis, chylomicron formation, and the effect of postprandial lipoproteins on factors involved in atherosclerosis. PMID:22007304

  9. Mitochondrial genome sequencing in atherosclerosis: what's next?

    PubMed

    Sazonova, Margarita A; Shkurat, Tatiana P; Demakova, Natalya A; Zhelankin, Andrey V; Barinova, Valeria A; Sobenin, Igor A; Orekhov, Alexander N

    2016-01-01

    Cardiovascular diseases are currently a basic cause of mortality in highly developed countries. The major reason for genesis and development of cardiovascular diseases is atherosclerosis. At the present time high technology methods of molecular genetic diagnostics can significantly simplify early presymptomatic recognition of patients with atherosclerosis, to detect risk groups and to perform a family analysis of this pathology. A Next-Generation Sequencing (NGS) technology can be characterized by high productivity and cheapness of full genome analysis of each DNA sample. We suppose that in the nearest future NGS methods will be widely used for scientific and diagnostic purposes, including personalized medicine. In the present review article literature data on using NGS technology were described in studying mitochondrial genome mutations associated with atherosclerosis and its risk factors, such as mitochondrial diabetes, mitochondrial cardiomyopathy, diabetic nephropathy and left ventricular hypertrophy. With the use of the NGS technology it proved to be possible to detect a range of homoplasmic and heteroplasmic mutations and mitochondrial genome haplogroups which are associated with these pathologies. Meanwhile some mutations and haplogroups were detected both in atherosclerosis and in its risk factors. It conveys the suggestion that there are common pathogenetic mechanisms causing these pathologies. What comes next? New paradigm of crosstalk between non-pharmaceutical (including molecular genetic) and true pharmaceutical approaches may be developed to fill the niche of effective and pathogenically targeted pretreatment and treatment of preclinical and subclinical atherosclerosis to avoid the development of chronic life-threatening disease. PMID:26561059

  10. Chemokines and their receptors in Atherosclerosis.

    PubMed

    van der Vorst, Emiel P C; Döring, Yvonne; Weber, Christian

    2015-09-01

    Atherosclerosis, a chronic inflammatory disease of the medium- and large-sized arteries, is the main underlying cause of cardiovascular diseases (CVDs) most often leading to a myocardial infarction or stroke. However, atherosclerosis can also develop without this clinical manifestation. The pathophysiology of atherosclerosis is very complex and consists of many cells and molecules interacting with each other. Over the last years, chemokines (small 8-12 kDa cytokines with chemotactic properties) have been identified as key players in atherogenesis. However, this remains a very active and dynamic field of research. Here, we will give an overview of the current knowledge about the involvement of chemokines in all phases of atherosclerotic lesion development. Furthermore, we will focus on two chemokines that recently have been associated with atherogenesis, CXCL12, and macrophage migration inhibitory factor (MIF). Both chemokines play a crucial role in leukocyte recruitment and arrest, a critical step in atherosclerosis development. MIF has shown to be a more pro-inflammatory and thus pro-atherogenic chemokine, instead CXCL12 seems to have a more protective function. However, results about this protective role are still quite debatable. Future research will further elucidate the precise role of these chemokines in atherosclerosis and determine the potential of chemokine-based therapies. PMID:26175090

  11. Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming.

    PubMed

    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; Björkhem, Ingemar; Gustafsson, Jan-Åke; Westerterp, Marit; Tall, Alan R; Wright, Samuel D; Espevik, Terje; Schultze, Joachim L; Nickenig, Georg; Lütjohann, Dieter; Latz, Eicke

    2016-04-01

    Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. 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. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger 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. We showed 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 antiatherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Because 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

  12. 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

  13. Oxidative theory of atherosclerosis and antioxidants.

    PubMed

    Salvayre, R; Negre-Salvayre, A; Camaré, C

    2016-06-01

    Atherosclerosis is a multifactorial process that begins early in infancy and affects all the humans. Early steps of atherogenesis and the evolution towards complex atherosclerotic plaques are briefly described. After a brief history of the 'Lipid theory of atherosclerosis', we report the most prominent discoveries on lipoproteins, their receptors and metabolism, and their role in atherogenesis. The main focus is the 'oxidative theory of atherosclerosis', with emphasis on free radicals and reactive oxygen species, lipid peroxidation and LDL oxidation, biological properties of oxidized LDL and their potential role in atherogenesis. Then, we report the properties of antioxidants and antioxidant systems and their effects in vitro, on cultured cells, in animal models and in humans. The surprising discrepancy between the efficacy of antioxidants in vitro and in animal models of atherosclerosis and the lack of protective effect against cardiovascular events and death in epidemiological study and clinical trials are discussed. In contrast, epidemiological studies seem to indicate that the Mediterranean diet may protect (in part) against atherosclerosis complications (myocardial infarction and cardiovascular death). PMID:26717905

  14. Atherosclerosis: Process, Indicators, Risk Factors and New Hopes

    PubMed Central

    Rafieian-Kopaei, Mahmoud; Setorki, Mahbubeh; Doudi, Monir; Baradaran, Azar; Nasri, Hamid

    2014-01-01

    Background: Atherosclerosis is the major cause of morbidities and mortalities worldwide. In this study we aimed to review the mechanism of atherosclerosis and its risk factors, focusing on new findings in atherosclerosis markers and its risk factors. Furthermore, the role of antioxidants and medicinal herbs in atherosclerosis and endothelial damage has been discussed and a list of important medicinal plants effective in the treatment and prevention of hyperlipidemia and atherosclerosis is presented. Methods: The recently published papers about atherosclerosis pathogenesis and herbal medicines effective in the treatment and prevention of hyperlipidemia and atherosclerosis were searched. Results: Inflammation has a crucial role in pathogenesis of atherosclerosis. The disease is accompanied by excessive fibrosis of the intima, fatty plaques formation, proliferation of smooth muscle cells, and migration of a group of cells such as monocytes, T cells, and platelets which are formed in response to inflammation. The oxidation of low density lipoprotein (LDL) to Ox-LDL indicates the first step of atherosclerosis in cardiovascular diseases. Malondialdehyde factor shows the level of lipoperoxidation and is a sign of increased oxidative pressure and cardiovascular diseases. In special pathological conditions such as severe hypercholesterolemia, peroxynitrite concentration increases and atherosclerosis and vascular damage are intensified. Medicinal plants have shown to be capable of interacting these or other pathogenesis factors to prevent atherosclerosis. Conclusions: The pathogenesis factors involved in atherosclerosis have recently been cleared and the discovery of these factors has brought about new hopes for better prevention and treatment of atherosclerosis. PMID:25489440

  15. Bioequivalence studies for 2 different strengths of irbesartan/hydrochlorothiazide combination in healthy volunteers: 300/25 mg and 300/12.5 mg film-coated tablets.

    PubMed

    Cánovas, M; Cabré, F; Polonio, F

    2014-05-01

    Two bioequivalence studies of irbesartan (CAS 138402-11-6) and hydrochlorothiazide (CAS 58-93-5) combination at 300/12.5 mg and 300/25 mg strengths were carried out in order to assess the bioequivalence of these film-coated tablet formulations in comparison with the marketed reference formulations.Both studies were performed with 30 healthy volunteers according to an open label, randomized, 2-period, 2-sequence, crossover, single dose and fasting conditions design. In each study, test and reference formulations were administered in 2 treatment days, separated by a washout period of 7 days. Blood samples were drawn up to 72 h following drug administration in case of irbesartan and up to 24 h in case of hydrochlorothiazide. Plasma concentrations of both analytes were obtained by a validated HPLC method using MS/MS detection. Log-transformed AUC0-t and Cmax values were tested for bioequivalence based on the ratios of the geometric LSmeans (test/reference).For both studies, the 90% confidence intervals of the geometric LSmean values for the test/reference ratios for AUC0-t [(irbesartan: 300/12.5 mgstrength: 95.33-111.74%. 300/25 mg strength: 91.27-103.93%) (hydrochlorothiazide: 300/12.5 mg strength: 99.63-107.50%. 300/25 mg strength: 95.72-102.24%)] and Cmax [(irbesartan: 300/12.5 mg strength: 98.73-115.03%. 300/25 mg strength: 97.27-112.12%) (hydrochlorothiazide: 300/12.5 mg strength: 97.34-112.06%. 300/25 mg strength: 93.29-106.38%)] were within the bio-equivalence acceptance range of 80-125%.According to the European Guideline on the Investigation of Bioequivalence it may be therefore concluded that both test formulations are bioequivalent to the corresponding reference formulations. Overall, it was judged that both studies were conducted with a good tolerance of the subjects to study drugs. PMID:24105103

  16. Pokkuri Death Syndrome; sudden cardiac death cases without coronary atherosclerosis in South Asian young males.

    PubMed

    Nakajima, Katsuyuki; Takeichi, Sanae; Nakajima, Yasuhiro; Fujita, Masaki Q

    2011-04-15

    Sudden death is one of the major concerns in forensic medicine. Especially when the deceased is a young subject without significant history, the case will be of major interest to the authorities. Sudden unexplained cardiac death has been known as "Pokkuri Death Syndrome" (PDS) in Japan, "Lai Tai" in Thailand, "Bangungut" in the Philippines, "Dream Disease" in Hawaii, and "Sudden Unexpected Nocturnal Death Syndrome" among South Asian immigrants in the USA. However, the clinical and pathological features of these sudden death cases, especially the characteristics of no coronary atherosclerosis, are surprisingly similar and mainly occur among Southeast Asian young males during sleep in the midnight. In this manuscript, we have reviewed the pathological characteristics and the possible mechanism of death in PDS cases, which were associated with significantly elevated remnant lipoproteins in plasma as revealed from our studies during the past 15 years in Japan. Although elevated plasma remnant lipoproteins have been known to be strongly atherogenic, coronary atherosclerosis was not observed in PDS cases. PDS cases were shown to be an interesting cardiovascular disease death discovered in forensic medicine research, which may suggest the difference between the occurrence of cardiovascular events and the severity of coronary atherosclerosis as separate factors. These observations in PDS cases suggest the possibility that the intervention could be more targeted to suppress the cardiovascular events rather than to slow down the progression of atherosclerosis, which is now most extensively targeted for the therapy of cardiovascular disease in Western countries. PMID:21084168

  17. Antigen-tailored therapy based on the inflammatory theory of atherosclerosis.

    PubMed

    Harats, Dror; George, Jacob

    2004-10-01

    In recent years, considerable data has been provided to support the role of the immune system in atherosclerosis. These reports came from studies involving knockout murine models of atherosclerosis and human subjects. The notion that inflammatory mechanisms are operable in atherogenesis has fueled a series of studies demonstrating that autoimmune responses are also evident in the atherosclerotic lesions and appear to influence the initiation and progression of the plaque. The principal autoantigens that have been suggested as potential triggers of autoimmune responses in atherosclerosis are modified forms of low-density lipoproteins, heat shock proteins and beta2 glycoprotein I. Immunization against these antigens influenced the generation of lesions and adoptive transfer studies of lymphocytes reactive to some of these antigens have also been demonstrated to enhance the growth of the plaques. The realization that autoimmune-like responses may play a role in the progression of atherosclerotic lesions has paved the way for exciting modes of manipulating lesions, irrespective of the effect on the lipid profile. Thus, recent studies indicate that oral tolerance with antigens or derivatives could suppress the respective immune responses and reduce the extent of the lesions in transgenic atherosclerosis-prone mice. These observations should be further explored and if validated, could represent novel modalities for influencing atherogenessis in humans. PMID:15485340

  18. A study on regression of hypercholesterolemic atherosclerosis in rabbits by flax lignan complex.

    PubMed

    Prasad, Kailash

    2007-12-01

    Flax lignan complex (FLC) isolated from flaxseed suppresses the development of hypercholesterolemic atherosclerosis. The objectives of this study were to investigate if FLC produces regression of atherosclerosis and if regression is associated with reductions in serum lipids and oxidative stress. The studies were conducted in 4 groups of rabbits: group I, control diet (2 months); group II, 0.25% cholesterol diet (2 months); group III, 0.25% cholesterol diet (2 months) followed by regular diet (4 months); and group IV, 0.25% cholesterol diet (2 months) followed by regular diet and FLC (4 months). Serum lipids and oxidative stress parameters were measured before and at various intervals thereafter on their respective diets. The aortas were removed at the end of the protocol for assessment of atherosclerotic plaques and oxidative parameters. Atherosclerosis in group II was associated with hyperlipidemia and increased oxidative stress. Atherosclerotic changes were accelerated in group III, and this was associated with reductions in serum lipids and oxidative stress. Atherosclerotic lesions in group IV were similar to group II, but significantly smaller than those in group III, and were associated with reductions in serum lipids and oxidative stress similar to that in group III. These results indicate that FLC does not produce regression but prevents the acceleration of atherosclerosis due to the removal of cholesterol in the diet. These effects of FLC are not associated with reductions in serum lipids and oxidative stress. PMID:18172225

  19. Regression of hypercholesterolemic atherosclerosis in rabbits by secoisolariciresinol diglucoside isolated from flaxseed.

    PubMed

    Prasad, Kailash

    2008-03-01

    Secoisolariciresinol diglucoside (SDG) isolated from flaxseed is a lipid-lowering and antioxidant agent. It suppresses the development of hypercholesterolemic atherosclerosis in rabbits. It is however not known if SDG would produce regression of atherosclerosis. The objectives of this study were to determine (i) if SDG produces regression of atherosclerosis; (ii) if regression is associated with reduction in serum lipids, oxidative stress or both; and (iii) if the duration of treatment has an effect on regression. Rabbits were assigned to five groups: Group I, regular diet (control); Group II, 0.5% cholesterol diet for 2 months (mo); Group III, same as Group II but followed by regular diet for 2 mo; Group IV, same as Group II and followed by regular diet with SDG (20mg x kg body wt(-1) x day(-1) PO) for 2 mo; and Group V, same as Group IV but SDG treatment for an additional 2 mo. Blood samples were collected from rabbits before and at monthly intervals thereafter on their respective diet regimen for measurement of triglycerides (TG), total cholesterol (TC), LDL-C, HDL-C and malondialdehyde (MDA), a lipid peroxidation product. At the end of the protocol, the aorta was removed for assessment of atherosclerotic lesions, aortic MDA and aortic chemiluminescence (Aortic-CL), a measure of antioxidant reserve. MDA and Aortic-CL provide an index of oxidative stress. Increases in serum TG, TC, LDL-C, HDL-C and the risk ratio TC/HDL-C in Group II were associated with an increase in oxidative stress and development of atherosclerosis (57% of aortic intimal surface covered with lesions). Serum lipids decreased to a similar extent in Groups III-V, however atherosclerotic lesions were 84%, 63% and 44%, respectively in Groups III-V. There were more atherosclerotic lesions in Group III (+48.9%) as compared to Group II. The atherosclerotic lesions decreased by 24% and 45%, respectively in Groups IV and V compared to Group III. The reduction in atherosclerotic lesions was associated

  20. Inflammatory cytokines in atherosclerosis: current therapeutic approaches.

    PubMed

    Tousoulis, Dimitris; Oikonomou, Evangelos; Economou, Evangelos K; Crea, Filippo; Kaski, Juan Carlos

    2016-06-01

    The notion of atherosclerosis as a chronic inflammatory disease has intensified research on the role of cytokines and the way these molecules act and interact to initiate and sustain inflammation in the microenvironment of an atherosclerotic plaque. Cytokines are expressed by all types of cells involved in the pathogenesis of atherosclerosis, act on a variety of targets exerting multiple effects, and are largely responsible for the crosstalk among endothelial, smooth muscle cells, leucocytes, and other vascular residing cells. It is now understood that widely used drugs such as statins, aspirin, methotrexate, and colchicine act in an immunomodulatory way that may beneficially affect atherogenesis and/or cardiovascular disease progression. Moreover, advancement in pharmaceutical design has enabled the production of highly specific antibodies against key molecules involved in the perpetuation of the inflammatory cascade, raising hope for advances in the treatment of atherosclerosis. This review describes the actions and effects of these agents, their potential clinical significance, and future prospects. PMID:26843277

  1. The thyromimetic T-0681 protects from atherosclerosis

    PubMed Central

    Tancevski, Ivan; Wehinger, Andreas; Demetz, Egon; Hoefer, Julia; Eller, Philipp; Huber, Eva; Stanzl, Ursula; Duwensee, Kristina; Auer, Kristina; Schgoer, Wilfried; Kuhn, Volker; Fievet, Catherine; Stellaard, Frans; Rudling, Mats; Foeger, Bernhard; Patsch, Josef R.; Ritsch, Andreas

    2009-01-01

    This report describes studies in hyperlipidemic New Zealand White (NZW) rabbits investigating the impact of the liver-selective thyromimetic T-0681 on lipoprotein metabolism and the development of atherosclerosis. Prolonged treatment with T-0681 increased the hepatic expression of both LDL receptor and scavenger receptor class B, type I without affecting cholesteryl ester transfer protein activity. Upregulation of hepatic lipoprotein receptors was accompanied by a marked decrease of apolipoprotein B-containing lipoproteins, reflected by a 60% reduction of plasma cholesterol and a >70% reduction of plasma triglyceride levels. Most importantly, T-0681 reduced the development of atherosclerosis by 80% in NZW rabbits on high-cholesterol chow. Our data suggest that liver-selective thyromimetics, such as T-0681, may prove to be useful therapeutic agents against the development of atherosclerosis in humans. PMID:19106072

  2. Atherosclerosis - A matter of unresolved inflammation.

    PubMed

    Viola, Joana; Soehnlein, Oliver

    2015-05-01

    Atherosclerosis is commonly looked upon as a chronic inflammatory disease of the arterial wall arising from an unbalanced lipid metabolism and a maladaptive inflammatory response. However, atherosclerosis is not merely an inflammation of the vessel wall. In fact, the cardinal signs of unstable atherosclerotic lesions are primarily characteristics of failed resolution of a chronic inflammation. In contrast to acute inflammatory events which are typically self-limiting, atherosclerosis is an unresolved inflammatory condition, lacking the switch from the pro-inflammatory to the pro-resolving phase, the latter characterized by termination of inflammatory cell recruitment, removal of inflammatory cells from the site of inflammation by apoptosis and dead cell clearance, reprogramming of macrophages toward an anti-inflammatory, regenerative phenotype, and finally egress of effector cells and tissue regeneration. Here we present an overview on mechanisms of failed resolution contributing to atheroprogression and deliver a summary of novel therapeutic strategies to restore resolution in inflamed arteries. PMID:25865626

  3. Adipokines, diabetes and atherosclerosis: an inflammatory association

    PubMed Central

    Freitas Lima, Leandro C.; Braga, Valdir de Andrade; do Socorro de França Silva, Maria; Cruz, Josiane de Campos; Sousa Santos, Sérgio H.; de Oliveira Monteiro, Matheus M.; Balarini, Camille de Moura

    2015-01-01

    Cardiovascular diseases can be considered the most important cause of death in diabetic population and diabetes can in turn increase the risk of cardiovascular events. Inflammation process is currently recognized as responsible for the development and maintenance of diverse chronic diseases, including diabetes and atherosclerosis. Considering that adipose tissue is an important source of adipokines, which may present anti and proinflammatory effects, the aim of this review is to explore the role of the main adipokines in the pathophysiology of diabetes and atherosclerosis, highlighting the therapeutic options that could arise from the manipulation of these signaling pathways both in humans and in translational models. PMID:26578976

  4. Long Noncoding RNA: Recent Updates in Atherosclerosis

    PubMed Central

    Li, Hao; Zhu, Hongming; Ge, Junbo

    2016-01-01

    Long noncoding RNAs belong to a class of noncoding RNAs longer than 200 nucleotides with the epigenetic regulation potential. As a novel molecular regulator, lncRNAs are often dysregulated in various pathological conditions and display multiple functions in a wide range of biological processes. Given that recent studies have indicated that lncRNAs are involved in atherosclerosis-related smooth muscle cell, endothelial cell, macrophage and lipid metabolism regulation, it is pertinent to understand the potential function of lncRNAs in atherosclerosis development. This review will highlight the recent updates of lncRNAs in atherogenesis and also discuss their potential roles as novel therapeutic targets. PMID:27314829

  5. HIV, inflammation, and calcium in atherosclerosis.

    PubMed

    Shrestha, Sadeep; Irvin, Marguerite R; Grunfeld, Carl; Arnett, Donna K

    2014-02-01

    Atherosclerosis is consistently higher among the HIV-positive patients, with or without treatment, than among the HIV-negative population. Risk factors linked to atherosclerotic cardiovascular disease in HIV infection are both traditional and HIV specific although the underlying mechanisms are not fully delineated. Three key sequential biological processes are postulated to accelerate progression of atherosclerosis in the context of HIV: (1) inflammation, (2) transformation of monocytes to macrophages and then foam cells, and (3) apoptosis of foam cells leading to plaque development through Ca(2+)-dependent endoplasmic reticulum stress. These proatherogenic mechanisms are further affected when HIV interacts with the genes involved in various phases within this network. PMID:24265418

  6. Positron emission tomography imaging of coronary atherosclerosis.

    PubMed

    Moss, Alastair J; Adamson, Philip D; Newby, David E; Dweck, Marc R

    2016-07-01

    Inflammation has a central role in the progression of coronary atherosclerosis. Recent developments in cardiovascular imaging with the advent of hybrid positron emission tomography have provided a window into the molecular pathophysiology underlying coronary plaque inflammation. Using novel radiotracers targeted at specific cellular pathways, the potential exists to observe inflammation, apoptosis, cellular hypoxia, microcalcification and angiogenesis in vivo. Several clinical studies are now underway assessing the ability of this hybrid imaging modality to inform about atherosclerotic disease activity and the prediction of future cardiovascular risk. A better understanding of the molecular mechanisms governing coronary atherosclerosis may be the first step toward offering patients a more stratified, personalized approach to treatment. PMID:27322032

  7. 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. PMID:26978582

  8. Inflammation in atherosclerosis: new opportunities for drug discovery.

    PubMed

    Meng, Charles Q

    2005-01-01

    Many lines of evidence indicate that inflammation is the ultimate cause of atherosclerosis; high cholesterol levels cause atherosclerosis through mechanism of inflammation. Drugs designed to address inflammatory aspects of atherosclerosis will likely be more effective than current therapies in treating and preventing coronary artery disease. PMID:15638790

  9. Infections, atherosclerosis, and coronary heart disease.

    PubMed

    Famularo, G; Trinchieri, V; Santini, G; De Simone, C

    2000-01-01

    There is growing evidence that the immune response is involved in atherosclerosis. Studies done over the past several years have shown an association between markers of inflammation and coronary atherosclerosis with an exacerbation of the inflammatory process during acute myocardial ischemia. Overall, these data have greatly renewed interest in the infectious theory of atherosclerosis and coronary heart disease. Search of bibliographic databases (from January 1991 through December 1999) and manual scanning of both peer-reviewed publications and other documents were used to identify pertinent literature. Infections and coronary heart disease were indexed as key words. A large number of studies have reported an association of human coronary heart disease and certain persistent bacterial and viral infections. The association between Chlamydia pneumoniae and coronary heart disease appears quite significant although the sequence of infection and disease is uncertain. The association between Helicobacter pylori and coronary heart disease may be accounted for by residual confounding from classic risk factors. Preliminary findings indicate that this association could be due to a higher prevalence of more virulent Helicobacter strains. Infection with Cytomegalovirus appears to be associated with a greater risk of restenosis after angioplasty rather than primary atherosclerosis. Early trials of appropriate antibiotic therapy in subjects with recent acute myocardial infarction have been encouraging. A causal relationship between infections and coronary heart disease is still elusive. Improved studies involving prospective collection of data are required to demonstrate such an association with potential implications for public health worldwide. PMID:10920505

  10. 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

  11. Non-coding RNAs and atherosclerosis

    PubMed Central

    Fernández-Hernando, Carlos

    2014-01-01

    Non-coding RNAs (ncRNAs) represent a class of RNA molecules that typically do not code for proteins. Emerging data suggest that ncRNAs play an important role in several physiological and pathological conditions such as cancer and cardiovascular diseases (CVDs) including atherosclerosis. The best-characterized ncRNAs are the microRNAs (miRNAs), which are small, ~22 nucleotide (nt) sequences of RNA that regulate gene expression at the posttranscriptional level through transcript degradation or translational repression. MiRNAs control several aspects of atherosclerosis including endothelial cell, vascular smooth cell, and macrophage functions as well as lipoprotein metabolism. Apart from miRNAs, recently ncRNAs, especially long ncRNAs (lncRNAs), have emerged as important potential regulators of the progression of atherosclerosis. However, the molecular mechanism of their regulation and function as well as significance of other ncRNAs such as small nucleolar RNAs (snoRNAs) during atherogenesis is largely unknown. In this review, we summarize the recent findings in the field, highlighting the importance of ncRNAs in atherosclerosis and discuss their potential use as therapeutic targets in CVDs. PMID:24623179

  12. 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.

  13. ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY (ARIC)

    EPA Science Inventory

    Epidemiology Study -- ARIC is a large-scale, long-term prospective study that measures associations of established and suspected coronary heart disease risk factors with both atherosclerosis and new CHD events in men and women from four geographically diverse communities. The pro...

  14. 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

  15. Self-eating in the Plaque: What Macrophage Autophagy Reveals About Atherosclerosis

    PubMed Central

    Sergin, Ismail; Razani, Babak

    2014-01-01

    Autophagy (or “self-eating”) is the process by which cellular contents are recycled to support downstream metabolism. An explosion in research in the past decade has implicated its role in both health and disease and established the importance of the autophagic response during periods of stress and nutrient deprivation. Atherosclerosis is a state where chronic exposure to cellular stressors promotes disease progression and alterations in autophagy is predicted to be consequential. Recent reports linking macrophage autophagy to lipid metabolism, blunted inflammatory signaling, and an overall suppression of proatherogenic processes support this notion. We review this data and provide a framework for understanding the role of macrophage autophagy in the pathogenesis of atherosclerosis, one of the most formidable diseases of our time. PMID:24746519

  16. Probucol via inhibition of NHE1 attenuates LPS-accelerated atherosclerosis and promotes plaque stability in vivo.

    PubMed

    Li, Jian-Fei; Chen, Song; Feng, Jun-Duo; Zhang, Ming-Yu; Liu, Xiao-Xia

    2014-04-01

    Activation of Na(+)/H(+) exchanger 1 (NHE1) by lipopolysaccharide (LPS) via Ca(2+)/calpain is responsible in vascular smooth muscle cell (VSMC) apoptosis and to the process of atherosclerosis. Probucol is a lipid-lowering drug which has an anti-atherosclerosis effect. The mechanism remains poorly understood. Here we hypothesized that probucol via inhibition of NHE1 in VSMCs attenuates LPS-accelerated atherosclerosis and promotes plaque stability. Our results revealed that treatment of VSMCs with LPS increased the NHE1 activity in a time-dependent manner, associated with the increased Ca(2+)i. Probucol inhibited the LPS-induced increase of NHE1 activity in a dose-dependent manner in VSMCs for 24-hour co-incubation, as well as the change of Ca(2+)i. In addition, LPS enhanced the calpain activity. Both probucol and calcium chelation of Ca(2+) abolished the LPS-induced increase of calpain activity. Treatment of VSMCs with LPS reduced the expression of Bcl-2 without altering the mRNA level. Probucol inhibited the LPS-reduced expression of Bcl-2 protein in VSMCs. Animal studies indicated administration of probucol suppressed LPS-accelerated apoptosis, atherosclerosis and plaque instability in Apoe(-/-) mice. In conclusion, probucol via inhibition of NHE1 attenuates atherosclerosis lesion growth and promotes plaque stability. PMID:24594116

  17. CLI-095 decreases atherosclerosis by modulating foam cell formation in apolipoprotein E-deficient mice.

    PubMed

    Wang, Xiao-Qing; Wan, Hui-Qing; Wei, Xian-Jing; Zhang, Ying; Qu, Peng

    2016-07-01

    Toll-like receptor 4 (TLR4) is considered to have a critical role in the occurrence and development of atherosclerosis in atherosclerosis-prone mice; however, it remains uncertain whether treatment with a TLR4 inhibitor may attenuate atherosclerosis. The present study aimed to determine the vascular protective effects of the TLR4 inhibitor CLI-095 on apolipoprotein E‑deficient (ApoE‑/‑) mice. ApoE‑/‑ mice were fed either chow or a high‑fat diet, and were treated with or without CLI‑095 for 10 weeks. The mean atherosclerotic plaque area in the aortic sections of CLI‑095‑treated mice was 54.3% smaller than in the vehicle‑treated mice (P=0.0051). In vitro, murine peritoneal macrophages were treated with or without CLI‑095, and were subsequently stimulated with oxidized low‑density lipoprotein. Treatment with CLI‑095 markedly reduced the expression levels of lectin‑like oxidized low‑density lipoprotein receptor‑1 and acyl-coenzyme A:cholesterol acyltransferase‑1, and significantly upregulated the expression levels of ATP‑binding cassette transporter A1, predominantly via suppressing activation of the TLR4/nuclear factor‑κB signaling pathway. The results of the present study indicated that the TLR4 inhibitor CLI‑095 has the ability to suppress the progression of atherosclerosis in an in vivo model by reducing macrophage foam cell formation. PMID:27176130

  18. Clinical Characteristics of Young Type 2 Diabetes Patients with Atherosclerosis

    PubMed Central

    Yang, Wenjia; Cai, Xiaoling; Han, Xueyao; Ji, Linong

    2016-01-01

    Objective The prevalence of type 2 diabetes is increasing rapidly in the young population. The clinical characteristics and risk factors for young type 2 diabetes patients with atherosclerosis are not fully explicated. The aim of the present study was to investigate various clinical and biochemical characteristics of young type 2 diabetic patients with atherosclerosis. Design and Methods This was a cross-sectional study. The study involved 2199 hospitalized patients with type 2 diabetes. The young patients were classified into the atherosclerotic group or the non-atherosclerotic group, and we also enrolled an older group with peripheral atherosclerosis disease and an age of at least 45 years. Comparisons were made between the different groups to investigate the cardiovascular and metabolic risk profiles of young type 2 diabetes patients with atherosclerosis. We also used logistic regression models to assess the atherosclerosis risk factors for young patients. Results Compared to older type 2 diabetes patients with atherosclerosis, young patients with atherosclerosis had more deleterious profiles of weight and hyperlipidemia. Only age and diabetes duration were found to be significant independent risk factors for atherosclerosis in young patients. The ratio of the presence of atherosclerosis in the lower extremity arteries alone was significantly higher in young patients than older patients (26.4% vs. 14.0%, P = 0.000). Conclusion Young type 2 diabetes patients with atherosclerosis have more adverse cardiovascular risk profiles and inadequate control of these risk factors. Lower extremity examination is of high importance in young patients. PMID:27391819

  19. Current status of carotid ultrasound in atherosclerosis

    PubMed Central

    2016-01-01

    Cardiovascular disease (CVD) primarily caused by atherosclerosis is a major cause of death and disability in developed countries. Sonographic carotid intima-media thickness (CIMT) is widely studied as a surrogate marker for detecting subclinical atherosclerosis for risk prediction and disease progress to guide medical intervention. However, there is no standardized CIMT measurement methodology in clinical studies resulting in inconsistent findings, thereby undermining the clinical value of CIMT. Increasing evidences show that CIMT alone has weak predictive value for CVD while CIMT including plaque presence consistently improves the predictive power. Quantification of plaque burden further enhances the predictive power beyond plaque presence. Sonographic carotid plaque characteristics have been found to be predictive of cerebral ischaemic events. With advances in ultrasound technology, enhanced assessment of carotid plaques is feasible to detect high-risk/vulnerable plaques, and provide risk assessment for ischemic stroke beyond measurement of luminal stenosis. PMID:27429912

  20. Detection and Characterization of Early Atherosclerosis

    PubMed Central

    Barnes, R. W.; Bond, M. G.; Riley, W. A.; Czapla, L.; Mazzola, C. J.; Birdwell, J. D.

    1983-01-01

    Early stages of atherosclerosis in human subjects can be detected by lumen diameter and the pressure-strain elastic modulus. Results from non-human primate studies show that the intima thickens increasing the area enclosed by the elastic lamina. During this time the artery dilates so that the lumen area remains essentially constant. Only after the artery reaches its elastic limit does the lumen area decrease. Accurate measurements of arterial wall thickness and lumen diameter at diastole are important to the early detection of atherosclerosis. Axial resolutions of less than 0.1mm are required to detect tissue layers within the arterial wall itself. Two approaches and results of high axial resolution, deconvolution and high axial pulse generation, meeting range resolution requirements are presented.

  1. 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. PMID:26809711

  2. Inflammation, Atherosclerosis, and Coronary Artery Disease: PET/CT for the Evaluation of Atherosclerosis and Inflammation.

    PubMed

    Alie, Nadia; Eldib, Mootaz; Fayad, Zahi A; Mani, Venkatesh

    2014-01-01

    Atherosclerosis is a prevalent cardiovascular disease marked by inflammation and the formation of plaque within arterial walls. As the disease progresses, there is an increased risk of major cardiovascular events. Owing to the nature of atherosclerosis, it is imperative to develop methods to further understand the physiological implications and progression of the disease. The combination of positron emission tomography (PET)/computed tomography (CT) has proven to be promising for the evaluation of atherosclerotic plaques and inflammation within the vessel walls. The utilization of the radiopharmaceutical tracer, 18F-fluorodeoxyglucose ((18)F-FDG), with PET/CT is invaluable in understanding the pathophysiological state involved in atherosclerosis. In this review, we will discuss the use of (18)F-FDG-PET/CT imaging for the evaluation of atherosclerosis and inflammation both in preclinical and clinical studies. The potential of more specific novel tracers will be discussed. Finally, we will touch on the potential benefits of using the newly introduced combined PET/magnetic resonance imaging (MRI) for non-invasive imaging of atherosclerosis. PMID:25674025

  3. Inflammation, Atherosclerosis, and Coronary Artery Disease: PET/CT for the Evaluation of Atherosclerosis and Inflammation

    PubMed Central

    Alie, Nadia; Eldib, Mootaz; Fayad, Zahi A; Mani, Venkatesh

    2014-01-01

    Atherosclerosis is a prevalent cardiovascular disease marked by inflammation and the formation of plaque within arterial walls. As the disease progresses, there is an increased risk of major cardiovascular events. Owing to the nature of atherosclerosis, it is imperative to develop methods to further understand the physiological implications and progression of the disease. The combination of positron emission tomography (PET)/computed tomography (CT) has proven to be promising for the evaluation of atherosclerotic plaques and inflammation within the vessel walls. The utilization of the radiopharmaceutical tracer, 18F-fluorodeoxyglucose (18F-FDG), with PET/CT is invaluable in understanding the pathophysiological state involved in atherosclerosis. In this review, we will discuss the use of 18F-FDG-PET/CT imaging for the evaluation of atherosclerosis and inflammation both in preclinical and clinical studies. The potential of more specific novel tracers will be discussed. Finally, we will touch on the potential benefits of using the newly introduced combined PET/magnetic resonance imaging (MRI) for non-invasive imaging of atherosclerosis. PMID:25674025

  4. Translational Coronary Atherosclerosis Imaging with PET.

    PubMed

    Adamson, Philip D; Newby, David E; Dweck, Marc R

    2016-02-01

    Although still in its infancy, coronary atherosclerosis imaging with PET holds promise in improving understanding of the pathophysiologic processes that underlie plaque progression and adverse cardiovascular events. Fludeoxyglucose F 18 offers the potential to measure inflammatory activity within the plaque itself whereas fluoride F 18 allows detection of microcalcification, both of which are key characteristics of plaques at risk of rupture. Further work is required to improve these imaging techniques and to assess their ability to predict cardiac events prospectively. PMID:26590788

  5. 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.

  6. Mesenchymal Stem Cells Reduce Murine Atherosclerosis Development

    PubMed Central

    Frodermann, Vanessa; van Duijn, Janine; van Pel, Melissa; van Santbrink, Peter J.; Bot, Ilze; Kuiper, Johan; de Jager, Saskia C. A.

    2015-01-01

    Mesenchymal stem cells (MSCs) have regenerative properties, but recently they were also found to have immunomodulatory capacities. We therefore investigated whether MSCs could reduce atherosclerosis, which is determined by dyslipidaemia and chronic inflammation. We adoptively transferred MSCs into low-density lipoprotein-receptor knockout mice and put these on a Western-type diet to induce atherosclerosis. Initially after treatment, we found higher levels of circulating regulatory T cells. In the long-term, overall numbers of effector T cells were reduced by MSC treatment. Moreover, MSC-treated mice displayed a significant 33% reduction in circulating monocytes and a 77% reduction of serum CCL2 levels. Most strikingly, we found a previously unappreciated effect on lipid metabolism. Serum cholesterol was reduced by 33%, due to reduced very low-density lipoprotein levels, likely a result of reduced de novo hepatic lipogenesis as determined by a reduced expression of Stearoyl-CoA desaturase-1 and lipoprotein lipase. MSCs significantly affected lesion development, which was reduced by 33% in the aortic root. These lesions contained 56% less macrophages and showed a 61% reduction in T cell numbers. We show here for the first time that MSC treatment affects not only inflammatory responses but also significantly reduces dyslipidaemia in mice. This makes MSCs a potent candidate for atherosclerosis therapies. PMID:26490642

  7. Myeloperoxidase-generated oxidants and atherosclerosis.

    PubMed

    Podrez, E A; Abu-Soud, H M; Hazen, S L

    2000-06-15

    Atherosclerosis is a chronic inflammatory process where oxidative damage within the artery wall is implicated in the pathogenesis of the disease. Mononuclear phagocytes, an inflammatory cell capable of generating a variety of oxidizing species, are early components of arterial lesions. Their normal functions include host defense and surveillance through regulated generation of diffusible radical species, reactive oxygen or nitrogen species, and HOCl (hypochlorous acid). However, under certain circumstances an excess of these oxidizing species can overwhelm local antioxidant defenses and lead to oxidant stress and oxidative tissue injury, processes implicated in the pathogenesis of atherosclerosis. This review focuses on oxidation reactions catalyzed by myeloperoxidase (MPO), an abundant heme protein secreted from activated phagocytes which is present in human atherosclerotic lesions. Over the past several years, significant evidence has accrued demonstrating that MPO is one pathway for protein and lipoprotein oxidation during the evolution of cardiovascular disease. Multiple distinct products of MPO are enriched in human atherosclerotic lesions and LDL recovered from human atheroma. However, the biological consequences of these MPO-catalyzed reactions in vivo are still unclear. Here we discuss evidence for the occurrence of MPO-catalyzed oxidation reactions in vivo and the potential role MPO plays in both normal host defenses and inflammatory diseases like atherosclerosis. PMID:10946213

  8. Lifestyle effects on hematopoiesis and atherosclerosis

    PubMed Central

    Nahrendorf, Matthias; Swirski, Filip K.

    2015-01-01

    Diet, exercise, stress and sleep are receiving attention as environmental modifiers of chronic inflammatory diseases, including atherosclerosis, the culprit condition of myocardial infarction and stroke. Accumulating data indicate that psychosocial stress and a high-fat, high-cholesterol diet aggravate cardiovascular disease, whereas regular physical activity and healthy sleeping habits help prevent it. Here we raise the possibility that inflammation-associated leukocyte production plays a causal role in lifestyle effects on atherosclerosis progression. Specifically, we explore whether and how potent real-life disease modifiers influence hematopoiesis’ molecular and cellular machinery. Lifestyle, we hypothesize, may rearrange hematopoietic topography, diverting production from the bone marrow to the periphery, thus propagating a quantitative and qualitative drift of the macrophage supply chain. These changes may involve progenitor-extrinsic and intrinsic communication nodes that connect organ systems along neuro-immune and immuno-metabolic axes, ultimately leading to an altered number and phenotype of lesional macrophages. We propose that, in conjunction with improved public health policy, future therapeutics could aim to modulate the quantitative and qualitative output, as well as the location, of the hematopoietic tree to decrease the risk of atherosclerosis complications. PMID:25722442

  9. Coronary atherosclerosis -- a postmortem histopathological study.

    PubMed

    Kumar, S; Kumar, Verma A; Kumar, N; Baranwal, R K; Kumar, Verma R; Singh, M

    2012-01-01

    Cardiovascular disease in general and coronary heart disease in particular remains the leading cause of morbidity and mortality in developed countries. The aim of this study was to look at the prevalence of coronary atherosclerosis, its severity and site of involvement in postmortem hearts. The hearts of 30-60 yrs old, fifty dead victims were considered who died from various natural and unnatural deaths. After autopsy, coronary arteries were inspected grossly and microscopically. Out of all these cases, 10 cases (20 %) showed no pathological lesions. Total distribution of lesions in the coronaries are as follows; 34 (68 %) atheromatous lesions in Left Anterior Descending Artery, 25 (50 %) lesions in the Right Coronary Artery, 18 (36 %) lesions in Left Circumflex. Proximal involvement was more common except in the right coronary artery, which was involved distally. The overall prevalence of coronary atherosclerosis in the present study was comparable with that noted by other investigators in autopsy studied. There is a higher prevalence of atherosclerosis in Indians, which may be due to changes in life-styles and other risks factors (Tab. 1, Ref. 14). Full Text in PDF www.elis.sk. PMID:22502752

  10. [Mitogen-activated protein kinases in atherosclerosis].

    PubMed

    Bryk, Dorota; Olejarz, Wioletta; Zapolska-Downar, Danuta

    2014-01-01

    Intracellular signalling cascades, in which MAPK (mitogen-activated protein kinases) intermediate, are responsible for a biological response of a cell to an external stimulus. MAP kinases, which include ERK1/2 (extracellular signalling-regulated kinase), JNK (c-Jun N-terminal kinase) and p 38 MAPK, regulate the activity of many proteins, enzymes and transcription factors and thus have a wide spectrum of biological effects. Many basic scientific studies have defined numerous details of their pathway organization and activation. There are also more and more studies suggesting that individual MAP kinases probably play an important role in the pathogenesis of atherosclerosis. They may mediate inflammatory processes, endothelial cell activation, monocyte/macrophage recruitment and activation, smooth muscle cell proliferation and T-lymphocyte differentiation, all of which represent crucial mechanisms involved in pathogenesis of atherosclerosis. The specific inhibition of an activity of the respective MAP kinases may prove a new therapeutic approach to attenuate atherosclerotic plaque formation in the future. In this paper, we review the current state of knowledge concerning MAP kinase-dependent cellular and molecular mechanisms underlying atherosclerosis. PMID:24491891

  11. Short and Long-Term Effects of the Angiotensin II Receptor Blocker Irbesartan on Intradialytic Central Hemodynamics: A Randomized Double-Blind Placebo-Controlled One-Year Intervention Trial (the SAFIR Study)

    PubMed Central

    Peters, Christian Daugaard; Kjaergaard, Krista Dybtved; Jensen, Jens Dam; Christensen, Kent Lodberg; Strandhave, Charlotte; Tietze, Ida Noerager; Novosel, Marija Kristina; Bibby, Bo Martin; Jespersen, Bente

    2015-01-01

    Background and Aim Little is known about the tolerability of antihypertensive drugs during hemodialysis treatment. The present study evaluated the use of the angiotensin II receptor blocker (ARB) irbesartan. Design Randomized, double-blind, placebo-controlled, one-year intervention trial. Setting and Participants Eighty-two hemodialysis patients with urine output >300 mL/day and dialysis vintage <1 year. Intervention Irbesartan/placebo 300 mg/day for 12 months administered as add-on to antihypertensive treatment using a predialytic systolic blood pressure target of 140 mmHg in all patients. Outcomes and Measurements Cardiac output, stroke volume, central blood volume, total peripheral resistance, mean arterial blood pressure, and frequency of intradialytic hypotension. Results At baseline, the groups were similar regarding age, comorbidity, blood pressure, antihypertensive medication, ultrafiltration volume, and dialysis parameters. Over the one-year period, predialytic systolic blood pressure decreased significantly, but similarly in both groups. Mean start and mean end cardiac output, stroke volume, total peripheral resistance, heart rate, and mean arterial pressure were stable and similar in the two groups, whereas central blood volume increased slightly but similarly over time. The mean hemodynamic response observed during a dialysis session was a drop in cardiac output, in stroke volume, in mean arterial pressure, and in central blood volume, whereas heart rate increased. Total peripheral resistance did not change significantly. Overall, this pattern remained stable over time in both groups and was uninfluenced by ARB treatment. The total number of intradialytic hypotensive episodes was (placebo/ARB) 50/63 (P = 0.4). Ultrafiltration volume, left ventricular mass index, plasma albumin, and change in intradialytic total peripheral resistance were significantly associated with intradialytic hypotension in a multivariate logistic regression analysis based on

  12. Atherosclerosis and atheroma plaque rupture: normal anatomy of vasa vasorum and their role associated with atherosclerosis.

    PubMed

    Sun, Zhonghua

    2014-01-01

    Atherosclerosis is primarily a degenerative disorder related to aging with a chronic inflammatory component. There are differences in expression among different vascular beds, inflicting a range of vascular diseases. The majority of studies focus on the inner and medial vascular layers, which are affected at the development of atherosclerosis. Recent evidence shows that the outer layer of blood vessels, composed of the adventitial layer and the vasa vasorum, not only plays a significant role in maintaining vessel integrity, but also reacts to atheroma. What is not clear is the extent of contribution of the outer layer to the process of atherosclerosis. Is it involved in the initiation, progression, and clinical expression of atheroma? Is the inflammation associated with atheroma limited to being merely reactive or is there a proactive element? This paper provides an overview of the normal anatomy of vasa vasorum and potential mechanism of plaque formation due to vascular injury (vasa vasorum) and microhemorrhage. PMID:24790560

  13. Atherosclerosis and Atheroma Plaque Rupture: Normal Anatomy of Vasa Vasorum and Their Role Associated with Atherosclerosis

    PubMed Central

    2014-01-01

    Atherosclerosis is primarily a degenerative disorder related to aging with a chronic inflammatory component. There are differences in expression among different vascular beds, inflicting a range of vascular diseases. The majority of studies focus on the inner and medial vascular layers, which are affected at the development of atherosclerosis. Recent evidence shows that the outer layer of blood vessels, composed of the adventitial layer and the vasa vasorum, not only plays a significant role in maintaining vessel integrity, but also reacts to atheroma. What is not clear is the extent of contribution of the outer layer to the process of atherosclerosis. Is it involved in the initiation, progression, and clinical expression of atheroma? Is the inflammation associated with atheroma limited to being merely reactive or is there a proactive element? This paper provides an overview of the normal anatomy of vasa vasorum and potential mechanism of plaque formation due to vascular injury (vasa vasorum) and microhemorrhage. PMID:24790560

  14. Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications.

    PubMed

    Tikoo, Kulbhushan; Patel, Gaurang; Kumar, Sandeep; Karpe, Pinakin Arun; Sanghavi, Maitri; Malek, Vajir; Srinivasan, K

    2015-02-01

    Growing body of evidence points out the crucial role of ACE2 in preventing atherosclerosis. However, data on how atherosclerosis affects ACE2 expression in heart and kidney remains unknown. Atherosclerosis was induced by feeding New Zealand White rabbits with high cholesterol diet (HCD - 2%) for 12 weeks and atorvastatin was administered (5mg/kg/day p.o) in last 3 weeks. ACE2 mRNA and protein expression was assessed by Western blotting and real time PCR. HCD fed rabbits developed atherosclerosis as confirmed by increase in plasma total cholesterol, LDL and triglycerides as well as formation atherosclerotic plaques in arch of aorta. The ACE2 protein but not mRNA expression was reduced in heart and kidney of HCD rabbits. Interestingly, atorvastatin increased the ACE2 protein expression in heart and kidney of HCD rabbits. However, atorvastatin increased ACE2 mRNA in heart but not in kidney of HCD rabbits. Atorvastatin increased the occupancy of histone H3 acetylation (H3-Ac) mark on ACE2 promoter region in heart of HCD rabbits indicating direct or indirect epigenetic up-regulation of ACE2 by atorvastatin. Further, atorvastatin suppressed Ang II-induced contractile responses and enhanced AT2 receptor mediated relaxant responses in atherosclerotic aorta. We propose that atherosclerosis is associated with reduced ACE2 expression in heart and kidney. We also show an unexplored potential of atorvastatin to up-regulate ACE2 via epigenetic histone modifications. Our data suggest a novel way of replenishing ACE2 expression for preventing not only atherosclerosis but also other cardiovascular disorders. PMID:25482567

  15. Accelerated atherosclerosis in patients with chronic inflammatory rheumatologic conditions

    PubMed Central

    Hong, Jison; Maron, David J; Shirai, Tsuyoshi; Weyand, Cornelia M

    2015-01-01

    Atherosclerosis is a complex inflammatory disease involving aberrant immune and tissue healing responses, which begins with endothelial dysfunction and ends with plaque development, instability and rupture. The increased risk for coronary artery disease in patients with rheumatologic diseases highlights how aberrancy in the innate and adaptive immune system may be central to development of both disease states and that atherosclerosis may be on a spectrum of immune-mediated conditions. Recognition of the tight association between chronic inflammatory disease and complications of atherosclerosis will impact the understanding of underlying pathogenic mechanisms and change diagnostic and therapeutic approaches in patients with rheumatologic syndromes as well as patients with coronary artery disease. In this review, we provide a summary of the role of the immune system in atherosclerosis, discuss the proposed mechanisms of accelerated atherosclerosis seen in association with rheumatologic diseases, evaluate the effect of immunosuppression on atherosclerosis and provide updates on available risk assessment tools, biomarkers and imaging modalities. PMID:27042216

  16. LDL biochemical modifications: a link between atherosclerosis and aging

    PubMed Central

    Alique, Matilde; Luna, Carlos; Carracedo, Julia; Ramírez, Rafael

    2015-01-01

    Atherosclerosis is an aging disease in which increasing age is a risk factor. Modified low-density lipoprotein (LDL) is a well-known risk marker for cardiovascular disease. High-plasma LDL concentrations and modifications, such as oxidation, glycosylation, carbamylation and glycoxidation, have been shown to be proatherogenic experimentally in vitro and in vivo. Atherosclerosis results from alterations to LDL in the arterial wall by reactive oxygen species (ROS). Evidence suggests that common risk factors for atherosclerosis raise the likelihood that free ROS are produced from endothelial cells and other cells. Furthermore, oxidative stress is an important factor in the induction of endothelial senescence. Thus, endothelial damage and cellular senescence are well-established markers for atherosclerosis. This review examines LDL modifications and discusses the mechanisms of the pathology of atherosclerosis due to aging, including endothelial damage and oxidative stress, and the link between aging and atherosclerosis. PMID:26637360

  17. Hypercholesterolemia Tunes Hematopoietic Stem/Progenitor Cells for Inflammation and Atherosclerosis

    PubMed Central

    Ma, Xiaojuan; Feng, Yingmei

    2016-01-01

    As the pathological basis of cardiovascular disease (CVD), atherosclerosis is featured as a chronic inflammation. Hypercholesterolemia is an independent risk factor for CVD. Accumulated studies have shown that hypercholesterolemia is associated with myeloid cell expansion, which stimulates innate and adaptive immune responses, strengthens inflammation, and accelerates atherosclerosis progression. Hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM) expresses a panel of lipoprotein receptors to control cholesterol homeostasis. Deficiency of these receptors abrogates cellular cholesterol efflux, resulting in HSPC proliferation and differentiation in hypercholesterolemic mice. Reduction of the cholesterol level in the lipid rafts by infusion of reconstituted high-density lipoprotein (HDL) or its major apolipoprotein, apoA-I, reverses hypercholesterolemia-induced HSPC expansion. Apart from impaired cholesterol metabolism, inhibition of reactive oxygen species production suppresses HSPC activation and leukocytosis. These data indicate that the mechanisms underlying the effects of hypercholesterolemia on HSPC proliferation and differentiation could be multifaceted. Furthermore, dyslipidemia also regulates HSPC-neighboring cells, resulting in HSPC mobilization. In the article, we review how hypercholesterolemia evokes HSPC activation and mobilization directly or via its modification of BM microenvironment. We hope this review will bring light to finding key molecules to control HSPC expansion, inflammation, and atherosclerosis for the treatment of CVD. PMID:27447612

  18. Fibroblast Growth Factor 21 Protects against Atherosclerosis via Fine-Tuning the Multiorgan Crosstalk.

    PubMed

    Jin, Leigang; Lin, Zhuofeng; Xu, Aimin

    2016-02-01

    Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on energy metabolism and insulin sensitivity. Besides its antiobese and antidiabetic activity, FGF21 also possesses the protective effects against atherosclerosis. Circulating levels of FGF21 are elevated in patients with atherosclerosis, macrovascular and microvascular complications of diabetes, possibly due to a compensatory upregulation. In apolipoprotein E-deficient mice, formation of atherosclerotic plaques is exacerbated by genetic depletion of FGF21, but is attenuated upon replenishment with recombinant FGF21. However, the blood vessel is not the direct target of FGF21, and the antiatherosclerotic activity of FGF21 is attributed to its actions in adipose tissues and liver. In adipocytes, FGF21 promotes secretion of adiponectin, which in turn acts directly on blood vessels to reduce endothelial dysfunction, inhibit proliferation of smooth muscle cells and block conversion of macrophages to foam cells. Furthermore, FGF21 suppresses cholesterol biosynthesis and attenuates hypercholesterolemia by inhibiting the transcription factor sterol regulatory element-binding protein-2 in hepatocytes. The effects of FGF21 on elevation of adiponectin and reduction of hypercholesterolemia are also observed in a phase-1b clinical trial in patients with obesity and diabetes. Therefore, FGF21 exerts its protection against atherosclerosis by fine-tuning the interorgan crosstalk between liver, brain, adipose tissue, and blood vessels. PMID:26912152

  19. Fibroblast Growth Factor 21 Protects against Atherosclerosis via Fine-Tuning the Multiorgan Crosstalk

    PubMed Central

    Jin, Leigang; Lin, Zhuofeng

    2016-01-01

    Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on energy metabolism and insulin sensitivity. Besides its antiobese and antidiabetic activity, FGF21 also possesses the protective effects against atherosclerosis. Circulating levels of FGF21 are elevated in patients with atherosclerosis, macrovascular and microvascular complications of diabetes, possibly due to a compensatory upregulation. In apolipoprotein E-deficient mice, formation of atherosclerotic plaques is exacerbated by genetic depletion of FGF21, but is attenuated upon replenishment with recombinant FGF21. However, the blood vessel is not the direct target of FGF21, and the antiatherosclerotic activity of FGF21 is attributed to its actions in adipose tissues and liver. In adipocytes, FGF21 promotes secretion of adiponectin, which in turn acts directly on blood vessels to reduce endothelial dysfunction, inhibit proliferation of smooth muscle cells and block conversion of macrophages to foam cells. Furthermore, FGF21 suppresses cholesterol biosynthesis and attenuates hypercholesterolemia by inhibiting the transcription factor sterol regulatory element-binding protein-2 in hepatocytes. The effects of FGF21 on elevation of adiponectin and reduction of hypercholesterolemia are also observed in a phase-1b clinical trial in patients with obesity and diabetes. Therefore, FGF21 exerts its protection against atherosclerosis by fine-tuning the interorgan crosstalk between liver, brain, adipose tissue, and blood vessels. PMID:26912152

  20. Hypercholesterolemia Tunes Hematopoietic Stem/Progenitor Cells for Inflammation and Atherosclerosis.

    PubMed

    Ma, Xiaojuan; Feng, Yingmei

    2016-01-01

    As the pathological basis of cardiovascular disease (CVD), atherosclerosis is featured as a chronic inflammation. Hypercholesterolemia is an independent risk factor for CVD. Accumulated studies have shown that hypercholesterolemia is associated with myeloid cell expansion, which stimulates innate and adaptive immune responses, strengthens inflammation, and accelerates atherosclerosis progression. Hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM) expresses a panel of lipoprotein receptors to control cholesterol homeostasis. Deficiency of these receptors abrogates cellular cholesterol efflux, resulting in HSPC proliferation and differentiation in hypercholesterolemic mice. Reduction of the cholesterol level in the lipid rafts by infusion of reconstituted high-density lipoprotein (HDL) or its major apolipoprotein, apoA-I, reverses hypercholesterolemia-induced HSPC expansion. Apart from impaired cholesterol metabolism, inhibition of reactive oxygen species production suppresses HSPC activation and leukocytosis. These data indicate that the mechanisms underlying the effects of hypercholesterolemia on HSPC proliferation and differentiation could be multifaceted. Furthermore, dyslipidemia also regulates HSPC-neighboring cells, resulting in HSPC mobilization. In the article, we review how hypercholesterolemia evokes HSPC activation and mobilization directly or via its modification of BM microenvironment. We hope this review will bring light to finding key molecules to control HSPC expansion, inflammation, and atherosclerosis for the treatment of CVD. PMID:27447612

  1. Study on atherosclerosis treated with theory of detoxification.

    PubMed

    Xu, Yingchun; Wang, Hualiang; Ding, Jing

    2006-06-01

    Starting with the contents, classification and pathogenic characteristics of the toxic pathogen and combining the modern medical research on the correlation of atherosclerosis with inflammation and immune reaction, authors have studied and expounded the interrelationship between the toxic pathogen and atherosclerosis. The toxic pathogen affecting the whole pathological process of atherosclerosis is a key factor for the disease to remain lingering and a cause of various cardiocerebrovascular diseases. Detoxification can be used to treat atherosclerosis so as to enhance the toxin-removing ability of the body and resist the damage to the body from the toxic pathogen. PMID:16817276

  2. Atherosclerosis Induced by Chlamydophila pneumoniae: A Controversial Theory.

    PubMed

    Honarmand, Hamidreza

    2013-01-01

    More than a century ago, inflammation and infection were considered to have atherogenic effects. The old idea that coronary heart disease (CHD) possibly has an infectious etiology has only reemerged in recent years. Atherosclerosis is the main pathological process involved in CHD and is, logically, the first place to look for infectious etiology. The process of atherosclerosis itself provides the first hints of potential infectious cause. Smooth muscle proliferation, with subsequent intimal thickening, luminal narrowing, and endothelial degeneration, constitutes the natural history of atherosclerosis, being with the severity and speed of these changes. Both viral and bacterial pathogens have been proposed to be associated with the inflammatory changes found in atherosclerosis. Recently, Chlamydophila pneumoniae (C. pneumoniae) has been implicated as a possible etiologic agent of coronary artery disease and atherosclerosis. New evidence which supports a role for C. pneumoniae in the pathogenesis of atherosclerosis has emerged. C. pneumoniae has been detected in atherosclerotic arteries by several techniques, and the organism has been isolated from both coronary and carotid atheromas. Recent animal models have suggested that C. pneumoniae is capable of inducing atherosclerosis in both rabbit and mouse models of atherosclerosis. Furthermore, human clinical treatment studies which examined the use of antichlamydial macrolide antibiotics in patients with coronary atherosclerosis have been carried out. The causal relationship has not yet been proven, but ongoing large intervention trials and research on pathogenetic mechanisms may lead to the use of antimicrobial agents in the treatment of CHD in the future. PMID:23956742

  3. 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. PMID:24582386

  4. The paradoxical role of IL-17 in atherosclerosis.

    PubMed

    Gong, Fangchen; Liu, Zhengxia; Liu, Jingning; Zhou, Ping; Liu, Ying; Lu, Xiang

    2015-09-01

    Atherosclerosis is a chronic inflammatory disease mediated by innate and adaptive immune responses. In recent years, CD4(+) T cells (Th1, Th2, Treg, and Th17) have been increasingly studied for their role in atherosclerosis pathophysiology, atheroma stability, plaque rupture, and life-threatening acute coronary syndrome. IL-17, a marker cytokine of Th17 cells, has been reported to be involved in the pathogenesis of rheumatoid arthritis, inflammatory bowel disease, and asthma. However, its role in atherosclerosis has been poorly characterized. This article provides a comprehensive overview of the role of IL-17 in the development of atherosclerosis and human coronary artery diseases. PMID:26077826

  5. Is the Use of Fullerene in Photodynamic Therapy Effective for Atherosclerosis?

    SciTech Connect

    Nitta, Norihisa Seko, Ayumi; Sonoda, Akinaga; Ohta, Shinichi; Tanaka, Toyohiko; Takahashi, Masashi; Murata, Kiyoshi; Takemura, Shizuki; Sakamoto, Tsutomu; Tabata, Yasuhiko

    2008-03-15

    The purpose of this study was to evaluate Fullerene as a therapeutic photosensitizer in the treatment of atherosclerosis. An atherosclerotic experimental rabbit model was prepared by causing intimal injury to bilateral external iliac arteries using balloon expansion. In four atherosclerotic rabbits and one normal rabbit, polyethylene glycol-modified Fullerene (Fullerene-PEG) was infused into the left external iliac artery and illuminated by light emitting diode (LED), while the right external iliac artery was only illuminated by LED. Two weeks later, the histological findings for each iliac artery were evaluated quantitatively and comparisons were made among atherosclerotic Fullerene+LED artery (n = 4), atherosclerotic light artery (n = 4), normal Fullerene+LED artery (n = 1), and normal light artery (n = 1). An additional two atherosclerotic rabbits were studied by fluorescence microscopy, after Fullerene-PEG-Cy5 complex infusion into the left external iliac artery, for evaluation of Fullerene-PEG incorporated within the atherosclerotic lesions. The degree of atherosclerosis in the atherosclerotic Fullerene+LED artery was significantly (p < 0.05) more severe than that in the atherosclerotic LED artery. No pathological change was observed in normal Fullerene+LED and LED arteries. In addition, strong accumulation of Fullerene-PEG-Cy5 complex within the plaque of the left iliac artery of the two rabbits was demonstrated, in contrast to no accumulation in the right iliac artery. We conclude that infusion of a high concentration of Fullerene-PEG followed by photo-illumination resulted not in a suppression of atherosclerosis but in a progression of atherosclerosis in experimental rabbit models. However, this intervention showed no adverse effects on the normal iliac artery.

  6. Future imaging of atherosclerosis: molecular imaging of coronary atherosclerosis with (18)F positron emission tomography.

    PubMed

    Scherer, Daniel J; Psaltis, Peter J

    2016-08-01

    Atherosclerosis is characterized by the formation of complex atheroma lesions (plaques) in arteries that pose risk by their flow-limiting nature and propensity for rupture and thrombotic occlusion. It develops in the context of disturbances to lipid metabolism and immune response, with inflammation underpinning all stages of plaque formation, progression and rupture. As the primary disease process responsible for myocardial infarction, stroke and peripheral vascular disease, atherosclerosis is a leading cause of morbidity and mortality on a global scale. A precise understanding of its pathogenic mechanisms is therefore critically important. Integral to this is the role of vascular wall imaging. Over recent years, the rapidly evolving field of molecular imaging has begun to revolutionize our ability to image beyond just the anatomical substrate of vascular disease, and more dynamically assess its pathobiology. Nuclear imaging by positron emission tomography (PET) can target specific molecular and biological pathways involved in atherosclerosis, with the application of (18)Fluoride PET imaging being widely studied for its potential to identify plaques that are vulnerable or high risk. In this review, we discuss the emergence of (18)Fluoride PET as a promising modality for the assessment of coronary atherosclerosis, focusing on the strengths and limitations of the two main radionuclide tracers that have been investigated to date: 2-deoxy-2-((18)F)fluoro-D-glucose ((18)F-FDG) and sodium (18)F-fluoride ((18)F-NaF). PMID:27500093

  7. Future imaging of atherosclerosis: molecular imaging of coronary atherosclerosis with 18F positron emission tomography

    PubMed Central

    Psaltis, Peter J.

    2016-01-01

    Atherosclerosis is characterized by the formation of complex atheroma lesions (plaques) in arteries that pose risk by their flow-limiting nature and propensity for rupture and thrombotic occlusion. It develops in the context of disturbances to lipid metabolism and immune response, with inflammation underpinning all stages of plaque formation, progression and rupture. As the primary disease process responsible for myocardial infarction, stroke and peripheral vascular disease, atherosclerosis is a leading cause of morbidity and mortality on a global scale. A precise understanding of its pathogenic mechanisms is therefore critically important. Integral to this is the role of vascular wall imaging. Over recent years, the rapidly evolving field of molecular imaging has begun to revolutionize our ability to image beyond just the anatomical substrate of vascular disease, and more dynamically assess its pathobiology. Nuclear imaging by positron emission tomography (PET) can target specific molecular and biological pathways involved in atherosclerosis, with the application of 18Fluoride PET imaging being widely studied for its potential to identify plaques that are vulnerable or high risk. In this review, we discuss the emergence of 18Fluoride PET as a promising modality for the assessment of coronary atherosclerosis, focusing on the strengths and limitations of the two main radionuclide tracers that have been investigated to date: 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) and sodium 18F-fluoride (18F-NaF). PMID:27500093

  8. Chronic intermittent hypoxia exposure-induced atherosclerosis: a brief review.

    PubMed

    Song, Dongmei; Fang, Guoqiang; Greenberg, Harly; Liu, Shu Fang

    2015-12-01

    Obstructive sleep apnea (OSA) is highly prevalent in the USA and is recognized as an independent risk factor for atherosclerotic cardiovascular disease. Identification of atherosclerosis risk factor attributable to OSA may provide opportunity to develop preventive measures for cardiovascular risk reduction. Chronic intermittent hypoxia (CIH) is a prominent feature of OSA pathophysiology and may be a major mechanism linking OSA to arteriosclerosis. Animal studies demonstrated that CIH exposure facilitated high-cholesterol diet (HCD)-induced atherosclerosis, accelerated the progression of existing atherosclerosis, and induced atherosclerotic lesions in the absence of other atherosclerosis risk factors, demonstrating that CIH is an independent causal factor of atherosclerosis. Comparative studies revealed major differences between CIH-induced and the classic HCD-induced atherosclerosis. Systemically, CIH was a much weaker inducer of atherosclerosis. CIH and HCD differentially activated inflammatory pathways. Histologically, CIH-induced atherosclerotic plaques had no clear necrotic core, contained a large number of CD31+ endothelial cells, and had mainly elastin deposition, whereas HCD-induced plaques had typical necrotic cores and fibrous caps, contained few endothelial cells, and had mainly collagen deposition. Metabolically, CIH caused mild, but HCD caused more severe dyslipidemia. Mechanistically, CIH did not, but HCD did, cause macrophage foam cell formation. NF-κB p50 gene deletion augmented CIH-induced, but not HCD-induced atherosclerosis. These differences reflect the intrinsic differences between the two types of atherosclerosis in terms of pathological nature and underlying mechanisms and support the notion that CIH-induced atherosclerosis is a new paradigm that differs from the classic HCD-induced atherosclerosis. PMID:26407987

  9. Association of Fat Density With Subclinical Atherosclerosis

    PubMed Central

    Alvey, Nicholas J.; Pedley, Alison; Rosenquist, Klara J.; Massaro, Joseph M.; O'Donnell, Christopher J.; Hoffmann, Udo; Fox, Caroline S.

    2014-01-01

    Background Ectopic fat density is associated with cardiovascular disease (CVD) risk factors above and beyond fat volume. Volumetric measures of ectopic fat have been associated with CVD risk factors and subclinical atherosclerosis. The aim of this study was to investigate the association between fat density and subclinical atherosclerosis. Methods and Results Participants were drawn from the Multi‐Detector Computed Tomography (MDCT) substudy of the Framingham Heart Study (n=3079; mean age, 50.1 years; 49.2% women). Fat density was indirectly estimated by computed tomography attenuation (Hounsfield Units [HU]) on abdominal scan slices. Visceral fat (VAT), subcutaneous fat (SAT), and pericardial fat HU and volumes were quantified using standard protocols; coronary and abdominal aortic calcium (CAC and AAC, respectively) were measured radiographically. Multivariable‐adjusted logistic regression models were used to evaluate the association between adipose tissue HU and the presence of CAC and AAC. Overall, 17.1% of the participants had elevated CAC (Agatston score [AS]>100), and 23.3% had elevated AAC (AS>age‐/sex‐specific cutoffs). Per 5‐unit decrement in VAT HU, the odds ratio (OR) for elevated CAC was 0.76 (95% confidence interval [CI], 0.65 to 0.89; P=0.0005), even after adjustment for body mass index or VAT volume. Results were similar for SAT HU. With decreasing VAT HU, we also observed an OR of 0.79 (95% CI, 0.67 to 0.92; P=0.004) for elevated AAC after multivariable adjustment. We found no significant associations between SAT HU and AAC. There was no significant association between pericardial fat HU and either CAC or AAC. Conclusions Lower VAT and SAT HU, indirect estimates of fat quality, are associated with a lower risk of subclinical atherosclerosis. PMID:25169793

  10. MicroRNA-26a prevents endothelial cell apoptosis by directly targeting TRPC6 in the setting of atherosclerosis

    PubMed Central

    Zhang, Yong; Qin, Wei; Zhang, Longyin; Wu, Xianxian; Du, Ning; Hu, Yingying; Li, Xiaoguang; Shen, Nannan; Xiao, Dan; Zhang, Haiying; Li, Zhange; Zhang, Yue; Yang, Huan; Gao, Feng; Du, Zhimin; Xu, Chaoqian; Yang, Baofeng

    2015-01-01

    Atherosclerosis, a chronic inflammatory disease, is the major cause of life-threatening complications such as myocardial infarction and stroke. Endothelial apoptosis plays a vital role in the initiation and progression of atherosclerotic lesions. Although a subset of microRNAs (miRs) have been identified as critical regulators of atherosclerosis, studies on their participation in endothelial apoptosis in atherosclerosis have been limited. In our study, we found that miR-26a expression was substantially reduced in the aortic intima of ApoE−/− mice fed with a high-fat diet (HFD). Treatment of human aortic endothelial cells (HAECs) with oxidized low-density lipoprotein (ox-LDL) suppressed miR-26a expression. Forced expression of miR-26a inhibited endothelial apoptosis as evidenced by MTT assay and TUNEL staining results. Further analysis identified TRPC6 as a target of miR-26a, and TRPC6 overexpression abolished the anti-apoptotic effect of miR-26a. Moreover, the cytosolic calcium and the mitochondrial apoptotic pathway were found to mediate the beneficial effects of miR-26a on endothelial apoptosis. Taken together, our study reveals a novel role of miR-26a in endothelial apoptosis and indicates a therapeutic potential of miR-26a for atherosclerosis associated with apoptotic cell death. PMID:25801675

  11. 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. PMID:25261526

  12. MicroRNA-26a prevents endothelial cell apoptosis by directly targeting TRPC6 in the setting of atherosclerosis

    NASA Astrophysics Data System (ADS)

    Zhang, Yong; Qin, Wei; Zhang, Longyin; Wu, Xianxian; Du, Ning; Hu, Yingying; Li, Xiaoguang; Shen, Nannan; Xiao, Dan; Zhang, Haiying; Li, Zhange; Zhang, Yue; Yang, Huan; Gao, Feng; Du, Zhimin; Xu, Chaoqian; Yang, Baofeng

    2015-03-01

    Atherosclerosis, a chronic inflammatory disease, is the major cause of life-threatening complications such as myocardial infarction and stroke. Endothelial apoptosis plays a vital role in the initiation and progression of atherosclerotic lesions. Although a subset of microRNAs (miRs) have been identified as critical regulators of atherosclerosis, studies on their participation in endothelial apoptosis in atherosclerosis have been limited. In our study, we found that miR-26a expression was substantially reduced in the aortic intima of ApoE-/- mice fed with a high-fat diet (HFD). Treatment of human aortic endothelial cells (HAECs) with oxidized low-density lipoprotein (ox-LDL) suppressed miR-26a expression. Forced expression of miR-26a inhibited endothelial apoptosis as evidenced by MTT assay and TUNEL staining results. Further analysis identified TRPC6 as a target of miR-26a, and TRPC6 overexpression abolished the anti-apoptotic effect of miR-26a. Moreover, the cytosolic calcium and the mitochondrial apoptotic pathway were found to mediate the beneficial effects of miR-26a on endothelial apoptosis. Taken together, our study reveals a novel role of miR-26a in endothelial apoptosis and indicates a therapeutic potential of miR-26a for atherosclerosis associated with apoptotic cell death.

  13. 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

  14. Imaging and Nanomedicine in Inflammatory Atherosclerosis

    PubMed Central

    Mulder, Willem J. M.; Jaffer, Farouc A.; Fayad, Zahi A.; Nahrendorf, Matthias

    2014-01-01

    Bioengineering provides unique opportunities to better understand and manage atherosclerotic disease. The field is entering a new era that merges the latest biological insights into inflammatory disease processes with targeted imaging and nanomedicine. Preclinical cardiovascular molecular imaging allows the in vivo study of targeted nanotherapeutics specifically directed toward immune system components that drive atherosclerotic plaque development and complication. The first multicenter trials highlight the potential contribution of multimodality imaging to more efficient drug development. This review describes how the integration of engineering, nanotechnology, and cardiovascular immunology may yield precision diagnostics and efficient therapeutics for atherosclerosis and its ischemic complications. PMID:24898749

  15. [Atherosclerosis in childhood: the role of obesity].

    PubMed

    Sarni, P; Vinci, A; Fierro, S; Del Buono, S

    1997-01-01

    A variety of studies indicates that the process of atherosclerosis begins in childhood and progresses during adulthood. Chronic obesity, inadequate caloric intake, and hypertension and smoke, are associated with an increased cardiovascular disease. The aim of this study is to investigate if the presence of some risk factors during adolescence may involve in accelerated atherosclerosis disease. 50 subjects, median age 11 +/- 0.6 SD (27 females, and 23 males) are admitted to the study. After overnight fasting we have investigated: lipoproteina A (nephelometric test), glycemia and insulin baseline and after load 120', tryglycerides, cholesterolo, apolipoproteina A, B, plasma concentrations. In addition to general medical evaluation, anthropometric measurements of weight, height, blood pressure, BMI, overnight ratio were calculated according to Tanner's charts. The means anthropometric and metabolic values in different groups were compared. One group affected with abdominal obesity state (waist-hips ratio > 0.9), the second with mid obesity condition (waist-hip ratio < 0.9). Tryglycerides, cholesterolo, insulin plasma concentrations in both groups were considered similar. However in the first group higher levels of apolipoproteina A (means 102 + 10.2 SD) and lipoproteina A were demonstrated (P = 0.03 in males, P = 0.01 Statview for Mann Whitney test). Childhood is an important period for the development of the atherosclerosis such as the presence of obesity during this time has a very high likelihood of persisting into adulthood. The severity of obesity in adults is greater in those who were obese as adolescents. In accord with other authors we have not observed abnormal tryglicerides and cholesterolo plasma concentrations, which probably are found in adulthood obesity. We believe indeed the risk factors are different in obesity of childhood, atherosclerosis may be induced by high endogenous insulin secretion and abnormal uptake of lipoprotein. However the potential

  16. Statins and atherosclerosis: the role of epigenetics.

    PubMed

    Storino Farina, Marcelo; Rojano Rada, Jairo; Molina Garrido, Antony; Martínez, Xiomara; Pulgar, Alfredo; Paniagua, Roxanna; Garrido, Jorge

    2015-01-01

    Atherosclerosis is an immune-inflammatory disease, in which pathophysiological mechanisms include inflammation patterns and epigenetic changes that alter gene expression of several inflammatory and non-inflammatory mediators. Epigenetics is offering explanations on how diet, environmental factors and lifestyle can influence the onset and progression of the disease, and how these alterations can be transmitted to the following generations without any changes in DNA sequences. Statins, through their pleiotropic effects, provide a useful tool in controlling the progression of plaques and their subsequent impact. PMID:26639162

  17. Alexander I. Ignatowski: a pioneer in the study of atherosclerosis.

    PubMed

    Konstantinov, Igor E; Jankovic, Gradimir M

    2013-01-01

    In 1908, Alexander I. Ignatowski (1875-1955) published his pioneering work that first revealed a relationship between cholesterol-rich food and experimental atherosclerosis. This early experimental work paved a way to the metabolic study of the mechanism of atherosclerosis. Herein, we present a brief account of Ignatowski's work and life. PMID:23914012

  18. Modulation of atherosclerosis by N-3 polyunsaturated fatty acids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have reviewed literature regarding the effects of n-3 polyunsaturated fatty acids (PUFA) on risk factors for atherosclerosis in human subjects. Dietary intervention with long chain n-3 PUFA decreased some risk factor (s) for atherosclerosis in most human studies reviewed. These benefits resulted ...

  19. Atherosclerosis: a chronic inflammatory disease mediated by mast cells.

    PubMed

    Conti, Pio; Shaik-Dasthagirisaeb, Yazdami

    2015-01-01

    Inflammation is a process that plays an important role in the initiation and progression of atherosclerosis and immune disease, involving multiple cell types, including macrophages, T-lymphocytes, endothelial cells, smooth muscle cells and mast cells. The fundamental damage of atherosclerosis is the atheromatous or fibro-fatty plaque which is a lesion that causes several diseases. In atherosclerosis the innate immune response, which involves macrophages, is initiated by the arterial endothelial cells which respond to modified lipoproteins and lead to Th1 cell subset activation and generation of inflammatory cytokines and chemoattractant chemokines. Other immune cells, such as CD4+ T inflammatory cells, which play a critical role in the development and progression of atherosclerosis, and regulatory T cells [Treg], which have a protective effect on the development of atherosclerosis are involved. Considerable evidence indicates that mast cells and their products play a key role in inflammation and atherosclerosis. Activated mast cells can have detrimental effects, provoking matrix degradation, apoptosis, and enhancement as well as recruitment of inflammatory cells, which actively contributes to atherosclerosis and plaque formation. Here we discuss the relationship between atherosclerosis, inflammation and mast cells. PMID:26648785

  20. Atherosclerosis: a chronic inflammatory disease mediated by mast cells

    PubMed Central

    Shaik-Dasthagirisaeb, Yazdami

    2015-01-01

    Inflammation is a process that plays an important role in the initiation and progression of atherosclerosis and immune disease, involving multiple cell types, including macrophages, T-lymphocytes, endothelial cells, smooth muscle cells and mast cells. The fundamental damage of atherosclerosis is the atheromatous or fibro-fatty plaque which is a lesion that causes several diseases. In atherosclerosis the innate immune response, which involves macrophages, is initiated by the arterial endothelial cells which respond to modified lipoproteins and lead to Th1 cell subset activation and generation of inflammatory cytokines and chemoattractant chemokines. Other immune cells, such as CD4+ T inflammatory cells, which play a critical role in the development and progression of atherosclerosis, and regulatory T cells [Treg], which have a protective effect on the development of atherosclerosis are involved. Considerable evidence indicates that mast cells and their products play a key role in inflammation and atherosclerosis. Activated mast cells can have detrimental effects, provoking matrix degradation, apoptosis, and enhancement as well as recruitment of inflammatory cells, which actively contributes to atherosclerosis and plaque formation. Here we discuss the relationship between atherosclerosis, inflammation and mast cells. PMID:26648785

  1. Basic science for the clinician 44: atherosclerosis: an immunologically mediated (autoimmune?) disease.

    PubMed

    Sigal, Leonard H

    2007-06-01

    There has been a sea change in our understanding of atherosclerosis. We have come a long way from the days where eating too much fat and not getting enough exercise and having the wrong genetic background was thought to be the entire story. A few years ago, the cardiologists began to embrace inflammation as a possible pathogenetic mechanism and from that came high-sensitivity C-reactive protein testing for just about everyone. Chronic systemic inflammation became an area of interest. We have learned that it is more than just corticosteroid use that causes accelerated atherosclerosis in our rheumatoid and lupus patients. Even C-reactive protein may be a pathogenetic player, not only a diagnostic clue. Oxidized phospholipids and the cells that recognize them may be crucial in the evolution of the atherosclerotic plaque. Statins may be useful in suppressing inflammation, not only in suppressing cholesterol levels. And now even cardiologists are thinking about immune mechanisms! A strange world, but the beneficiaries of going through this looking glass will be our patients. A true understanding of this seems to have required a most circuitous route-sometimes you have to leave for a long journey before you can return and really see home for the first time. PMID:17551386

  2. MicroRNA-125b is involved in atherosclerosis obliterans in vitro by targeting podocalyxin.

    PubMed

    Li, Xiaobing; Yao, Na; Zhang, Juan; Liu, Zhenjiang

    2015-07-01

    Cardiovascular disease associated with oxidative stress, including atherosclerosis, is the leading cause of mortality worldwide. The accelerated proliferation and migration of vascular smooth muscle cells are the predominant characteristics of atherogenesis, and endothelial dysfunction is a major risk factor for the pathogenesis of atherosclerosis. Podocalyxin (PODXL), a type I member of the cluster of differentiation 34 family of sialomucins, functions as a pro-adhesive molecule. Emerging evidence has revealed the importance of micro (mi)RNAs in the cardiovascular system. The present study demonstrated that there was an inverse association between miRNA (miR)-125b and PODXL in human umbilical vein endothelial cells and human aortic vascular smooth muscle cells (HAVSMCs) treated with oxidized low‑density lipoprotein (LDL) and platelet derived growth factor. Additionally, miR-125b had a suppressive function in cell proliferation and migration, at least partially via targeting PODXL in the HAVSMCs. Furthermore, the data suggested that the functions of miR-125b in arteriosclerosis obliterans may be associated with transgelin, lectin-type oxidized LDL receptor-1, vascular endothelial-cadherin, intercellular adhesion molecule-1, interleukin-6 and monocyte chemotactic protein-1. In conclusion, miR-125b was found to be important in arteriosclerosis obliterans by suppressing the expression of PODXL and may serve as a potential therapeutic target for the treatment of arteriosclerosis obliterans. PMID:25738314

  3. Quantum dot mediated imaging of atherosclerosis

    NASA Astrophysics Data System (ADS)

    Jayagopal, Ashwath; Su, Yan Ru; Blakemore, John L.; Linton, MacRae F.; Fazio, Sergio; Haselton, Frederick R.

    2009-04-01

    The progression of atherosclerosis is associated with leukocyte infiltration within lesions. We describe a technique for the ex vivo imaging of cellular recruitment in atherogenesis which utilizes quantum dots (QD) to color-code different cell types within lesion areas. Spectrally distinct QD were coated with the cell-penetrating peptide maurocalcine to fluorescently-label immunomagnetically isolated monocyte/macrophages and T lymphocytes. QD-maurocalcine bioconjugates labeled both cell types with a high efficiency, preserved cell viability, and did not perturb native leukocyte function in cytokine release and endothelial adhesion assays. QD-labeled monocyte/macrophages and T lymphocytes were reinfused in an ApoE-/- mouse model of atherosclerosis and age-matched controls and tracked for up to four weeks to investigate the incorporation of cells within aortic lesion areas, as determined by oil red O (ORO) and immunofluorescence ex vivo staining. QD-labeled cells were visible in atherosclerotic plaques within two days of injection, and the two cell types colocalized within areas of subsequent ORO staining. Our method for tracking leukocytes in lesions enables high signal-to-noise ratio imaging of multiple cell types and biomarkers simultaneously within the same specimen. It also has great utility in studies aimed at investigating the role of distinct circulating leukocyte subsets in plaque development and progression.

  4. Macrophage-mediated cholesterol handling in atherosclerosis.

    PubMed

    Chistiakov, Dimitry A; Bobryshev, Yuri V; Orekhov, Alexander N

    2016-01-01

    Formation of foam cells is a hallmark at the initial stages of atherosclerosis. Monocytes attracted by pro-inflammatory stimuli attach to the inflamed vascular endothelium and penetrate to the arterial intima where they differentiate to macrophages. Intimal macrophages phagocytize oxidized low-density lipoproteins (oxLDL). Several scavenger receptors (SR), including CD36, SR-A1 and lectin-like oxLDL receptor-1 (LOX-1), mediate oxLDL uptake. In late endosomes/lysosomes of macrophages, oxLDL are catabolysed. Lysosomal acid lipase (LAL) hydrolyses cholesterol esters that are enriched in LDL to free cholesterol and free fatty acids. In the endoplasmic reticulum (ER), acyl coenzyme A: cholesterol acyltransferase-1 (ACAT1) in turn catalyses esterification of cholesterol to store cholesterol esters as lipid droplets in the ER of macrophages. Neutral cholesteryl ester hydrolases nCEH and NCEH1 are involved in a secondary hydrolysis of cholesterol esters to liberate free cholesterol that could be then out-flowed from macrophages by cholesterol ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 and SR-BI. In atherosclerosis, disruption of lipid homoeostasis in macrophages leads to cholesterol accumulation and formation of foam cells. PMID:26493158

  5. Photoangioplasty: new applications of photodynamic therapy in atherosclerosis

    NASA Astrophysics Data System (ADS)

    Rockson, Stanley G.

    2000-05-01

    Atherosclerosis has traditionally held appeal as a pathologic entity in which photodynamic therapy might arrest or reverse the manifestations of disease. Earlier attempts to bring photodynamic therapy to the human clinical arena were hampered by the limitations of the photosensitizers under investigation, including the propensity to phototoxic manifestations and light-induced trauma to surrounding, normal vascular tissues. Many of these inherent limitations may be circumvented by newer photosensitizers that are activated at longer, more optimal wavelengths of light energy. Advances in fiberoptic catheter design for the endovascular delivery of light have also contributed to the greater applicability of photodynamic therapy to human atherosclerosis. Initial experiences with one family of photosensitizers, the texaphyrins, indicate that photodynamic therapy of human peripheral arterial atherosclerosis is feasible, safe, and well-tolerated. Photodynamic therapy of atherosclerosis holds promise for the treatment of de novo atherosclerosis and may have future applicability in the treatment, and perhaps prevention, of restenosis.

  6. Intranasal immunization with heat shock protein 60 induces CD4(+) CD25(+) GARP(+) and type 1 regulatory T cells and inhibits early atherosclerosis.

    PubMed

    Zhong, Y; Tang, H; Wang, X; Zeng, Q; Liu, Y; Zhao, X I; Yu, K; Shi, H; Zhu, R; Mao, X

    2016-03-01

    Atherosclerosis is an autoimmune inflammatory disease involving both innate and adaptive immune mechanisms. Immune tolerance induction may have therapeutic potential for the suppression of atherosclerosis. Current interest is directed towards mucosal tolerance induction, especially nasal tolerance. Previous studies have shown that heat shock protein 60 (HSP60) is recognized as an important autoantigen in atherosclerosis, and nasal or oral HSP60 can induce tolerance and ameliorate atherosclerosis by inducing several subsets of regulatory T cells (Tregs ) such as latency-associated peptide (LAP)(+) and forkhead box transcription factor 3 (FoxP3)(+) Tregs. However, little is known regarding the detailed mechanisms of nasal tolerance. Here, we again investigated the impact of nasal HSP60 on atherosclerosis and the mechanisms underlying the anti-atherosclerosis responses. We found that nasal HSP60 caused a significant 33·6% reduction in plaque size at the aortic root in the early stages of atherosclerosis (P < 0·001). Notably, a significant increase in activated CD4(+) CD25(+) glycoprotein A repetitions predominant (GARP)(+) Tregs, type 1 Tregs (Tr1 cells), and CD4(+) CD25(+) FoxP3(+) Tregs, as well as a marked decrease in the numbers of type 1 and 17 T helper cells was detected in the spleens and cervical lymph nodes of HSP60-treated mice. Moreover, nasal HSP60 increases the production of transforming growth factor (TGF)-β and interleukin (IL)-10 and decreases the secretion of IFN-γ and IL-17. Interestingly, the atheroprotective role of nasal HSP60 treatment was abrogated partly by the neutralization of IL-10. Our findings show that nasal administration of HSP60 can attenuate atherosclerotic formation by inducing GARP(+) Tregs, Tr1 cells and FoxP3(+) Tregs, and that these Tregs maintain immune homeostasis by secreting IL-10 and TGF-β. PMID:26452441

  7. Correlation between Mitochondrial Reactive Oxygen and Severity of Atherosclerosis

    PubMed Central

    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. PMID:26635912

  8. Atherosclerosis and Rheumatoid Arthritis: More Than a Simple Association

    PubMed Central

    Cavagna, Lorenzo; Boffini, Nicola; Cagnotto, Giovanni; Inverardi, Flora; Grosso, Vittorio; Caporali, Roberto

    2012-01-01

    In the last decades a large amount of evidence linked rheumatoid arthritis (RA) to atherosclerosis. In fact, RA patients have an increased risk of cardiovascular events that is not fully explained by other classic cardiovascular risk factors. RA and atherosclerosis may share several common pathomechanisms and inflammation undoubtedly plays a primary role. The proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-6, involved in the pathogenesis of RA, are also independently predictive of subsequent cardiovascular disease (CVD). In RA, inflammation alters HDL constituents and the concentration of LDL and HDL, thus facilitating atherosclerosis and CVD events. On the other hand, also the increase of oxidative processes, frequently observed in RA, induces atherosclerosis. Interestingly, some genetic polymorphisms associated with RA occurrence enhance atherosclerosis, however, other polymorphisms associated with RA susceptibility do not increase CVD risk. Several other mechanisms may influence atherosclerotic processes in RA. Moreover, atherosclerosis may be directly mediated also by underlying autoimmune processes, and indirectly by the occurrence of metabolic syndrome and impaired physical activity. Finally, the effects of RA therapies on cardiovascular system in general and on atherosclerosis in particular are really wide and different. However, the starting point of every RA treatment is that disease control, or better remission, is the best way we have for the reduction of CVD occurrence. PMID:23024462

  9. [Cholesterol and atherosclerosis. Historical considerations and treatment].

    PubMed

    Zárate, Arturo; Manuel-Apolinar, Leticia; Basurto, Lourdes; De la Chesnaye, Elsa; Saldívar, Iván

    2016-01-01

    Cholesterol is a precursor of steroid hormones and an essential component of the cell membrane, however, altered regulation of the synthesis, absorption and excretion of cholesterol predispose to cardiovascular diseases of atherosclerotic origin. Despite, the recognition of historical events for 200 years, starting with Michel Chevreul naming «cholesterol»; later on, Lobstein coining the term atherosclerosis and Marchand introducing it, Anichkov identifying cholesterol in atheromatous plaque, and Brown and Goldstein discovering LDL receptor; as well as the emerging of different drugs, such as fibrates, statins and cetrapibs this decade, promising to increase HDL and the most recent ezetimibe and anti-PCSK9 to inhibit the degradation of LDL receptor, however morbidity has not been reduced in cardiovascular disease. PMID:26774359

  10. Homocysteine and the pathogenesis of atherosclerosis.

    PubMed

    McCully, Kilmer S

    2015-03-01

    The homocysteine theory of arteriosclerosis was discovered by study of arteriosclerotic plaques occurring in homocystinuria, a disease caused by deficiencies of cystathionine synthase, methionine synthase or methylenetetrahydrofolate reductase. According to the homocysteine theory, metabolic and nutritional abnormalities leading to elevation of plasma homocysteine cause atherosclerosis in the general population without these rare enzymatic abnormalities. Through studies of metabolism of homocysteine thiolactone, the anhydride of homocysteine, in cell cultures from homocystinuric children, the pathway for synthesis of sulfate was found to be dependent upon thioretinamide, the amide formed from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide form the complex thioretinaco with cobalamin, and oxidative phosphorylation is catalyzed by reduction of oxygen, which is bound to thioretinaco ozonide, by electrons from electron transport particles. Atherogenesis is attributed to formation of aggregates of homocysteinylated lipoproteins with microorganisms, which obstruct the vasa vasorum during formation of arterial vulnerable plaques. PMID:25653125

  11. Atherosclerosis staging: imaging using FLIM technique

    NASA Astrophysics Data System (ADS)

    Sicchieri, Leticia B.; Barioni, Marina Berardi; Silva, Mônica Nascimento; Monteiro, Andrea Moreira; Figueiredo Neto, Antonio Martins; Ito, Amando S.; Courrol, Lilia C.

    2014-03-01

    In this work it was used fluorescence lifetime imaging (FLIM) to analyze biochemical composition of atherosclerotic plaque. For this purpose an animal experimentation was done with New Zealand rabbits divided into two groups: a control group of 4 rabbits that received a regular diet for 0, 20, 40 and 60 days; and an experimental group of 9 rabbits, divided in 3 subgroups, that were fed with 1% cholesterol diet for 20, 40 and 60 days respectively. The aortas slices stained with europium chlortetracycline were analyzed by FLIM exciting samples at 440 nm. The results shown an increase in the lifetime imaging of rabbits fed with cholesterol. It was observed that is possible to detect the metabolic changes associated with atherosclerosis at an early stage using FLIM technique exciting the tissue around 440 nm and observing autofluorescence lifetime. Lifetimes longer than 1.75 ns suggest the presence of porphyrins in the tissue and consequently, inflammation and the presence of macrophages.

  12. Role of Matrix Metalloproteinase-8 in Atherosclerosis

    PubMed Central

    Lenglet, Sébastien; Mach, François; Montecucco, Fabrizio

    2013-01-01

    Plaque rupture is the main cause of acute myocardial infarction and stroke. Atherosclerotic plaques have been described to be vulnerable and more prone to rupture when they are characterized by thin, highly inflamed, and collagen-poor fibrous caps and contain elevated levels of proteases, including metalloproteinases (MMPs). Initiation of collagen breakdown in plaques requires interstitial collagenases, a MMP subfamily consisting of MMP-1, MMP-8, and MMP-13. Previous reports demonstrated that MMP-1 and MMP-13 might be overexpressed in both human and experimental atherosclerosis. Since neutrophils have been only recently reported in atherosclerotic plaques, the role of MMP-8 (formerly known as “neutrophil collagenase”) was only marginally evaluated. In this paper, we will update and comment on evidence of the most relevant regulatory pathways and activities mediated by MMP-8 in atherogenesis. PMID:23365489

  13. Autophagy: An Exposing Therapeutic Target in Atherosclerosis.

    PubMed

    Luo, Yun; Lu, Shan; Zhou, Ping; Ai, Qi-Di; Sun, Gui-Bo; Sun, Xiao-Bo

    2016-03-01

    Autophagy is an evolutionarily conserved catabolic process whereby the cytoplasmic contents of a cell are sequestered within autophagosomes through a lysosome-dependent pathway. Increasing evidence shows that this process is of great importance in a wide range of diseases, including atherosclerosis (AS). Autophagy can be modulated in advanced AS plaques by cytokines, reactive lipids, lipopolysaccharides, advanced glycation end products, and microRNAs. Autophagy exerts both protective and detrimental functions in vascular disorders. However, despite an increasing interest in autophagy, it remains an underestimated and overlooked phenomenon in AS. Therefore, the precise role of autophagy and its relationship with apoptosis need to be described. This review highlights recent findings on the autophagy activities and signaling pathways in endothelial cells, macrophages, and smooth muscle cells that are accompanied by apoptosis in AS. We conclude with recent studies on autophagy modulation as a new therapeutic approach to treat AS. PMID:26580134

  14. Antihypercholesterolemic and antioxidant efficacies of zerumbone on the formation, development, and establishment of atherosclerosis in cholesterol-fed rabbits

    PubMed Central

    Hemn, Hassan Othman; Noordin, Muhammad Mustapha; Rahman, Heshu Sulaiman; Hazilawati, Hamza; Zuki, Abubakr; Chartrand, Max Stanley

    2015-01-01

    Owing to the high incidence of cholesterol-induced cardiovascular disease, particularly atherosclerosis, the current study was designed to investigate the preventive and therapeutic efficacies of dietary zerumbone (ZER) supplementation on the formation and development of atherosclerosis in rabbits fed with a high cholesterol diet. A total of 72 New Zealand white rabbits were divided randomly on two experimental studies carried out 8 weeks apart. The first experiment was designed to investigate the prophylactic efficacy of ZER in preventing early developed atheromatous lesion. The second experimental trial was aimed at investigating the therapeutic effect of ZER in reducing the atherosclerotic lesion progression and establishment. Sudanophilia, histopathological, and ultrastructural changes showed pronounced reduction in the plaque size in ZER-medicated aortas. On the other hand, dietary supplementation of ZER for almost 10 weeks as a prophylactic measure indicated substantially decreasing lipid profile values, and similarly, plaque size in comparison with high-cholesterol non-supplemented rabbits. Furthermore, the results of oxidative stress and antioxidant biomarker evaluation indicated that ZER is a potent antioxidant in suppressing the generation of free radicals in terms of atherosclerosis prevention and treatment. ZER significantly reduced the value of malondialdehyde and augmented the value of superoxide dismutase. In conclusion, our data indicated that dietary supplementation of ZER at doses of 8, 16, and 20 mg/kg alone as a prophylactic measure, and as a supplementary treatment with simvastatin, significantly reduced early plague formation, development, and establishment via significant reduction in serum lipid profile, together with suppression of oxidative damage, and therefore alleviated atherosclerosis lesions. PMID:26347047

  15. Association Between Psoriasis and Subclinical Atherosclerosis

    PubMed Central

    Fang, Na; Jiang, Menglin; Fan, Yu

    2016-01-01

    Abstract The association between psoriasis and carotid intima-media thickness (CIMT) or impaired flow-mediated dilation (FMD) remains controversial. We aimed to evaluate the extent of subclinical atherosclerosis as measured by CIMT and FMD in patients with psoriasis by conducting a meta-analysis. A systematic literature search was performed using PubMed, Embase, Cochrane databases, China National Knowledge Infrastructure, and VIP databases up to February 2015. Observational studies investigating CIMT or FMD in patients with psoriasis and controls were eligible. Psoriatic patients and controls were at least age- and sex-matched. Random-effects analysis was used to estimate the weighted mean difference (WMD) and 95% confidence interval (CI) between psoriatic patients and controls. A total of 20 studies were identified and analyzed. Meta-analysis showed that psoriatic patients had a significantly thicker CIMT (WMD 0.11 mm; 95% CI 0.08–0.15) and lower FMD (WMD −2.79%; −4.14% to −1.43%) than those in controls. Subgroup analysis indicated that psoriatic arthritis appeared to have less impaired FMD (WMD −2.45%) and thinner CIMT (WMD 0.10 mm). Psoriatic patients with mean age >45 years had much thicker CIMT (WMD 0.13 mm). The impaired FMD (WMD −3.99%) seemed more pronounced in psoriatic patients with mean age <45 years. This meta-analysis suggests that patients with psoriasis are associated with excessive risk of subclinical atherosclerosis. Screening and monitoring CIMT and brachial artery FMD may be recommended to identify a subgroup of psoriatic patients at higher risk for cardiovascular events. PMID:27196459

  16. Systemic lupus erythematosus and atherosclerosis: Review of the literature.

    PubMed

    Frieri, Marianne; Stampfl, Heather

    2016-01-01

    The purpose of this manuscript is to extensively review the literature related to systemic lupus erythematosus and atherosclerosis. The conclusion of this review has covered accelerated atherosclerosis in systemic lupus erythematosus, the role of complement, interferon in premature atherosclerosis, inflammatory mediators such as cytokines, leukocytes, innate and adaptive immunity, hydrolytic enzymes, reactive oxygen species, vascular endothelial growth factor, toll receptors in lupus nephritis, several specific anti-inflammatory pharmacological therapies, and potential prevention strategies for atherothrombotic events, interferons and the inflammasome. It is important for allergist-immunologists, rheumatologists both in academic institutions and in practice to understand this important disorder. PMID:26299985

  17. Imaging Macrophage Development and Fate in Atherosclerosis and Myocardial Infarction

    PubMed Central

    Swirski, Filip K.; Nahrendorf, Matthias

    2013-01-01

    Macrophages are central regulators of disease progression in both atherosclerosis and myocardial infarction. In atherosclerosis, macrophages are the dominant leukocyte population that influences lesional development. In myocardial infarction, which is caused by atherosclerosis, macrophages accumulate readily and play important roles in inflammation and healing. Molecular imaging has grown considerably as a field and can reveal biological process at the molecular, cellular, and tissue levels. Here we explore how various imaging modalities, from intravital microscopy in mice to organ-level imaging in patients, are contributing to our understanding of macrophages and their progenitors in cardiovascular disease. PMID:23207281

  18. Dataset of mitochondrial genome variants associated with asymptomatic atherosclerosis

    PubMed Central

    Sazonova, Margarita A.; Zhelankin, Andrey V.; Barinova, Valeria A.; Sinyov, Vasily V.; Khasanova, Zukhra B.; Postnov, Anton Y.; Sobenin, Igor A.; Bobryshev, Yuri V.; Orekhov, Alexander N.

    2016-01-01

    This dataset report is dedicated to mitochondrial genome variants associated with asymptomatic atherosclerosis. These data were obtained using the method of next generation pyrosequencing (NGPS). The whole mitochondrial genome of the sample of patients from the Moscow region was analyzed. In this article the dataset including anthropometric, biochemical and clinical parameters along with detected mtDNA variants in patients with carotid atherosclerosis and healthy individuals was presented. Among 58 of the most common homoplasmic mtDNA variants found in the observed sample, 7 variants occurred more often in patients with atherosclerosis and 16 variants occurred more often in healthy individuals. PMID:27222855

  19. Dataset of mitochondrial genome variants associated with asymptomatic atherosclerosis.

    PubMed

    Sazonova, Margarita A; Zhelankin, Andrey V; Barinova, Valeria A; Sinyov, Vasily V; Khasanova, Zukhra B; Postnov, Anton Y; Sobenin, Igor A; Bobryshev, Yuri V; Orekhov, Alexander N

    2016-06-01

    This dataset report is dedicated to mitochondrial genome variants associated with asymptomatic atherosclerosis. These data were obtained using the method of next generation pyrosequencing (NGPS). The whole mitochondrial genome of the sample of patients from the Moscow region was analyzed. In this article the dataset including anthropometric, biochemical and clinical parameters along with detected mtDNA variants in patients with carotid atherosclerosis and healthy individuals was presented. Among 58 of the most common homoplasmic mtDNA variants found in the observed sample, 7 variants occurred more often in patients with atherosclerosis and 16 variants occurred more often in healthy individuals. PMID:27222855

  20. Roles of antibody against oxygenized low density lipoprotein in atherosclerosis: recent advances

    PubMed Central

    Zhang, Jing; Wang, Daxin; He, Shenghu

    2015-01-01

    Atherosclerosis is a chronic immune inflammatory disease. Atherosclerosis and relevant disease are threatening human life and health. Oxygenized low density lipoprotein (oxLDL) is a molecular basis in the pathogenesis of atherosclerosis and able to induce inflammation, stimulate immune system and interfere with lipid metabolism in the occurrence and development of atherosclerosis. Antibody against oxLDL has been an important molecule in the immune related pathogenesis of atherosclerosis. In available studies on atherosclerosis, antibody against oxLDL has been a focus, but how oxLDL acts to affect the atherosclerosis and relevant diseases, whether oxLDL is protective or detrimental, and whether oxLDL acts in different ways at different stages of atherosclerosis are still unclear. This paper focuses on the role of antibody against oxLDL in the atherosclerosis and relevant diseases, and summarizes the advances in this field, aiming to provide new clue and new methods for the therapy of atherosclerosis. PMID:26550105

  1. [Pathogenesis of atherosclerosis: an update on the three main theories].

    PubMed

    Capron, L

    1989-12-30

    The causes and mechanisms of atherosclerosis remain incompletely understood. Almost all the present investigations are still connected with one of the main three historical theories of atherosclerosis: 1) the incrustation theory, as developed by von Rokitansky, has now led to the many studies on the roles of thrombosis and platelets; 2) the irritation theory, as opposed to the preceding one by Virchow and his school, is reviving through the rediscovery that leukocytes are present in the plaques, and that atherosclerosis (Virchow's endarteritis chronica deformans sive nodosa) has the features of a chronic inflammatory reaction; 3) the lipid infiltration theory, as initiated by the experiments of Anitschkov and Chalatov in rabbits fed a cholesterol enriched diet, motivates the huge mass of studies devoted to plasma lipids and their cellular metabolism. This article provides a brief update on each of these three complementary approaches of atherosclerosis. PMID:2698116

  2. 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

  3. Atherosclerosis and aortic aneurysm - is inflammation a common denominator?

    PubMed

    Peshkova, Iuliia O; Schaefer, Giulia; Koltsova, Ekaterina K

    2016-05-01

    Cardiovascular diseases (CVD) are the major cause of death in developed countries. Various risk factors including host genetics and, more importantly, environmental factors such as lifestyle, diet and smoking influence CVD progression. Two common forms of CVD are atherosclerosis and abdominal aortic aneurysm (AAA). Emerging evidence suggests that inflammation plays a pivotal role in CVD. However, it remains unclear whether the same inflammatory pathways prove essential for atherosclerosis and AAA because, in some cases, the same mechanisms uniformly promote both diseases, while in others they function in opposite ways. Cytokines, key mediators of inflammation, play an important role in the development of atherosclerosis but have only been scarcely studied in AAA. In this review, we discuss the importance of immune-mediated mechanisms and cytokines in the pathogenesis of atherosclerosis and AAA. PMID:26700480

  4. Coronary Atherosclerosis: Pathophysiologic Basis for Diagnosis and Management.

    PubMed

    Boudoulas, Konstantinos Dean; Triposciadis, Filippos; Geleris, Paraschos; Boudoulas, Harisios

    2016-01-01

    Coronary atherosclerosis is a long lasting and continuously evolving disease with multiple clinical manifestations ranging from asymptomatic to stable angina, acute coronary syndrome (ACS), heart failure (HF) and sudden cardiac death (SCD). Genetic and environmental factors contribute to the development and progression of coronary atherosclerosis. In this review, current knowledge related to the diagnosis and management of coronary atherosclerosis based on pathophysiologic mechanisms will be discussed. In addition to providing state-of-the-art concepts related to coronary atherosclerosis, special consideration will be given on how to apply data from epidemiologic studies and randomized clinical trials to the individual patient. The greatest challenge for the clinician in the twenty-first century is not in absorbing the fast accumulating new knowledge, but rather in applying this knowledge to the individual patient. PMID:27091673

  5. Human oral, gut, and plaque microbiota in patients with atherosclerosis

    PubMed Central

    Koren, Omry; Spor, Aymé; Felin, Jenny; Fåk, Frida; Stombaugh, Jesse; Tremaroli, Valentina; Behre, Carl Johan; Knight, Rob; Fagerberg, Björn; Ley, Ruth E.; Bäckhed, Fredrik

    2011-01-01

    Periodontal disease has been associated with atherosclerosis, suggesting that bacteria from the oral cavity may contribute to the development of atherosclerosis and cardiovascular disease. Furthermore, the gut microbiota may affect obesity, which is associated with atherosclerosis. Using qPCR, we show that bacterial DNA was present in the atherosclerotic plaque and that the amount of DNA correlated with the amount of leukocytes in the atherosclerotic plaque. To investigate the microbial composition of atherosclerotic plaques and test the hypothesis that the oral or gut microbiota may contribute to atherosclerosis in humans, we used 454 pyrosequencing of 16S rRNA genes to survey the bacterial diversity of atherosclerotic plaque, oral, and gut samples of 15 patients with atherosclerosis, and oral and gut samples of healthy controls. We identified Chryseomonas in all atherosclerotic plaque samples, and Veillonella and Streptococcus in the majority. Interestingly, the combined abundances of Veillonella and Streptococcus in atherosclerotic plaques correlated with their abundance in the oral cavity. Moreover, several additional bacterial phylotypes were common to the atherosclerotic plaque and oral or gut samples within the same individual. Interestingly, several bacterial taxa in the oral cavity and the gut correlated with plasma cholesterol levels. Taken together, our findings suggest that bacteria from the oral cavity, and perhaps even the gut, may correlate with disease markers of atherosclerosis. PMID:20937873

  6. Obstructive Sleep Apnea, Hypertension, and Their Additive Effects on Atherosclerosis

    PubMed Central

    Damiani, Mario Francesco; Zito, Annapaola; Carratù, Pierluigi; Falcone, Vito Antonio; Bega, Elioda; Scicchitano, Pietro; Ciccone, Marco Matteo; Resta, Onofrio

    2015-01-01

    Background and Aims. It is widely accepted that obstructive sleep apnea (OSA) is independently associated with atherosclerosis. Similar to OSA, hypertension (HTN) is a condition associated with atherosclerosis. However, to date, the impact of the simultaneous presence of OSA and HTN on the risk of atherosclerosis has not been extensively studied. The aim of this study was to evaluate the consequences of the coexistence of OSA and HTN on carotid intima-media thickness (IMT) and on inflammatory markers of atherosclerosis (such as interleukin- [IL-] 6 and pentraxin- [PTX-] 3). Methods. The study design allowed us to define 4 groups: (1) controls (n = 30); (2) OSA patients without HTN (n = 30); (3) HTN patients without OSA (n = 30); (4) patients with OSA and HTN (n = 30). In the morning after portable monitoring (between 7 am and 8 am), blood samples were collected, and carotid IMT was measured. Results. Carotid IMT, IL-6, and PTX-3 in OSA normotensive patients and in non-OSA HTN subjects were significantly higher compared to control subjects; in addition, in OSA hypertensive patients they were significantly increased compared to OSA normotensive, non-OSA HTN, or control subjects. Conclusions. OSA and HTN have an additive role in the progression of carotid atherosclerosis and in blood levels of inflammatory markers for atherosclerosis, such as interleukin-6 and pentraxin-3. PMID:26697221

  7. Subclinical Atherosclerosis in Rheumatoid Arthritis and Systemic Lupus Erythematosus

    PubMed Central

    Salmon, Jane E.; Roman, Mary J.

    2008-01-01

    Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are associated with increased mortality, largely as a consequence of cardiovascular disease. Increased cardiovascular morbidity and mortality in patients with RA and SLE cannot be entirely explained by traditional risk factors, suggesting that the systemic inflammation that characterizes these diseases may accelerate atherosclerosis. We used carotid ultrasonography to investigate the prevalence and correlates to preclinical atherosclerosis in patients with RA and SLE. Because atherosclerosis is a systemic disease, assessment of carotid plaque by ultrasonography provides a robust, direct measure of systemic atherosclerosis. We observed a substantially increased prevalence of carotid plaque in RA and SLE patients compared with age- and sex-matched controls, which remained after adjustment for traditional risk factors. The presence of carotid atherosclerosis was associated with disease duration in both RA and SLE and damage in SLE. These data support the hypothesis that inflammation associated with RA and SLE contributes to accelerated atherosclerosis and argue that RA and SLE disease activity should be more aggressively managed. PMID:18926167

  8. Insulin decreases atherosclerosis by inducing endothelin receptor B expression

    PubMed Central

    Park, Kyoungmin; Mima, Akira; Li, Qian; Rask-Madsen, Christian; He, Pingnian; Mizutani, Koji; Katagiri, Sayaka; Maeda, Yasutaka; Wu, I-Hsien; Khamaisi, Mogher; Preil, Simone Rordam; Maddaloni, Ernesto; Sørensen, Ditte; Rasmussen, Lars Melholt; Huang, Paul L.; King, George L.

    2016-01-01

    Endothelial cell (EC) insulin resistance and dysfunction, caused by diabetes, accelerates atherosclerosis. It is unknown whether specifically enhancing EC-targeted insulin action can decrease atherosclerosis in diabetes. Accordingly, overexpressing insulin receptor substrate-1 (IRS1) in the endothelia of Apoe−/− mice (Irs1/Apoe−/−) increased insulin signaling and function in the aorta. Atherosclerosis was significantly reduced in Irs1/ApoE−/− mice on diet-induced hyperinsulinemia and hyperglycemia. The mechanism of insulin’s enhanced antiatherogenic actions in EC was related to remarkable induction of NO action, which increases endothelin receptor B (EDNRB) expression and intracellular [Ca2+]. Using the mice with knockin mutation of eNOS, which had Ser1176 mutated to alanine (AKI), deleting the only known mechanism for insulin to activate eNOS/NO pathway, we observed that IRS1 overexpression in the endothelia of Aki/ApoE−/− mice significantly decreased atherosclerosis. Interestingly, endothelial EDNRB expression was selectively reduced in intima of arteries from diabetic patients and rodents. However, endothelial EDNRB expression was upregulated by insulin via P13K/Akt pathway. Finally EDNRB deletion in EC of Ldlr−/− and Irs1/Ldlr−/− mice decreased NO production and accelerated atherosclerosis, compared with Ldlr−/− mice. Accelerated atherosclerosis in diabetes may be reduced by improving insulin signaling selectively via IRS1/Akt in the EC by inducing EDNRB expression and NO production. PMID:27200419

  9. Specific autoantigens in experimental autoimmunity-associated atherosclerosis.

    PubMed

    Merched, Aksam J; Daret, Danièle; Li, Lan; Franzl, Nathalie; Sauvage-Merched, Maria

    2016-06-01

    Higher cardiovascular morbidity in patients with a wide range of autoimmune diseases highlights the importance of autoimmunity in promoting atherosclerosis. Our purpose was to investigate the mechanisms of accelerated atherosclerosis and identified vascular autoantigens targeted by autoimmunity. We created a mouse model of autoimmunity-associated atherosclerosis by transplanting bone marrow from FcγRIIB knockout (FcRIIB(-/-)) mice into LDL receptor knockout mice. We characterized the cellular and molecular mechanisms of atherogenesis and identified specific aortic autoantigens using serologic proteomic studies. En face lesion area analysis showed more aggressive atherosclerosis in autoimmune mice compared with control mice (0.64 ± 0.12 vs 0.32 ± 0.05 mm(2); P < 0.05, respectively). At the cellular level, FcRIIB(-/-) macrophages showed significant reduction (46-72%) in phagocytic capabilities. Proteomic analysis revealed circulating autoantibodies in autoimmune mice that targeted 25 atherosclerotic lesion proteins, including essential components of adhesion complex, cytoskeleton, and extracellular matrix, and proteins involved in critical functions and pathways. Microscopic examination of atherosclerotic plaques revealed essential colocalization of autoantibodies with endothelial cells, their adherence to basement membranes, the internal elastica lamina, and necrotic cores. The new vascular autoimmunosome may be a useful target for diagnostic and immunotherapeutic interventions in autoimmunity-associated diseases that have accelerated atherosclerosis.-Merched, A. J., Daret, D., Li, L., Franzl, N., Sauvage-Merched, M. Specific autoantigens in experimental autoimmunity-associated atherosclerosis. PMID:26891734

  10. Macrophage Phenotype and Function in Different Stages of Atherosclerosis.

    PubMed

    Tabas, Ira; Bornfeldt, Karin E

    2016-02-19

    The remarkable plasticity and plethora of biological functions performed by macrophages have enticed scientists to study these cells in relation to atherosclerosis for >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 high-density lipoprotein; proliferate and migrate; undergo apoptosis and death; and secrete a large number of inflammatory and proresolving 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

  11. 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

  12. 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. PMID:23563705

  13. Endothelium Preserving Microwave Treatment for Atherosclerosis

    NASA Technical Reports Server (NTRS)

    Carl, James R. (Inventor); Arndt, G. Dickey (Inventor); Fink, Patrick W. (Inventor); Beer, N. Reginald (Inventor); Henry, Phillip D. (Inventor); Pacifico, Antonio (Inventor); Raffoul, George W. (Inventor)

    2001-01-01

    Method and apparatus are provided to treat atherosclerosis wherein the artery is partially closed by dilating the artery while preserving the vital and sensitive endothelial layer thereof. Microwave energy having a frequency from 3 GHz to 300 GHz is propagated into the arterial wall to produce a desired temperature profile therein at tissue depths sufficient for thermally necrosing connective tissue and softening fatty and waxy plaque while limiting heating of surrounding tissues including the endothelial layer and/or other healthy tissue, organs, and blood. The heating period for raising the temperature a potentially desired amount, about 20 C. within the atherosclerotic lesion may be less than about one second. In one embodiment of the invention, a radically beveled waveguide antenna is used to deliver microwave energy at frequencies from 25 GHz or 30 GHz to about 300 GHz and is focused towards a particular radial sector of the artery. Because the atherosclerotic lesions are often asymmetrically disposed directable or focussed heating preserves healthy sectors of the artery and applies energy to the asymmetrically positioned lesion faster than a non-directed beam. A computer simulation predicts isothermic temperature profiles for the given conditions and may be used in selecting power, pulse duration, beam width, and frequency of operation to maximize energy deposition and control heat rise within the atherosclerotic lesion without harming healthy tissues or the sensitive endothelium cells.

  14. Endothelium Preserving Microwave Treatment for Atherosclerosis

    NASA Technical Reports Server (NTRS)

    Carl, James R. (Inventor); Arndt, G. Dickey (Inventor); Fink, Patrick W. (Inventor); Beer, N. Reginald (Inventor); Henry, Phillip D. (Inventor); Pacifico, Antonio (Inventor); Raffoul, George W. (Inventor)

    2000-01-01

    Method and apparatus are provided to treat atherosclerosis wherein the artery is partially closed by dilating the artery while preserving the vital and sensitive endothelial layer thereof Microwave energy having a frequency from 3 GHz to 300 GHz is propagated into the arterial wall to produce a desired temperature profile therein at tissue depths sufficient for thermally necrosing connective tissue and softening fatty and waxy plaque while limiting heating of surrounding tissues including the endothelial laser and/or other healthy tissue, organs, and blood. The heating period for raising the temperature a potentially desired amount, about 20 C., within the atherosclerotic lesion may be less than about one second. In one embodiment of the invention, a radically beveled waveguide antenna is used to deliver microwave energy at frequencies from 25 GHz or 30 GHz to about 300 GHz and is focused towards a particular radial sector of the artery. Because the atherosclerotic lesions are often asymmetrically disposed, directable of focussed heating preserves healthy sectors of the artery and applies energy to the asymmetrically positioned lesion faster than a non-directed beam. A computer simulation predicts isothermic temperature profiles for the given conditions and man be used in selecting power, pulse duration, beam width, and frequency of operation to maximize energy deposition and control heat rise within the atherosclerotic lesion without harming healthy tissues or the sensitive endothelium cells.

  15. Oxidative stress in atherosclerosis and diabetes.

    PubMed

    Lankin, V Z; Lisina, M O; Arzamastseva, N E; Konovalova, G G; Nedosugova, L V; Kaminnyi, A I; Tikhaze, A K; Ageev, F T; Kukharchuk, V V; Belenkov, Yu N

    2005-07-01

    We measured the content of lipid peroxides in plasma LDL from patients with chronic CHD not accompanied by hypercholesterolemia; CHD and hypercholesterolemia; type 2 diabetes mellitus and decompensation of carbohydrate metabolism; and CHD, circulatory insufficiency, and type 2 diabetes mellitus (without hypercholesterolemia). The content of lipid peroxides in LDL isolated from blood plasma by differential ultracentrifugation in a density gradient was estimated by a highly specific method with modifications (reagent Fe(2+) xylene orange and triphenylphosphine as a reducing agent for organic peroxides). The content of lipid peroxides in LDL from patients was much higher than in controls (patients without coronary heart disease and diabetes). Hypercholesterolemia and diabetes can be considered as factors promoting LDL oxidation in vivo. Our results suggest that stimulation of lipid peroxidation in low-density lipoproteins during hypercholesterolemia and diabetes is associated with strong autooxidation of cholesterol and glucose during oxidative and carbonyl (aldehyde) stress, respectively. These data illustrate a possible mechanism of the progression of atherosclerosis in patients with diabetes mellitus. PMID:16254616

  16. Thrombosis and blood cells in atherosclerosis development.

    PubMed

    Santolaya, C; Hernández, M R; Villaverde, C A

    1988-06-01

    Hemorheological changes produced in blood cells seem to be essential in atheroma plaque development and thrombotic episodes. In this study, we investigated the relationship between blood cells count, thrombogenic situations and morphological mesenteric alterations in atherosclerotic rats. Atherosclerosis was induced by an atherogenic diet made up of two phases, the first a hypervitaminic diet, and the second a hyperlipidic one. Cell counts were performed with Thoma's camera. Morphological changes were observed directly in rat mesentery. Thrombogenic situations were investigated by a mesenteric microthrombosis induction method. In atherosclerotic animals we can observe a higher mesenteric opacity, increase in blood viscosity and a thickness in vessel wall. Thrombosis time is shortened at 3 days, which indicates a thrombogenic situation although at 10 days there is a lenthening in this parameter. Blood cell counts were not modified significantly, but modifications in differential leukocyte counts were significant. We found a direct relationship between lymphocyte number and thrombosis time whereas with granulocytes this relationship was inverse: shortening in thrombosis time appearing simultaneously with an increase in cell number. PMID:3419397

  17. Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives.

    PubMed

    Beaudeux, Jean-Louis; Giral, Philippe; Bruckert, Eric; Foglietti, Marie-José; Chapman, M John

    2004-02-01

    Matrix metalloproteinases (MMPs), also called matrixins, are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are precisely regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in diseases such as cancer, fibrosis, arthritis and atherosclerosis. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression (including plaque disruption), MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review describes the members of the MMP and TIMP families and discusses the structure, function and regulation of MMP activity; finally, pharmacological approaches to MMP inhibition are highlighted. PMID:15061349

  18. Is Sudden Hearing Loss Associated with Atherosclerosis?

    PubMed Central

    Rajati, Mohsen; Azarpajooh, Mahmoud Reza; Mouhebati, Mohsen; Nasrollahi, Mostafa; Salehi, Maryam; Khadivi, Ehsan; Nourizadeh, Navid; Hashemi, Firoozeh; Bakhshaee, Mehdi

    2016-01-01

    Introduction: Sudden sensorineural hearing-loss (SSNHL) patients constitute approximately 2–3% of referrals to ear, nose and throat (ENT) clinics. Several predisposing factors have been proposed for this condition; one of which is vascular disorders and perfusion compromise. In this research the atherosclerotic changes and their known risk factors are studied in SSNHL patients. Materials and Methods: Thirty SSNHL patients and 30 controls were evaluated with regard to cardiovascular risks including history, heart examination, blood pressure, body mass index, waist circumference, electrocardiogram, blood sugar, triglycerides, cholesterol, high-sensitivity C-reactive protein (HSCRP); also, carotid artery color Doppler study was undertaken to measure intima media thickness(IMT). Results: IMT and HSCRP showed an increased risk in the case group compared with the controls (P= 0.005 & P=0.001). However, waist circumference, history of smoking, fasting blood sugar, lipid profile, and electrocardiogram revealed no significant difference between the two groups. Interestingly, blood pressure and body mass index were higher in the controls in this study. Conclusion: Sudden sensorineural hearing loss may be associated with subclinical atherosclerosis. PMID:27429947

  19. B Cells and Humoral Immunity in Atherosclerosis

    PubMed Central

    Tsiantoulas, Dimitrios; Diehl, Cody J.; Witztum, Joseph L.; Binder, Christoph J.

    2014-01-01

    Insights into the important contribution of inflammation and immune functions in the development and progression of atherosclerosis have greatly improved our understanding of this disease. Although the role of T cells has been extensively studied for decades, only recently has the role of B cells gained more attention. Recent studies have identified differential effects of different B-cell subsets and helped to clarify the still poorly understood mechanisms by which these act. B1 cells have been shown to prevent lesion formation, whereas B2 cells have been suggested to promote it. Natural IgM antibodies, mainly derived from B1 cells, have been shown to mediate atheroprotective effects, but the functional role of other immunoglobulin classes, particularly IgG, still remains elusive. In this review, we will focus on recent insights on the role of B cells and various immunoglobulin classes and how these may mediate their effects in atherosclerotic lesion formation. Moreover, we will highlight potential therapeutic approaches focusing on B-cell depletion that could be used to translate experimental evidence to human disease. PMID:24855199

  20. Noninvasive indicators of atherosclerosis in subclinical hypothyroidism

    PubMed Central

    Kilic, Ismail Dogu; Tanriverdi, Halil; Fenkci, Semin; Akin, Fulya; Uslu, Sukriye; Kaftan, Asuman

    2013-01-01

    Introduction: Cardiovascular system is rich in thyroid hormone receptors and is one of the major sites of action for thyroid hormones. However, the effect of subclinical hypothyroidism (SCH) on atherosclerosis has not been cleared yet. Materials and Methods: SCH is defined as high thyroid-stimulating hormone (TSH) levels in the presence of normal serum T4 and T3 levels. A total of 32 patients with SCH and 29 controls were included in the study. Carotid intima-media thickness, flow-mediated dilatation, and aortic distensibility were compared between the groups. Results: FMD was lower in patients with SCH than in controls. GTN-induced vasodilatation was similar in the patients with SCH and controls. There was no statistically significant difference between the patients with SCH and controls with respect to CIMT and aortic distensibility. Conclusion: SCH is associated with endothelial dysfunction as established by FMD. Inconsistent results of CIMT and aortic stiffness can be explained by these parameters being measures of structural changes whereas FMD is a dynamic measure that reflects the impact of both acute and chronic influences on endothelial function. PMID:23776901

  1. Genomic correlates of atherosclerosis in ancient humans.

    PubMed

    Zink, Albert; Wann, L Samuel; Thompson, Randall C; Keller, Andreas; Maixner, Frank; Allam, Adel H; Finch, Caleb E; Frohlich, Bruno; Kaplan, Hillard; Lombardi, Guido P; Sutherland, M Linda; Sutherland, James D; Watson, Lucia; Cox, Samantha L; Miyamoto, Michael I; Narula, Jagat; Stewart, Alexandre F R; Thomas, Gregory S; Krause, Johannes

    2014-06-01

    Paleogenetics offers a unique opportunity to study human evolution, population dynamics, and disease evolution in situ. Although histologic and computed x-ray tomographic investigations of ancient mummies have clearly shown that atherosclerosis has been present in humans for more than 5,000 years, limited data are available on the presence of genetic predisposition for cardiovascular disease in ancient human populations. In a previous whole-genome study of the Tyrolean Iceman, a 5,300-year-old glacier mummy from the Alps, an increased risk for coronary heart disease was detected. The Iceman's genome revealed several single nucleotide polymorphisms that are linked with cardiovascular disease in genome-wide association studies. Future genetic studies of ancient humans from various geographic origins and time periods have the potential to provide more insights into the presence and possible changes of genetic risk factors in our ancestors. The study of ancient humans and a better understanding of the interaction between environmental and genetic influences on the development of heart diseases may lead to a more effective prevention and treatment of the most common cause of death in the modern world. PMID:25667090

  2. A Histoenzymatic Study of Human Intracranial Atherosclerosis

    PubMed Central

    Hoff, Henry F.

    1972-01-01

    A light microscopy study on the localization of enzyme activity within atherosclerotic human intracranial arteries was performed on autopsy material obtained within 4 hours of death. The data suggests that the atherosclerotic process first goes through a proliferative phase and then a degenerative phase culminating in the formation of a plaque. In the proliferative phase, smooth muscle cell proliferation has formed a thickened intima. Tetrazolium reductase, adenosine triphosphatase (ATPase) and adenosine monophosphatase (AMPase) activities are present in these cells, while all dehydrogenases and acid phosphatase activities were weak or not present. As the degenerative phase commences, an area of necrosis, lipid and macrophage accumulation is formed on the lumen side of the elastica. This area increases in size until a plaque is formed. Unsaturated polar and nonpolar lipid, cholesterol, α-glycerophosphate dehydrogenase, acid phosphatase, and AMPase activities are associated with these areas and in foam cells, which are often found in the thickened intima of the proliferative phase. Tetrazolium reductase and ATPase activities decrease in the thickened intima as the area of necrosis increases in size, while dehydrogenase activity, except that for α-glycerophosphate, remains low or not present. Patterns of enzyme alterations for various stages of the disease process in intracranial arteries, the aorta and coronary arteries suggest a similar, if not identical, progression of the atherosclerotic process, irrespective of known differences in the prevalence of atherosclerosis. ImagesFig 2Fig 3Fig 5Fig 1Fig 4 PMID:4260721

  3. Endothelium Preserving Microwave Treatment for Atherosclerosis

    NASA Technical Reports Server (NTRS)

    Carl, James R. (Inventor); Arndt, Dickey (Inventor); Fink, Patrick W. (Inventor); Beer, Reginald (Inventor); Henry, Phillip D. (Inventor); Pacifico, Antonio (Inventor); Raffoul, George W. (Inventor)

    2002-01-01

    Method and apparatus are provided to treat atherosclerosis wherein the artery is partially closed by dilating the artery while preserving the vital and sensitive endothelial layer thereof. Microwave energy having a frequency from 3 GHz to 300 GHz is propagated into the arterial wall to produce a desired temperature profile therein at tissue depths sufficient for thermally necrosing connective tissue and softening fatty and waxy plaque while limiting heating of surrounding tissues including the endothelial layer and/or other healthy tissue, organs, and blood. The heating period for raising the temperature a potentially desired amount, about 20 C. within the atherosclerotic lesion may be less than about one second. In one embodiment of the invention, a radically beveled waveguide antenna is used to deliver microwave energy at frequencies from 25 GHz or 30 GHz to about 300 GHz and is focused towards a particular radial sector of the artery. Because the atherosclerotic lesions are often asymmetrically disposed, directable or focussed heating preserves healthy sectors or the artery and applies energy to the asymmetrically positioned lesion faster than a non-directed bean. A computer simulation predicts isothermic temperature profiles for the given conditions and may be used in selecting power, pulse duration, beam width, and frequency of operation to maximize energy deposition and control heat rise within the atherosclerotic lesion without harming healthy tissues or the sensitive endothelium cells.

  4. Molecular Imaging of Inflammation in Atherosclerosis

    PubMed Central

    Wildgruber, Moritz; Swirski, Filip K.; Zernecke, Alma

    2013-01-01

    Acute rupture of vulnerable plaques frequently leads to myocardial infarction and stroke. Within the last decades, several cellular and molecular players have been identified that promote atherosclerotic lesion formation, maturation and plaque rupture. It is now widely recognized that inflammation of the vessel wall and distinct leukocyte subsets are involved throughout all phases of atherosclerotic lesion development. The mechanisms that render a stable plaque unstable and prone to rupture, however, remain unknown and the identification of the vulnerable plaque remains a major challenge in cardiovascular medicine. Imaging technologies used in the clinic offer minimal information about the underlying biology and potential risk for rupture. New imaging technologies are therefore being developed, and in the preclinical setting have enabled new and dynamic insights into the vessel wall for a better understanding of this complex disease. Molecular imaging has the potential to track biological processes, such as the activity of cellular and molecular biomarkers in vivo and over time. Similarly, novel imaging technologies specifically detect effects of therapies that aim to stabilize vulnerable plaques and silence vascular inflammation. Here we will review the potential of established and new molecular imaging technologies in the setting of atherosclerosis, and discuss the cumbersome steps required for translating molecular imaging approaches into the clinic. PMID:24312156

  5. Particulate matter air pollution and atherosclerosis.

    PubMed

    Brook, Robert D; Rajagopalan, Sanjay

    2010-09-01

    Particulate matter (PM) air pollution less than 2.5 microm in diameter (PM(2.5)), which is now an all-pervading element of modern-day society, is associated with heightened cardiovascular morbidity and mortality. Not only can short-term PM(2.5) exposure trigger acute cardiovascular events, but longer-term exposure over years augments cardiovascular risk to an even greater extent. One biological mechanism capable of explaining this observation is that chronic exposure may promote the progression and vulnerability of atherosclerotic plaques. Indeed, recent epidemiologic studies have demonstrated an association between ambient PM(2.5) exposure and the presence or extent of atherosclerosis in humans. Several animal experiments have provided corroborating evidence that chronic exposures in fact do enhance the progression and perhaps vulnerability of atherosclerotic lesions. Due to the billions of people continually exposed to PM(2.5), the long-term pro-atherosclerotic effects of this ubiquitous air pollutant are likely to be of enormous and growing global public health importance. PMID:20617466

  6. Deletion of Macrophage Vitamin D Receptor Promotes Insulin Resistance and Monocyte Cholesterol Transport to Accelerate Atherosclerosis in Mice

    PubMed Central

    Oh, Jisu; Riek, Amy E.; Darwech, Isra; Funai, Katsuhiko; Shao, JianSu; Chin, Kathleen; Sierra, Oscar L.; Carmeliet, Geert; Ostlund, Richard E.; Bernal-Mizrachi, Carlos

    2015-01-01

    Summary Intense effort has been devoted to understanding predisposition to chronic systemic inflammation as this contributes to cardiometabolic disease. We demonstrate that deletion of the macrophage vitamin D receptor (VDR) in mice (KODMAC) is sufficient to induce insulin resistance by promoting M2 macrophage accumulation in the liver, as well as increase cytokine secretion and hepatic glucose production. Moreover, VDR deletion increases atherosclerosis by enabling lipid-laden M2 monocytes to adhere, migrate, and carry cholesterol into the atherosclerotic plaque, and by increasing macrophage cholesterol uptake and esterification. Increased foam cell formation results from lack of VDR-SERCA2b interaction, causing SERCA dysfunction, activation of ER stress-CaMKII-JNKp-PPARγ signaling, and induction of the scavenger receptors CD36 and SR-A1. BM transplant of VDR-expressing cells into KODMAC mice improved insulin sensitivity, suppressed atherosclerosis, and decreased foam cell formation. The immunomodulatory effects of vitamin D in macrophages are thus critical in diet-induced insulin resistance and atherosclerosis in mice. Graphical Abstract PMID:25801026

  7. Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation.

    PubMed

    Ding, Yinyuan; Huang, Linzhang; Xian, Xunde; Yuhanna, Ivan S; Wasser, Catherine R; Frotscher, Michael; Mineo, Chieko; Shaul, Philip W; Herz, Joachim

    2016-01-01

    The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood, and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis, we studied atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM1, VCAM1, and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing nuclear factor κB (NF-κB) activity in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease. PMID:26980442

  8. Suppression of adrenal βarrestin1-dependent aldosterone production by ARBs: head-to-head comparison

    PubMed Central

    Dabul, Samalia; Bathgate-Siryk, Ashley; Valero, Thairy Reyes; Jafferjee, Malika; Sturchler, Emmanuel; McDonald, Patricia; Koch, Walter J.; Lymperopoulos, Anastasios

    2015-01-01

    The known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion is mediated by either Gq/11 proteins or βarrestin1 (βarr1), both of which can couple to its type 1 receptors (AT1Rs), present in adrenocortical zona glomerulosa (AZG) cell membranes. In the present study, we examined the relative potencies of all the currently used in the clinic AT1R antagonist drugs (angiotensin receptor blockers, ARBs, or sartans) at preventing activation of these two signaling mediators (G proteins and βarrs) at the AngII-bound AT1R and, consequently, at suppression of aldosterone in vitro. All ARBs were found to be potent inhibitors of G protein activation at the AT1R. However, candesartan and valsartan were the most potent at blocking AngII-induced βarr activation at this receptor, among the tetrazolo-biphenyl-methyl derivatives, translating into excellent efficacies at aldosterone suppression in H295R cells. Conversely, irbesartan and losartan were largely G protein-selective inhibitors at the AT1R, with very low potency towards βarr inhibition. As a result, they were very weak suppressors of βarr1-dependent aldosterone production in H295R cells. These findings provide important pharmacological insights into the drug class of ARBs and medicinal chemistry insights for future drug development in the field of AngII antagonism. PMID:25631300

  9. Immune mechanisms in atherosclerosis, especially in diabetes type 2.

    PubMed

    Frostegård, Johan

    2013-01-01

    Atherosclerosis and ensuing cardiovascular disease (CVD) are major complications of diabetes type 2. Atherosclerosis is a chronic inflammatory condition involving immunocompetent cells of different types present in the lesions. Even though inflammation and immune activation may be more pronounced in atherosclerosis in diabetes type 2, there does not appear to be any major differences between diabetics and non-diabetics. Similar factors are thus implicated in atherosclerosis-associated immune activation in both groups. The cause of immune activation is not known and different mutually non-exclusive possibilities exist. Oxidized and/or enzymatically modified forms of low-density lipoprotein (OxLDL) and dead cells are present in atherosclerotic plaques. OxLDL could play a role, being pro-inflammatory and immunostimulatory as it activates T-cells and is cytotoxic at higher concentrations. Inflammatory phospholipids in OxLDL are implicated, with phosphorylcholine (PC) as one of the exposed antigens. Antibodies against PC (anti-PC) are anti-atherogenic in mouse studies, and anti-PC is negatively associated with development of atherosclerosis and CVD in humans. Bacteria and virus have been discussed as potential causes of immune activation, but it has been difficult to find direct evidence supporting this hypothesis, and antibiotic trials in humans have been negative or inconclusive. Heat shock proteins (HSP) could be one major target for atherogenic immune reactions. More direct causes of plaque rupture include cytokines such as interleukin 1β (IL-1β), tumor necrosis factor (TNF), and also lipid mediators as leukotrienes. In addition, in diabetes, hyperglycemia and oxidative stress appear to accelerate the development of atherosclerosis, one mechanism could be via promotion of immune reactions. To prove that immune reactions are causative of atherosclerosis and CVD, further studies with immune-modulatory treatments are needed. PMID:24194733

  10. [Aortic expression of monocyte chemotactic protein-1 (MCP-1) gene in rabbits with experimental atherosclerosis].

    PubMed

    Sekalska, Beata

    2003-01-01

    expression in relation to constitutive expression of the GAPDH gene. Significantly lower expression was found in rabbits given ibuprofen (groups IK2, IK3, IM3) as compared with groups K2, K3 and M2 (Tab. 1, Fig. 1). Significantly higher concentrations of cholesterol and triglycerides, as well as liver and adrenal mass indices were revealed in rabbits fed a cholesterol-rich diet with or without ibuprofen, in comparison to groups K2, K3, IK2 and IK3. No atherosclerotic lesions were disclosed in control groups. Atheromatous lesions were demonstrated in rabbits fed a cholesterol-rich diet with or without ibuprofen, occupying more than 60% of the intimal surface. The following conclusions were made: 1) RT-PCR corrected for contamination of RNA samples with genomic DNA is a reliable technique for studying MCP-1 gene expression in rabbit aorta, 2) Three months of cholesterol-rich diet is without effect on MCP-1 gene expression in rabbit aorta, 3) Ibuprofen suppresses MCP-1 gene expression in the aorta without affecting the progression of atherosclerosis induced with the cholesterol-rich diet. PMID:15552841

  11. Effects of ezetimibe on atherosclerosis in preclinical models.

    PubMed

    Davis, Harry R; Lowe, Robert S; Neff, David R

    2011-04-01

    Ezetimibe (Zetia(®), Ezetrol(®), Merck, Whitehouse Station, NJ) is a potent inhibitor of sterol absorption, which selectively blocks the uptake of biliary and dietary cholesterol in the small intestine. Clinical trials have demonstrated the beneficial effects of ezetimibe on the reduction of atherogenic lipoproteins and the attainment of guideline-recommended lipid levels. Direct evidence that these improvements translate to a reduction in atherosclerosis or cardiovascular events is limited, although reductions in major atherosclerotic events that are consistent with the LDL-C lowering achieved have recently been presented for patients with chronic kidney disease treated with ezetimibe/simvastatin 10/20mg in the SHARP trial. Animal models of atherosclerosis have played a central role in defining the mechanisms involved in initiation and development of disease and have been used in drug development to evaluate potential therapeutic efficacy. The effect of ezetimibe on atherosclerosis has been examined in several of these animal model systems. ApoE knockout mice develop severe hypercholesterolemia and premature atherosclerosis with features similar to that seen in humans and techniques ranging from gross visualization of plaque to high-resolution MRI have demonstrated the consistent ability of ezetimibe to significantly inhibit atherosclerosis. sr-b1(-/-)/apoE(-/-) double knockout mice exhibit additional characteristics common to human coronary heart disease (CHD), and the one study of ezetimibe in sr-b1(-/-)/apoE(-/-) mice showed a significant reduction in aortic sinus plaque (57%), coronary arterial occlusion (68%), myocardial fibrosis (57%), and cardiomegaly (12%) compared with untreated controls. The effects of ezetimibe have also been evaluated in ldlr(-/-)/apoE(-/-) double knockout mice, demonstrating that functional LDL receptors were not required for ezetimibe-mediated reduction of plasma cholesterol or atherosclerosis. For the few studies that have been

  12. Yindanxinnaotong, a Chinese compound medicine, synergistically attenuates atherosclerosis progress

    PubMed Central

    Cheng, Long; Pan, Guo-feng; Zhang, Xiao-dong; Wang, Jian-lu; Wang, Wan-dan; Zhang, Jian-yong; Wang, Hui; Liang, Ri-xin; Sun, Xiao-bo

    2015-01-01

    Yindanxinnaotong (YD), a traditional Chinese medicine, has been introduced to clinical medicine for more than a decade, while its pharmacological properties are still not to be well addressed. This report aimed to explore the anti-atherosclerosis properties and underlying mechanisms of YD. We initially performed a computational prediction based on a network pharmacology simulation, which clued YD exerted synergistically anti-atherosclerosis properties by vascular endothelium protection, lipid-lowering, anti-inflammation, and anti-oxidation. These outcomes were then validated in atherosclerosis rats. The experiments provided evidences indicating YD’s contribution in this study included, (1) significantly reduced the severity of atherosclerosis, inhibited reconstruction of the artery wall and regulated the lipid profile; (2) enhanced antioxidant power, strengthened the activity of antioxidant enzymes, and decreased malondialdhyde levels; (3) significantly increased the viability of umbilical vein endothelial cells exposed to oxidative stress due to pretreatment with YD; (4) significantly reduced the level of pro-inflammatory cytokines; (5) significantly down-regulated NF-kB/p65 and up-regulated IkB in the YD-treated groups. Overall, these results demonstrated that YD intervention relieves atherosclerosis through regulating lipids, reducing lipid particle deposition in the endothelial layer of artery, enhancing antioxidant power, and repressing inflammation activity by inhibiting the nuclear factor-kappa B signal pathway. PMID:26196108

  13. 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

  14. Serine protease inhibitor A3 in atherosclerosis and aneurysm disease.

    PubMed

    Wågsäter, Dick; Johansson, Daniel; Fontaine, Vincent; Vorkapic, Emina; Bäcklund, Alexandra; Razuvaev, Anton; Mäyränpää, Mikko I; Hjerpe, Charlotta; Caidahl, Kenneth; Hamsten, Anders; Franco-Cereceda, Anders; Wilbertz, Johannes; Swedenborg, Jesper; Zhou, Xinghua; Eriksson, Per

    2012-08-01

    Remodeling of extracellular matrix (ECM) plays an important role in both atherosclerosis and aneurysm disease. Serine protease inhibitor A3 (serpinA3) is an inhibitor of several proteases such as elastase, cathepsin G and chymase derived from mast cells and neutrophils. In this study, we investigated the putative role of serpinA3 in atherosclerosis and aneurysm formation. SerpinA3 was expressed in endothelial cells and medial smooth muscle cells in human atherosclerotic lesions and a 14-fold increased expression of serpinA3n mRNA was found in lesions from Apoe-/- mice compared to lesion-free vessels. In contrast, decreased mRNA expression (-80%) of serpinA3 was found in biopsies of human abdominal aortic aneurysm (AAA) compared to non-dilated aortas. Overexpression of serpinA3n in transgenic mice did not influence the development of atherosclerosis or CaCl2-induced aneurysm formation. In situ zymography analysis showed that the transgenic mice had lower cathepsin G and elastase activity, and more elastin in the aortas compared to wild-type mice, which could indicate a more stable aortic phenotype. Differential vascular expression of serpinA3 is clearly associated with human atherosclerosis and AAA but serpinA3 had no major effect on experimentally induced atherosclerosis or AAA development in mouse. However, serpinA3 may be involved in a phenotypic stabilization of the aorta. PMID:22580763

  15. Yindanxinnaotong, a Chinese compound medicine, synergistically attenuates atherosclerosis progress.

    PubMed

    Cheng, Long; Pan, Guo-feng; Zhang, Xiao-dong; Wang, Jian-lu; Wang, Wan-dan; Zhang, Jian-yong; Wang, Hui; Liang, Ri-xin; Sun, Xiao-bo

    2015-01-01

    Yindanxinnaotong (YD), a traditional Chinese medicine, has been introduced to clinical medicine for more than a decade, while its pharmacological properties are still not to be well addressed. This report aimed to explore the anti-atherosclerosis properties and underlying mechanisms of YD. We initially performed a computational prediction based on a network pharmacology simulation, which clued YD exerted synergistically anti-atherosclerosis properties by vascular endothelium protection, lipid-lowering, anti-inflammation, and anti-oxidation. These outcomes were then validated in atherosclerosis rats. The experiments provided evidences indicating YD's contribution in this study included, (1) significantly reduced the severity of atherosclerosis, inhibited reconstruction of the artery wall and regulated the lipid profile; (2) enhanced antioxidant power, strengthened the activity of antioxidant enzymes, and decreased malondialdhyde levels; (3) significantly increased the viability of umbilical vein endothelial cells exposed to oxidative stress due to pretreatment with YD; (4) significantly reduced the level of pro-inflammatory cytokines; (5) significantly down-regulated NF-kB/p65 and up-regulated IkB in the YD-treated groups. Overall, these results demonstrated that YD intervention relieves atherosclerosis through regulating lipids, reducing lipid particle deposition in the endothelial layer of artery, enhancing antioxidant power, and repressing inflammation activity by inhibiting the nuclear factor-kappa B signal pathway. PMID:26196108

  16. [Some historical considerations on the inflammatory theory of atherosclerosis].

    PubMed

    Marson, P; Zanchin, G; Stefanutti, C

    2004-01-01

    In the past 20 years several clinical and experimental observations have led to the hypothesis that an inflammatory response can trigger some key processes during the development of atherosclerosis. Here we briefly review, from the historical viewpoint, the inflammatory theory of atherosclerosis, as proposed by the Berliner pathologist Rudolf Virchow in the XIX century. Contrary to this hypothesis, in the same period the Viennese Karl von Rokitansky recognized blood dyscrasia (particularly fibrin-induced alterations) as the promoting factor in the process of atherogenesis. Moreover, we outline the relationship between atherosclerosis and arthritis, by reporting some passages from two scientific works published in the late XIX century, the former by the Italian Achille De Giovanni ("Sull'arterite. Sue forme cliniche e sua patogenesi", 1882) and the latter by the French Theophile Guyot ("L'arthritis. Maladie Constitutionnelle", 1890). PMID:15470528

  17. Nestin(+) cells direct inflammatory cell migration in atherosclerosis.

    PubMed

    Del Toro, Raquel; Chèvre, Raphael; Rodríguez, Cristina; Ordóñez, Antonio; Martínez-González, José; Andrés, Vicente; Méndez-Ferrer, Simón

    2016-01-01

    Atherosclerosis is a leading death cause. Endothelial and smooth muscle cells participate in atherogenesis, but it is unclear whether other mesenchymal cells contribute to this process. Bone marrow (BM) nestin(+) cells cooperate with endothelial cells in directing monocyte egress to bloodstream in response to infections. However, it remains unknown whether nestin(+) cells regulate inflammatory cells in chronic inflammatory diseases, such as atherosclerosis. Here, we show that nestin(+) cells direct inflammatory cell migration during chronic inflammation. In Apolipoprotein E (ApoE) knockout mice fed with high-fat diet, BM nestin(+) cells regulate the egress of inflammatory monocytes and neutrophils. In the aorta, nestin(+) stromal cells increase ∼30 times and contribute to the atheroma plaque. Mcp1 deletion in nestin(+) cells-but not in endothelial cells only- increases circulating inflammatory cells, but decreases their aortic infiltration, delaying atheroma plaque formation and aortic valve calcification. Therefore, nestin expression marks cells that regulate inflammatory cell migration during atherosclerosis. PMID:27586429

  18. Endogenous hydrogen sulfide is involved in the pathogenesis of atherosclerosis

    SciTech Connect

    Qiao, Wang; Chaoshu, Tang; Hongfang, Jin; Junbao, Du

    2010-05-28

    Atherosclerosis is a chronic, complex, and progressive pathological process in large and medium sized arteries. The exact mechanism of this process remains unclear. Hydrogen sulfide (H{sub 2}S), a novel gasotransmitter, was confirmed as playing a major role in the pathogenesis of many cardiovascular diseases. It plays a role in vascular smooth muscle cell (VSMC) proliferation and apoptosis, participates in the progress of hyperhomocysteinemia (HHCY), inhibits atherogenic modification of LDL, interferes with vascular calcification, intervenes with platelet function, and there are interactions between H{sub 2}S and inflammatory processes. The role of H{sub 2}S in atherosclerotic pathogenesis highlights the mysteries of atherosclerosis and inspires the search for innovative therapeutic strategies. Here, we review the studies to date that have considered the role of H{sub 2}S in atherosclerosis.

  19. Atherosclerosis and Thrombosis: Insights from Large Animal Models

    PubMed Central

    Vilahur, Gemma; Padro, Teresa; Badimon, Lina

    2011-01-01

    Atherosclerosis and its thrombotic complications are responsible for remarkably high numbers of deaths. The combination of in vitro, ex vivo, and in vivo experimental approaches has largely contributed to a better understanding of the mechanisms underlying the atherothrombotic process. Indeed, different animal models have been implemented in atherosclerosis and thrombosis research in order to provide new insights into the mechanisms that have already been outlined in isolated cells and protein studies. Yet, although no model completely mimics the human pathology, large animal models have demonstrated better suitability for translation to humans. Indeed, direct translation from mice to humans should be taken with caution because of the well-reported species-related differences. This paper provides an overview of the available atherothrombotic-like animal models, with a particular focus on large animal models of thrombosis and atherosclerosis, and examines their applicability for translational research purposes as well as highlights species-related differences with humans. PMID:21274431

  20. Relevance of hypercholesterolemia to fetal and pediatric atherosclerosis.

    PubMed

    Stehbens, William E

    2002-01-01

    Ubiquitous atherosclerotic changes in fetal and pediatric subjects demonstrate the fundamental importance of repetitive hemodynamic stresses and cannot be explained on the basis of the hypercholesterolemic/lipid hypothesis because serum cholesterol levels at this age lie within allegedly "desirable blood levels." This fact, inconsistent with the lipid hypothesis, renders absurd the widespread dietary restriction of cholesterol and animal fats as prevention of atherosclerosis. Iatrogenic effects of atherosclerosis in humans and its experimental production in herbivores at serum cholesterol levels below infant levels strongly support the "vascular fatige" concept and negate the lipid hypothesis. Neither is atherosclerosis a manifestation of senescence because age is merely a time factor indicating the duration of exposure to hemodynamic stresses that are variable with time and location. PMID:12056502

  1. Functional regulatory roles of microRNAs in atherosclerosis.

    PubMed

    Gao, Ya; Peng, Juan; Ren, Zhong; He, Ni-Ya; Li, Qing; Zhao, Xue-Shan; Wang, Mei-Mei; Wen, Hong-Yan; Tang, Zhi-Han; Jiang, Zhi-Sheng; Wang, Gui-Xue; Liu, Lu-Shan

    2016-09-01

    MicroRNAs are a group of endogenously small non-coding RNA molecules that downregulate gene expression at the post-transcriptional level through binding to the 3'UTR of target mRNAs. Recent findings have revealed a key role for microRNAs in the pathophysiological processes of atherosclerosis. As a complex disease, atherosclerosis is influenced by a combination of multiple genes and environmental factors. Both of them play a role in atherogenesis by affecting different types of cells (such as endothelial cell, vascular smooth muscle cell and monocyte/macrophage) function. MicroRNAs control the senescence and dysfunction of endothelial cells, proliferation and migration of vascular smooth muscle cells, and macrophage-driven cytokine production and polarization. By these effects, microRNAs can influence the processes of atherosclerosis and may represent new molecular targets for therapy. PMID:27384386

  2. 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

  3. Quantitative nonlinear optical assessment of atherosclerosis progression in rabbits.

    PubMed

    Mostaço-Guidolin, Leila B; Kohlenberg, Elicia K; Smith, Michael; Hewko, Mark; Major, Arkady; Sowa, Michael G; Ko, Alex C-T

    2014-07-01

    Quantification of atherosclerosis has been a challenging task owing to its complex pathology. In this study, we validated a quantitative approach for assessing atherosclerosis progression in a rabbit model using a numerical matrix, optical index for plaque burden, derived directly from the nonlinear optical microscopic images captured on the atherosclerosis-affected blood vessel. A positive correlation between this optical index and the severity of atherosclerotic lesions, represented by the age of the rabbits, was established based on data collected from 21 myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits with age ranging between new-born and 27 months old. The same optical index also accurately identified high-risk locations for atherosclerotic plaque formation along the entire aorta, which was validated by immunohistochemical fluorescence imaging. PMID:24892226

  4. Role of Helicobacter pylori infection in pathogenesis of atherosclerosis

    PubMed Central

    Vijayvergiya, Rajesh; Vadivelu, Ramalingam

    2015-01-01

    Though a century old hypothesis, infection as a cause for atherosclerosis is still a debatable issue. Epidemiological and clinical studies had shown a possible association but inhomogeneity in the study population and study methods along with potential confounders have yielded conflicting results. Infection triggers a chronic inflammatory state which along with other mechanisms such as dyslipidemia, hyper-homocysteinemia, hypercoagulability, impaired glucose metabolism and endothelial dysfunction, contribute in pathogenesis of atherosclerosis. Studies have shown a positive relations between Cytotoxic associated gene-A positive strains of Helicobacter pylori and vascular diseases such as coronary artery disease and stroke. Infection mediated genetic modulation is a new emerging theory in this regard. Further large scale studies on infection and atherosclerosis focusing on multiple pathogenetic mechanisms may help in refining our knowledge in this aspect. PMID:25810813

  5. Prostaglandin synthesis in aorta of atherosclerosis susceptible and atherosclerosis resistant pigeons.

    PubMed

    Subbiah, M T; Schweiger, E; Deitmeyer, D; Gallon, L; Sinzinger, H

    1980-01-01

    The aortas of 9 months aged Show Racer and White Carneau pigeons were examined for their PGE2, PGF2 alpha and 6-keto-PGF1 alpha synthesis from labelled arachidonic acid by radiothinlayer chromatography. The prostacyclin formation was estimated by means of Moncada's bioassay. PGE2 and PGF 2 alpha synthesis in the aorta of pigeons is higher than in rats, whereas less 6-keto-PGF1 alpha is formed in pigeon aortas. The susceptible White Carneau pigeons synthesitize more prostaglandins than the resistant Show Racer pigeons. PGI2 and 6-keto-PGF 1 alpha-formation is extremely low in avian arota. These data are in part contradicting to our findings im mammalians (where the atherosclerosis susceptible animals generate less PGI2) and warrants sequential measurements of prostaglandin synthesis in aorta to assess its significance during various stages of atherogenesis. PMID:7425865

  6. SUSCEPTIBILITY TO ATHEROSCLEROSIS IN AORTAS AND CORONARY ARTERIES OF SWINE WITH VON WILLEBRAND'S DISEASE

    EPA Science Inventory

    The development of coronary and aortic atherosclerosis was determined after balloon catheter injury of coronary arteries and administration of an atherogenic diet in normal pigs and pigs that were homozygous and heterozygous for von Willebrand's disease. Coronary atherosclerosis ...

  7. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis

    PubMed Central

    Karunakaran, Denuja; Geoffrion, Michele; Wei, Lihui; Gan, Wei; Richards, Laura; Shangari, Prakriti; DeKemp, Ella M.; Beanlands, Rachelle A.; Perisic, Ljubica; Maegdefessel, Lars; Hedin, Ulf; Sad, Subash; Guo, Liang; Kolodgie, Frank D.; Virmani, Renu; Ruddy, Terrence; Rayner, Katey J.

    2016-01-01

    Atherosclerosis results from maladaptive inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque necrosis, which underlies the instability that promotes plaque rupture and myocardial infarction. Hence, targeting macrophage cell death pathways may offer promise for the stabilization of vulnerable plaques. Necroptosis is a recently discovered pathway of programmed cell necrosis regulated by RIP3 and MLKL kinases that, in contrast to apoptosis, induces a proinflammatory state. We show herein that necroptotic cell death is activated in human advanced atherosclerotic plaques and can be targeted in experimental atherosclerosis for both therapeutic and diagnostic interventions. In humans with unstable carotid atherosclerosis, expression of RIP3 and MLKL is increased, and MLKL phosphorylation, a key step in the commitment to necroptosis, is detected in advanced atheromas. Investigation of the molecular mechanisms underlying necroptosis showed that atherogenic forms of low-density lipoprotein increase RIP3 and MLKL transcription and phosphorylation—two critical steps in the execution of necroptosis. Using a radiotracer developed with the necroptosis inhibitor necrostatin-1 (Nec-1), we show that 123I-Nec-1 localizes specifically to atherosclerotic plaques in Apoe−/− mice, and its uptake is tightly correlated to lesion areas by ex vivo nuclear imaging. Furthermore, treatment of Apoe−/− mice with established atherosclerosis with Nec-1 reduced lesion size and markers of plaque instability, including necrotic core formation. Collectively, our findings offer molecular insight into the mechanisms of macrophage cell death that drive necrotic core formation in atherosclerosis and suggest that this pathway can be used as both a diagnostic and therapeutic tool for the treatment of unstable atherosclerosis. PMID:27532042

  8. Hematopoietic Akt2 deficiency attenuates the progression of atherosclerosis

    PubMed Central

    Rotllan, Noemi; Chamorro-Jorganes, Aránzazu; Araldi, Elisa; Wanschel, Amarylis C.; Aryal, Binod; Aranda, Juan F.; Goedeke, Leigh; Salerno, Alessandro G.; Ramírez, Cristina M.; Sessa, William C.; Suárez, Yajaira; Fernández-Hernando, Carlos

    2015-01-01

    Atherosclerosis is the major cause of death and disability in diabetic and obese subjects with insulin resistance. Akt2, a phosphoinositide-dependent serine-threonine protein kinase, is highly express in insulin-responsive tissues; however, its role during the progression of atherosclerosis remains unknown. Thus, we aimed to investigate the contribution of Akt2 during the progression of atherosclerosis. We found that germ-line Akt2-deficient mice develop similar atherosclerotic plaques as wild-type mice despite higher plasma lipids and glucose levels. It is noteworthy that transplantation of bone marrow cells isolated from Akt2−/− mice to Ldlr−/− mice results in marked reduction of the progression of atherosclerosis compared with Ldlr−/− mice transplanted with wild-type bone marrow cells. In vitro studies indicate that Akt2 is required for macrophage migration in response to proatherogenic cytokines (monocyte chemotactic protein-1 and macrophage colony-stimulating factor). Moreover, Akt2−/− macrophages accumulate less cholesterol and have an alternative activated or M2-type phenotype when stimulated with proinflammatory cytokines. Together, these results provide evidence that macrophage Akt2 regulates migration, the inflammatory response and cholesterol metabolism and suggest that targeting Akt2 in macrophages might be beneficial for treating atherosclerosis.—Rotllan, N., Chamorro-Jorganes, A., Araldi, E., Wanschel, A. C., Aryal, B., Aranda, J. F., Goedeke, L., Salerno, A. G., Ramírez, C. M., Sessa,W. C., Suárez, Y., Fernández-Hernando, C. Hematopoietic Akt2 deficiency attenuates the progression of atherosclerosis. PMID:25392271

  9. Basic Mechanisms in Atherosclerosis: The Role of Calcium.

    PubMed

    Kalampogias, Aimilios; Siasos, Gerasimos; Oikonomou, Evangelos; Tsalamandris, Sotirios; Mourouzis, Konstantinos; Tsigkou, Vasiliki; Vavuranakis, Manolis; Zografos, Thodoris; Deftereos, Spyridon; Stefanadis, Christodoulos; Tousoulis, Dimitris

    2016-01-01

    In the beginning, atherosclerosis was considered to be the result of passive lipid accumulation in the vascular walls. After tremendous technological advancements in research, we are now able to almost admire the complexity of the atherosclerotic process. Atherosclerosis is a chronicinflammatory condition that begins with the formation of calcified plaque, influenced by a number of different factors inside the vascular wall in large and mid-sized arteries. Calcium mineralization of the lumen in the atherosclerotic artery promotes and solidifies plaque formation causing narrowing of the vessel. Soft tissue calcification associated with tissue denegation or necrosis is a passive precipitation event. The process of atherogenesis is mainly driven by CD4+ T cells, CD40L, macrophages, foam cells with elevated transcription of many matrix metalloproteinases, osteoblasts, cytokines, selectins, myeloperoxidases, vascular adhesion molecules (VCAM), and smooth muscle cells. Our knowledge in the genesis of atherosclerosis has changed dramatically in the last few years. New imaging techniques such as intravascular ultrasound or IVUS have made possible to investigate atherosclerosis in early stages. Arterial calcification emerges from two different types, the medial-elastin dependent and the intimal, both of which are directly related to atherosclerosis due to osteoblast differentiation of vascular smooth muscle cells. The deposition of minerals in the form of calcium (Ca(2+)) initially emerges from the inorganing mineral octacalcium phosphate [Ca8H2(PO4)6.5H2O] to the form of Hydroxylapatite [Ca10(PO4)6(OH)2]. This review is devoted to broaden the understanding regarding atherosclerosis and the central role of calcium in the development of the condition. PMID:26411606

  10. Tolerization against atherosclerosis using heat shock protein 60.

    PubMed

    Wick, Cecilia

    2016-03-01

    Atherosclerosis is a chronic inflammatory disease of the artery wall, and both innate and adaptive immunity play important roles in the pathogenesis of this disease. In several experimental and human experiments of early atherosclerotic lesions, it has been shown that the first pathogenic event in atherogenesis is intimal infiltration of T cells at predilection sites. These T cells react to heat shock protein 60 (HSP60), which is a ubiquitous self-antigen expressed on the surface of endothelial cells (ECs) together with adhesion molecules in response to classical risk factors for atherosclerosis. When HSP60 is expressed on the EC surface, it can act as a "danger-signal" for both cellular and humoral immune reactions. Acquired by infection or vaccination, beneficial protective immunity to microbial HSP60 and bona fide autoimmunity to biochemically altered autologous HSP60 is present in all humans. Thus, the development of atherosclerosis during aging is paid by the price for lifelong protective preexisting anti-HSP60 immunity by harmful (auto)immune cross-reactive attack on arterial ECs maltreated by atherosclerosis risk factors. This is supported by experiments, which shows that bacterial HSP60 immunization can lead and accelerate experimental atherosclerosis. This review article presents accumulating proof that supports the idea that tolerization with antigenic HSP60 protein or its peptides may arrest or even prevent atherosclerosis by increased production of regulatory T cells and/or anti-inflammatory cytokines. Recent data indicates that HSP60, or more likely some of its derivative peptides, has immunoregulatory functions. Therefore, these peptides may have important potential for being used as diagnostic agents or therapeutic targets. PMID:26577462

  11. 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

  12. Changes in transcriptome of macrophages in atherosclerosis

    PubMed Central

    Chistiakov, Dimitry A; Bobryshev, Yuri V; Orekhov, Alexander N

    2015-01-01

    characterize changes in macrophage transcriptome in atherosclerosis and discuss key markers that characterize different phenotypes of macrophages present in atherosclerotic lesions. PMID:25973901

  13. Monocyte chemoattractants in pigeon aortic atherosclerosis.

    PubMed Central

    Denholm, E. M.; Lewis, J. C.

    1987-01-01

    Atherosclerosis occurs in the aorta of White Carneau pigeons proximal to the celiac bifurcation, where monocyte adhesion and migration into lesions have been demonstrated. This study documents chemoattractants that might be responsible for monocyte adherence and migration. Ten-week-old pigeons were fed either a cholesterol-free (normal) diet or a 0.4% cholesterol diet for 12 or 24 weeks. Birds with a normal diet did not have lesions in the lesion-prone area of the aorta, whereas birds fed a cholesterol-containing diet had simple intimal foam-cell lesions (12 weeks) or foam-cell lesions complicated with extracellular lipid and fibrillar matrix material (24 weeks). Plasma cholesterol levels in birds on the cholesterol-containing diet were 780-1080 mg/dl versus 140-240 mg/dl in the normal diet control group(s) at necropsy. To assay for chemoattractants, tissue was collected from lesion-prone and nonsusceptible (nonlesion) areas of the aortas. Samples from the two types of regions were separately pooled, then homogenized and tested for chemoattractant activity for pigeon peripheral blood monocytes. Monocyte chemoattractants were demonstrated in lesion area homogenates from pigeons fed cholesterol for 12 or 24 weeks and also in analogous homogenates from pigeons fed a normal diet. Monocyte migration to lesion-prone homogenates was significantly greater than that to nonlesion area homogenates. The chemoattractants in homogenates were monocyte-specific. The chemoattractant activity in the birds fed cholesterol for 12 weeks was confined to the aqueous phase of lipid extracts. This activity was abolished by pronase but unaffected by heat (100 C, 30 minutes), which indicated that the chemoattractant(s) in these homogenates was heat-stable protein(s). Activity in lipid extracts of lesion area homogenates from birds fed a cholesterol-containing diet for 24 weeks was found in both the aqueous and organic phases, suggesting that these samples contained lipid as well as

  14. 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. PMID:25106086

  15. Fetal programming of atherosclerosis: possible role of the mitochondria.

    PubMed

    Leduc, Line; Levy, Emile; Bouity-Voubou, Maurice; Delvin, Edgard

    2010-04-01

    Growing evidence indicates that being small size at birth from malnutrition is associated with an increased risk of developing type 2 diabetes (T2D), metabolic syndrome and cardiovascular disease in adulthood. Atherosclerosis is common to these aforementioned disorders, and oxidative stress and chronic inflammation are now considered as initiating events in its development, with endothelial cell dysfunction being an early, fundamental step. According to the fetal programming hypothesis, growth-restricted neonates exposed to placental insufficiency exhibit endothelial cell dysfunction very early in life that later on predisposes them to atherosclerosis. Although many investigations have reported early alterations in vascular function in children and adolescents with low birth weight, the mechanisms of such fetal programming of atherosclerosis remain largely unknown. Experimental studies have demonstrated that low birth weight infants are prenatally subjected to conditions of oxidative stress and inflammation that might be involved in the later occurrence of atherosclerosis. Arterial endothelial dysfunction has been encountered in term infants, children and young adults with low birth weight. The loss of appropriate endothelium function with decreased nitric oxide production or activity, manifested as impaired vasodilatation, is considered a basic step in atherosclerosis development and progression. Several lines of evidence indicate that mitochondrial damage is central to this process and that reactive oxygen species (ROS) may act as a double-edged sword. On the one hand, it is well-accepted that the mitochondria are a major source of chronic ROS production under physiological conditions. On the other hand, it is known that ROS generation damages lipids, proteins and mitochondrial DNA, leading to dysregulated mitochondrial function. Elevated mitochondrial ROS production is associated with endothelial cell dysfunction as well as vascular smooth muscle cell

  16. Targeting and Therapeutic Peptides in Nanomedicine for Atherosclerosis

    PubMed Central

    Chung, Eun Ji

    2016-01-01

    Peptides in atherosclerosis nanomedicine provide structural, targeting, and therapeutic functionality, and can assist in overcoming delivery barriers of traditional pharmaceuticals. Moreover, their inherent biocompatibility and biodegradability make them especially attractive as materials intended for use in vivo. In this review, an overview of nanoparticle-associated targeting and therapeutic peptides for atherosclerosis are provided, including peptides designed for cellular targets such as endothelial cells, monocytes, and macrophages as well as for plaque components such as collagen and fibrin. An emphasis is placed on recent advances in multimodal strategies and a discussion on current challenges and barriers for clinical applicability is presented. PMID:27022138

  17. Potential cell-specific functions of CXCR4 in atherosclerosis.

    PubMed

    Weber, Christian; Döring, Yvonne; Noels, Heidi

    2016-05-10

    The chemokine CXCL12 and its receptor CXCR4 form an important axis contributing to cellular functions in homeostasis and disease. In addition, the atypical CXCL12 receptor CXCR7 may shape the availability and function of CXCL12. Further to their role through progenitor cell mobilization, CXCL12 and CXCR4 may affect native atherogenesis by modifying atherosclerosis-relevant cellular functions. This short review intends to provide a concise summary of current knowledge with regards to cell-specific functions of CXCL12 and its receptors CXCR4 and CXCR7 with potential implications for the initiation and progression of atherosclerosis. PMID:25586789

  18. Perspectives and opportunities for nanomedicine in the management of atherosclerosis

    PubMed Central

    Lobatto, Mark E.; Fuster, Valentin; Fayad, Zahi A.; Mulder, Willem J. M.

    2013-01-01

    The use of nanotechnology for medical purposes — nanomedicine — has grown exponentially over the past few decades. This is exemplified by the US Food and Drug Administration’s approval of several nanotherapies for various conditions, as well as the funding of nanomedical programmes worldwide. Although originally the domain of anticancer therapy, recent advances have illustrated the considerable potential of nanomedicine in the diagnosis and treatment of atherosclerosis. This Review elaborates on nanoparticle-targeting concepts in atherosclerotic disease, provides an overview of the use of nanomedicine in atherosclerosis, and discusses potential future applications and clinical benefits. PMID:22015921

  19. Molecular imaging in atherosclerosis, thrombosis and vascular inflammation

    PubMed Central

    Choudhury, Robin P.; Fisher, Edward A.

    2009-01-01

    Appreciation of the molecular and cellular processes of atherosclerosis, thrombosis and vascular inflammation has identified new targets for imaging. The common goals of molecular imaging approaches are to accelerate and refine diagnosis, provide insights that reveal disease diversity, guide specific therapies and monitor the effects of those therapies. Here we undertake a comparative analysis of imaging modalities that have been used in this disease area. We consider the elements of contrast agents, emphasizing how an understanding of the biology of atherosclerosis and its complications can inform optimal design. We address the potential and limitations of current contrast approaches in respect of translation to clinically usable agents and speculate on future applications. PMID:19213945

  20. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation

    PubMed Central

    Tang, Jun; Lobatto, Mark E.; Hassing, Laurien; van der Staay, Susanne; van Rijs, Sarian M.; Calcagno, Claudia; Braza, Mounia S.; Baxter, Samantha; Fay, Francois; Sanchez-Gaytan, Brenda L.; Duivenvoorden, Raphaël; Sager, Hendrik B.; Astudillo, Yaritzy M.; Leong, Wei; Ramachandran, Sarayu; Storm, Gert; Pérez-Medina, Carlos; Reiner, Thomas; Cormode, David P.; Strijkers, Gustav J.; Stroes, Erik S. G.; Swirski, Filip K.; Nahrendorf, Matthias; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.

    2015-01-01

    Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E–deficient mice (Apoe−/−) with advanced atherosclerotic plaques. This resulted in the rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an 8-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis. PMID:26295063

  1. 78 FR 77138 - Proposed Collection; 60-day Comment Request: The Atherosclerosis Risk in Communities Study (ARIC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-20

    ... Atherosclerosis Risk in Communities Study (ARIC) Summary: In compliance with the requirement of Section 3506(c) (2... days of the date of this publication. Proposed Collection: The Atherosclerosis Risk in Communities... primary objectives of the study are to: (1) investigate factors associated with both atherosclerosis...

  2. IRF5 deficiency ameliorates lupus but promotes atherosclerosis and metabolic dysfunction in a mouse model of lupus-associated atherosclerosis

    PubMed Central

    Watkins, Amanda A.; Yasuda, Kei; Wilson, Gabriella E.; Aprahamian, Tamar; Xie, Yao; Maganto-Garcia, Elena; Shukla, Prachi; Oberlander, Lillian; Laskow, Bari; Menn-Josephy, Hanni; Wu, Yuanyuan; Duffau, Pierre; Fried, Susan K.; Lichtman, Andrew H.; Bonegio, Ramon G.; Rifkin, Ian R.

    2015-01-01

    Premature atherosclerosis is a severe complication of lupus and other systemic autoimmune disorders. Gain-of-function polymorphisms in interferon regulatory factor 5 (IRF5) are associated with an increased risk of developing lupus and IRF5 deficiency in lupus mouse models ameliorates disease. However, whether IRF5 deficiency also protects against atherosclerosis development in lupus is not known. Here we addressed this question using the gld.apoE−/− mouse model. IRF5 deficiency markedly reduced lupus disease severity. Unexpectedly, despite the reduction in systemic immune activation, IRF5-deficient mice developed increased atherosclerosis and also exhibited metabolic dysregulation characterized by hyperlipidemia, increased adiposity and insulin resistance. Levels of the atheroprotective cytokine IL-10 were reduced in aortae of IRF5-deficient mice and in vitro studies demonstrated that IRF5 is required for IL-10 production downstream of TLR7 and TLR9 signaling in multiple immune cell types. Chimera studies showed that IRF5 deficiency in bone marrow-derived cells prevents lupus development and contributes in part to the increased atherosclerosis. Notably, IRF5 deficiency in non-bone marrow-derived cells also contributes to the increased atherosclerosis through the generation of hyperlipidemia and increased adiposity. Together, our results reveal a protective role for IRF5 in lupus-associated atherosclerosis that is mediated through the effects of IRF5 in both immune and non-immune cells. These findings have implications for the proposed targeting of IRF5 in the treatment of autoimmune disease as global IRF5 inhibition may exacerbate cardiovascular disease in these patients. PMID:25595782

  3. 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.

  4. 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

  5. Metabolic syndrome showed significant relationship with carotid atherosclerosis.

    PubMed

    Kawada, Tomoyuki; Andou, Takeshi; Fukumitsu, Masayuki

    2016-05-01

    Metabolic syndrome (MetS) is associated with an increased risk of cardiovascular disease. We assessed the associations between MetS and the indicators of carotid atherosclerosis as assessed by ultrasonography taking into consideration of confounders in the general population. A total of 1281 subjects (856 males, 425 females) were included in the present study. The total plaque score and maximum intima-media thickness (IMT) of the carotid arteries were measured as indicators of atherosclerosis. Cardiovascular risk factors were several metabolic components, serum uric acid, serum C-reactive protein (CRP), and lifestyle factors. MetS was defined according to the criteria of the National Cholesterol Education Program. The prevalences of an elevated total plaque score (≥5) and elevated IMT (>1 mm) of the carotid arteries were significantly higher in subjects with MetS as compared to subjects without MetS. Furthermore, a trend was observed towards higher prevalences of these indicators of atherosclerosis as the number of components of MetS increased. Logistic regression analysis revealed a significant association between elevated plaque score and MetS even after adjustments for age, serum uric acid, serum CRP and lifestyle factors in the males. Among the indicators of atherosclerosis assessed by carotid ultrasonography, a significant independent association was observed between the total plaque score and MetS in males in the general population. PMID:25810113

  6. The role of oxidative stress and autophagy in atherosclerosis.

    PubMed

    Perrotta, Ida; Aquila, Saveria

    2015-01-01

    Atherosclerosis is a multifactorial, multistep disorder of large- and medium-sized arteries involving, in addition to age, gender and menopausal status, a complex interplay between lifestyle and genetic risk factors. Atherosclerosis usually begins with the diffusion and retention of atherogenic lipoproteins into the subendothelial space of the artery wall where they become oxidized by local enzymes and accumulate, leading to the formation of a cushion called atheroma or atheromatous or fibrofatty plaque, composed of a mixture of macrophages, lymphocytes, smooth muscle cells (SMCs), cholesterol cleft, necrotic debris, and lipid-laden foam cells. The pathogenesis of atherosclerosis still remains incompletely understood but emerging evidence suggests that it may involve multiple cellular events, including endothelial cell (EC) dysfunction, inflammation, proliferation of vascular SMCs, matrix (ECM) alteration, and neovascularization. Actually, a growing body of evidence indicates that autophagy along with the chronic and acute overproduction of reactive oxygen species (ROS) is integral to the development and progression of the disease and may represent fruitful avenues for biological investigation and for the identification of new therapeutic targets. In this review, we give an overview of ROS and autophagy in atherosclerosis as background to understand their potential role in this vascular disease. PMID:25866599

  7. 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

  8. Interferon-γ: Promising therapeutic target in atherosclerosis

    PubMed Central

    Moss, Joe WE; Ramji, Dipak P

    2015-01-01

    Atherosclerosis is a chronic inflammatory disorder of the vasculature and is the primary cause of cardiovascular disease (CVD). CVD is currently the world’s leading cause of death and the numbers are predicted to rise further because of a global increase in risk factors such as diabetes and obesity. Current therapies such as statins have had a major impact in reducing mortality from CVD. However, there is a marked residual CVD risk in patients on statin therapy. It is therefore important to understand the molecular basis of this disease in detail and to develop alternative novel therapeutics. Interferon-γ (IFN-γ) is a pro-inflammatory cytokine that is often regarded as a master regulator of atherosclerosis development. IFN-γ is able to influence several key steps during atherosclerosis development, including pro-inflammatory gene expression, the recruitment of monocytes from the blood to the activated arterial endothelium and plaque stability. This central role of IFN-γ makes it a promising therapeutic target. The purpose of this editorial is to describe the key role IFN-γ plays during atherosclerosis development, as well as discuss potential strategies to target it therapeutically. PMID:26309816

  9. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development

    PubMed Central

    Berbée, Jimmy F. P.; Boon, Mariëtte R; Khedoe, P. Padmini S. J.; Bartelt, Alexander; Schlein, Christian; Worthmann, Anna; Kooijman, Sander; Hoeke, Geerte; Mol, Isabel M.; John, Clara; Jung, Caroline; Vazirpanah, Nadia; Brouwers, Linda P.J.; Gordts, Philip L.S.M.; Esko, Jeffrey D.; Hiemstra, Pieter S.; Havekes, Louis M.; Scheja, Ludger; Heeren, Joerg; Rensen, Patrick C.N.

    2015-01-01

    Brown adipose tissue (BAT) combusts high amounts of fatty acids, thereby lowering plasma triglyceride levels and reducing obesity. However, the precise role of BAT in plasma cholesterol metabolism and atherosclerosis development remains unclear. Here we show that BAT activation by β3-adrenergic receptor stimulation protects from atherosclerosis in hyperlipidemic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism that unlike hyperlipidemic Apoe−/− and Ldlr−/− mice expresses functional apoE and LDLR. BAT activation increases energy expenditure and decreases plasma triglyceride and cholesterol levels. Mechanistically, we demonstrate that BAT activation enhances the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT, subsequently accelerating the hepatic clearance of the cholesterol-enriched remnants. These effects depend on a functional hepatic apoE-LDLR clearance pathway as BAT activation in Apoe−/− and Ldlr−/− mice does not attenuate hypercholesterolaemia and atherosclerosis. We conclude that activation of BAT is a powerful therapeutic avenue to ameliorate hyperlipidaemia and protect from atherosclerosis. PMID:25754609

  10. 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.

  11. Increased LDL susceptibility to oxidation accelerates future carotid artery atherosclerosis

    PubMed Central

    2012-01-01

    Background We analyzed the causal relationship between LDL susceptibility to oxidation and the development of new carotid artery atherosclerosis over a period of 5 years. We previously described the determinants related to a risk of cardiovascular changes determined in a Japanese population participating in the Niigata Study, which is an ongoing epidemiological investigation of the prevention of cardiovascular diseases. Methods We selected 394 individuals (169 males and 225 females) who underwent a second carotid artery ultrasonographic examination in 2001 - 2002 for the present study. The susceptibility of LDL to oxidation was determined as the photometric absorbance and electrophoretic mobility of samples that had been collected in 1996 - 1997. The measurements were compared with ultrasonographic findings obtained in 2001 - 2002. Results The multivariate-adjusted model showed that age (odds ratio (OR), 1.034; 95% confidence interval (95%CI), 1.010 - 1.059), HbA1c (OR, 1.477; 95%CI, 0.980 - 2.225), and photometric O/N (OR, 2.012; 95%CI, 1.000 - 4.051) were significant variables that could independently predict the risk of new carotid artery atherosclerosis. Conclusion The susceptibility of LDL to oxidation was a significant parameter that could predict new carotid artery atherosclerosis over a 5-year period, and higher susceptibility was associated with a higher incidence of new carotid artery atherosclerosis. PMID:22230558

  12. Macrophage autophagy regulated by miR-384-5p-mediated control of Beclin-1 plays a role in the development of atherosclerosis

    PubMed Central

    Wang, Beiyun; Zhong, Yuan; Huang, Dong; Li, Jingbo

    2016-01-01

    Macrophages play an essential and complicated role in the pathogenesis of atherosclerosis. However, the regulation of macrophage autophagy as well as it role in the development of atherosclerosis is unclear. MicroRNA-384-5p (miR-384-5p) is a new miRNA that attracted attention very recently, while its effects on Beclin-1 and cell autophagy has not been reported. Here, we studied macrophage autophagy in ApoE (-/-) mice suppled with high-fat diet (HFD), a mouse model for atherosclerosis (simplified as HFD mice). We analyzed the levels of Beclin-1 and the levels of miR-384-5p in the purified F4/80+ macrophages from mouse aorta. Prediction of the binding between miR-384-5p and 3’-UTR of Beclin-1 mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. We found that HFD mice developed atherosclerosis in 12 weeks, while the control ApoE (-/-) mice that had received normal diet (simplified as NOR mice) did not. Compared to NOR mice, HFD mice had significantly lower levels of macrophage autophagy, and significantly higher levels of macrophage death, resulting from decreases in Beclin-1. The decreases in Beclin-1 in macrophages were due to HFD-induced increases in miR-384-5p, which suppressed the translation of Bectlin-1 mRNA via 3’-UTR binding. Together, our study suggests that upregulation of miR-384-5p by HFD may impair the Beclin-1-mediated protection of macrophages through autophagy to accelerate the development of atherosclerosis. PMID:27158352

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

    SciTech Connect

    Wang, Yi-Xiang J. Kuribayashi, Hideto; Wagberg, Maria; Holmes, Andrew P.; Tessier, Jean J.; Waterton, John C.

    2006-08-15

    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 killed 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 weeks of

  14. Subclinical Atherosclerosis and Obesity Phenotypes Among Mexican Americans

    PubMed Central

    Laing, Susan T.; Smulevitz, Beverly; Vatcheva, Kristina P.; Rahbar, Mohammad H.; Reininger, Belinda; McPherson, David D.; McCormick, Joseph B.; Fisher‐Hoch, Susan P.

    2015-01-01

    Background Data on the influence of obesity on atherosclerosis in Hispanics are inconsistent, possibly related to varying cardiometabolic risk among obese individuals. We aimed to determine the association of obesity and cardiometabolic risk with subclinical atherosclerosis in Mexican‐Americans. Methods and Results Participants (n=503) were drawn from the Cameron County Hispanic Cohort. Metabolic health was defined as <2 of the following: blood pressure ≥130/85; triglyceride ≥150 mg/dL; high‐density lipoprotein cholesterol <40 mg/dL (men) or <50 mg/dL (women); fasting glucose ≥100 mg/dL; homeostasis model assessment of insulin resistance value >5.13; or high‐sensitivity C‐reactive protein >3 mg/L. Carotid intima media thickness (cIMT) was measured. A high proportion of participants (77.8%) were metabolically unhealthy; they were more likely to be male, older, with fewer years of education, and less likely to meet daily recommendations regarding fruit and vegetable servings. One‐third (31.8%) had abnormal carotid ultrasound findings. After adjusting for covariates, mean cIMT varied across the obesity phenotypes (P=0.0001); there was no difference among the metabolically unhealthy regardless of whether they were obese or not. In multivariable analysis, after adjusting for covariates, cardiometabolic risk (P=0.0159), but not obesity (P=0.1446), was significantly associated with subclinical atherosclerosis. Conclusions In Mexican‐Americans, cardiometabolic risk has a greater effect on early atherosclerosis development than body mass index. Non‐obese but metabolically unhealthy participants had similar development of subclinical atherosclerosis as their obese counterparts. Interventions to maintain metabolic health among obese and non‐obese patients may be a more important goal than weight loss alone. PMID:25787312

  15. Beyond vascular inflammation--recent advances in understanding atherosclerosis.

    PubMed

    Wolf, Dennis; Zirlik, Andreas; Ley, Klaus

    2015-10-01

    Atherosclerosis is the most life-threatening pathology worldwide. Its major clinical complications, stroke, myocardial infarction, and heart failure, are on the rise in many regions of the world--despite considerable progress in understanding cause, progression, and consequences of atherosclerosis. Originally perceived as a lipid-storage disease of the arterial wall (Die cellularpathologie in ihrer begründung auf physiologische und pathologische gewebelehre. August Hirschwald Verlag Berlin, [1871]), atherosclerosis was recognized as a chronic inflammatory disease in 1986 (New Engl J Med 314:488-500, 1986). The presence of lymphocytes in atherosclerotic lesions suggested autoimmune processes in the vessel wall (Clin Exp Immunol 64:261-268, 1986). Since the advent of suitable mouse models of atherosclerosis (Science 258:468-471, 1992; Cell 71:343-353, 1992; J Clin Invest 92:883-893, 1993) and the development of flow cytometry to define the cellular infiltrate in atherosclerotic lesions (J Exp Med 203:1273-1282, 2006), the origin, lineage, phenotype, and function of distinct inflammatory cells that trigger or inhibit the inflammatory response in the atherosclerotic plaque have been studied. Multiphoton microscopy recently enabled direct visualization of antigen-specific interactions between T cells and antigen-presenting cells in the vessel wall (J Clin Invest 122:3114-3126, 2012). Vascular immunology is now emerging as a new field, providing evidence for protective as well as damaging autoimmune responses (Int Immunol 25:615-622, 2013). Manipulating inflammation and autoimmunity both hold promise for new therapeutic strategies in cardiovascular disease. Ongoing work (J Clin Invest 123:27-36, 2013; Front Immunol 2013; Semin Immunol 31:95-101, 2009) suggests that it may be possible to develop antigen-specific immunomodulatory prevention and therapy-a vaccine against atherosclerosis. PMID:26100516

  16. E-selectin-targeting delivery of microRNAs by microparticles ameliorates endothelial inflammation and atherosclerosis.

    PubMed

    Ma, Shuangtao; Tian, Xiao Yu; Zhang, Yunrong; Mu, Chaofeng; Shen, Haifa; Bismuth, Jean; Pownall, Henry J; Huang, Yu; Wong, Wing Tak

    2016-01-01

    E-selectin is a surface marker of endothelial cell (EC) inflammation, one of the hallmarks of atherogenesis. Thus, we tested the hypothesis that delivery of microRNA (miR)-146a and miR-181b with an E-selectin-targeting multistage vector (ESTA-MSV) to inflamed endothelium covering atherosclerotic plaques inhibits atherosclerosis. Cy5-conjugated miR-146a and miR-181b were packaged in polyethylene glycol-polyethyleneimine (PEG/PEI) nanoparticles and loaded into ESTA-MSV microparticles. Both miRs were downregulated in tumor necrosis factor (TNF)-α-treated ECs. Transfection of TNF-α-treated mouse aortas and cultured ECs with miRs was more efficient with ESTA-MSV than with the PEG/PEI. Likewise, miR-146a/-181b packaged in ESTA-MSV efficiently suppressed the chemokines, CCL2, CCL5, CCL8, and CXCL9, and monocyte adhesion to ECs. Complementary in vivo tests were conducted in male apolipoprotein E-deficient mice fed a Western diet and injected intravenously with the particles prepared as above biweekly for 12 weeks. Treatment with miRs packaged in ESTA-MSV but not in PEG/PEI reduced atherosclerotic plaque size. Concurrently, vascular inflammation markers, including macrophages in aortic root lesions and chemokine expression in aortic tissues were reduced while the vascular smooth muscle cells and collagen increased in plaques from ESTA-MSV/miRs-treated vs. vehicle-treated mice. Our data supported our hypothesis that ESTA-MSV microparticle-mediated delivery of miR-146a/-181b ameliorates endothelial inflammation and atherosclerosis. PMID:26956647

  17. Autologous Bone Marrow Mononuclear Cell Transplantation Delays Progression of Carotid Atherosclerosis in Rabbits.

    PubMed

    Cui, Kefei; Ma, Xiao; Yu, Lie; Jiang, Chao; Fu, Chao; Fu, Xiaojie; Yu, Xiaofang; Huang, Yuanjing; Hou, Suyun; Si, Caifeng; Chen, Zhengguang; Yu, Jing; Wan, Jieru; Wang, Jian

    2016-09-01

    Bone marrow mononuclear cells (BMMNCs) can counteract oxidative stress and inhibit the inflammatory response in focal ischemic stroke models. However, the effect of BMMNC transplantation on carotid atherosclerosis needs to be determined. The carotid atherosclerotic plaque model was established in New Zealand White rabbits by balloon injury and 8 weeks of high-fat diet. Rabbits were randomized to receive an intravenous injection of autologous bromodeoxyuridine (BrdU)-labeled BMMNCs or an equal volume of phosphate-buffered saline. Plaques were evaluated for expression of proinflammatory and anti-inflammatory cytokines, anti-oxidant proteins, and markers of cell death. BMMNCs migrated into atherosclerotic plaque on the first day after cell transplantation. BMMNC-treated rabbits had smaller plaques and more collagen deposition than did the vehicle-treated controls on day 28 (p < 0.05). BMMNC treatment significantly increased endothelial nitric oxide synthase and the anti-oxidant enzymes glutathione peroxidase and superoxide dismutase in plaques compared to vehicle treatment on day 7. BMMNC-treated rabbits also had lower levels of cleaved caspase-3 expression; lower levels of proinflammatory cytokines interleukin-1β, tumor necrosis factor alpha, and matrix metalloproteinase 9; and higher levels of insulin-like growth factor-1 and its receptor (p < 0.05). Autologous BMMNC transplantation can suppress the process of atherosclerotic plaque formation and is associated with enhanced anti-oxidative effect, reduced levels of inflammatory cytokines and cleaved caspase-3, and increased expression of insulin-like growth factor-1 and its receptor. BMMNC transplantation represents a novel approach for the treatment of carotid atherosclerosis. PMID:26232064

  18. Endothelial ATP-binding cassette G1 in mouse endothelium protects against hemodynamic-induced atherosclerosis.

    PubMed

    Xue, Shanshan; Wang, Jiaxing; Zhang, Xu; Shi, Ying; Li, Bochuan; Bao, Qiankun; Pang, Wei; Ai, Ding; Zhu, Yi; He, Jinlong

    2016-08-19

    Activated vascular endothelium inflammation under persistent hyperlipidemia is the initial step of atherogenesis. ATP-binding cassette G1 (ABCG1) is a crucial factor maintaining sterol and lipid homeostasis by transporting cholesterol efflux to high-density lipoprotein. In this study, we investigated the protective effects of ABCG1 in endothelial inflammation activation during early-stage atherogenesis in mice and the underlying mechanisms. Endothelial cell (EC)-specific ABCG1 transgenic (EC-ABCG1-Tg) mice were generated and cross-bred with low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. After a 4-week Western-type diet, the mice were sacrificed for assessing atherosclerosis. Human umbilical vein ECs were treated with different flows, and ABCG1 was adenovirally overexpressed to investigate the mechanism in vitro. Compared with Ldlr(-/-) mouse aortas, EC-ABCG1-Tg/Ldlr(-/-) aortas showed decreased early-stage lesions. Furthermore, the lesion area in the EC-ABCG1-Tg/Ldlr(-/-) mouse aortic arch but not thoracic aorta was significantly reduced, which suggests a protective role of ABCG1 under atheroprone flow. In vitro, overexpression of ABCG1 attenuated EC activation caused by oscillatory shear stress. Overexpression of ABCG1 blunted cholesterol-activated ECs in vitro. In exploring the mechanisms of ABCG1 attenuating endothelial inflammation, we found that ABCG1 inhibited oscillatory flow-activated nuclear factor kappa B and NLRP3 inflammasome in ECs. ABCG1 may play a protective role in early-stage atherosclerosis by reducing endothelial activation induced by oscillatory shear stress via suppressing the inflammatory response. PMID:27297110

  19. E-selectin-targeting delivery of microRNAs by microparticles ameliorates endothelial inflammation and atherosclerosis

    PubMed Central

    Ma, Shuangtao; Tian, Xiao Yu; Zhang, Yunrong; Mu, Chaofeng; Shen, Haifa; Bismuth, Jean; Pownall, Henry J.; Huang, Yu; Wong, Wing Tak

    2016-01-01

    E-selectin is a surface marker of endothelial cell (EC) inflammation, one of the hallmarks of atherogenesis. Thus, we tested the hypothesis that delivery of microRNA (miR)-146a and miR-181b with an E-selectin-targeting multistage vector (ESTA-MSV) to inflamed endothelium covering atherosclerotic plaques inhibits atherosclerosis. Cy5-conjugated miR-146a and miR-181b were packaged in polyethylene glycol-polyethyleneimine (PEG/PEI) nanoparticles and loaded into ESTA-MSV microparticles. Both miRs were downregulated in tumor necrosis factor (TNF)-α-treated ECs. Transfection of TNF-α-treated mouse aortas and cultured ECs with miRs was more efficient with ESTA-MSV than with the PEG/PEI. Likewise, miR-146a/-181b packaged in ESTA-MSV efficiently suppressed the chemokines, CCL2, CCL5, CCL8, and CXCL9, and monocyte adhesion to ECs. Complementary in vivo tests were conducted in male apolipoprotein E-deficient mice fed a Western diet and injected intravenously with the particles prepared as above biweekly for 12 weeks. Treatment with miRs packaged in ESTA-MSV but not in PEG/PEI reduced atherosclerotic plaque size. Concurrently, vascular inflammation markers, including macrophages in aortic root lesions and chemokine expression in aortic tissues were reduced while the vascular smooth muscle cells and collagen increased in plaques from ESTA-MSV/miRs-treated vs. vehicle-treated mice. Our data supported our hypothesis that ESTA-MSV microparticle-mediated delivery of miR-146a/-181b ameliorates endothelial inflammation and atherosclerosis. PMID:26956647

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

    PubMed

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

    2016-03-24

    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. PMID:26972797

  1. 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.

  2. Growth hormone suppression test

    MedlinePlus

    The growth hormone suppression test determines whether growth hormone production is being suppressed by high blood sugar. ... away. The lab measures the glucose and growth hormone (GH) levels in each sample.

  3. Dexamethasone suppression test

    MedlinePlus

    Dexamethasone suppression test measures whether adrenocorticotrophic hormone ( ACTH ) secretion by the pituitary can be suppressed. ... During this test, you will receive dexamethasone. This is a strong ... your blood is drawn so that the cortisol level in your blood ...

  4. Dexamethasone suppression test

    MedlinePlus

    DST; ACTH suppression test; Cortisol suppression test ... During this test, you will receive dexamethasone. This is a strong man-made (synthetic) glucocorticoid medication. Afterward, your blood is drawn ...

  5. Growth hormone suppression test

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/003376.htm Growth hormone suppression test To use the sharing features on this page, please enable JavaScript. The growth hormone suppression test determines whether growth hormone production is ...

  6. Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis.

    PubMed

    van der Valk, Fleur M; Schulte, Dominik M; Meiler, Svenja; Tang, Jun; Zheng, Kang He; Van den Bossche, Jan; Seijkens, Tom; Laudes, Matthias; de Winther, Menno; Lutgens, Esther; Alaarg, Amr; Metselaar, Josbert M; Dallinga-Thie, Geesje M; Mulder, Willem J M; Stroes, Erik S G; Hamers, Anouk A J

    2016-08-01

    Atherosclerosis is a lipid-driven inflammatory disease, for which nanomedicinal interventions are under evaluation. Previously, we showed that liposomal nanoparticles loaded with prednisolone (LN-PLP) accumulated in plaque macrophages, however, induced proatherogenic effects in patients. Here, we confirmed in low-density lipoprotein receptor knockout (LDLr(-/-)) mice that LN-PLP accumulates in plaque macrophages. Next, we found that LN-PLP infusions at 10mg/kg for 2weeks enhanced monocyte recruitment to plaques. In follow up, after 6weeks of LN-PLP exposure we observed (i) increased macrophage content, (ii) more advanced plaque stages, and (iii) larger necrotic core sizes. Finally, in vitro studies showed that macrophages become lipotoxic after LN-PLP exposure, exemplified by enhanced lipid loading, ER stress and apoptosis. These findings indicate that liposomal prednisolone may paradoxically accelerate atherosclerosis by promoting macrophage lipotoxicity. Hence, future (nanomedicinal) drug development studies are challenged by the multifactorial nature of atherosclerotic inflammation. PMID:27015770

  7. The Impact of Organokines on Insulin Resistance, Inflammation, and Atherosclerosis.

    PubMed

    Choi, Kyung Mook

    2016-03-01

    Immoderate energy intake, a sedentary lifestyle, and aging have contributed to the increased prevalence of obesity, sarcopenia, metabolic syndrome, type 2 diabetes, and cardiovascular disease. There is an urgent need for the development of novel pharmacological interventions that can target excessive fat accumulation and decreased muscle mass and/or strength. Adipokines, bioactive molecules derived from adipose tissue, are involved in the regulation of appetite and satiety, inflammation, energy expenditure, insulin resistance and secretion, glucose and lipid metabolism, and atherosclerosis. Recently, there is emerging evidence that skeletal muscle and the liver also function as endocrine organs that secrete myokines and hepatokines, respectively. Novel discoveries and research into these organokines (adipokines, myokines, and hepatokines) may lead to the development of promising biomarkers and therapeutics for cardiometabolic disease. In this review, I summarize recent data on these organokines and focus on the role of adipokines, myokines, and hepatokines in the regulation of insulin resistance, inflammation, and atherosclerosis. PMID:26996418

  8. Defects in Regulation of Local Immune Responses Resulting in Atherosclerosis

    PubMed Central

    Ferenčík, Miroslav; Štvrtinová, Viera; Hulín, Ivan

    2005-01-01

    Atherosclerosis is nowadays generally accepted as an inflammatory disease but the mechanism of its origin and development have not yet been fully clarified. The present review focuses on the role of the local immune system as one of the key players in the pathogenesis of the complex process. Its part represented by vascular-associated lymphoid tissue (VALT) within the arterial wall participates directly in the vascular wall's homeostatis. Its inordinate activation during ontogenic development of an individual, this formerly defensive and physiologic mechanism transform into a pathological process resulting in an impairing inflammation. Hsp60, CRP and oxidized or otherwise modified LDL are serious candidates for triggering these pathological changes. The principal role is played by anti-Hsp60 antibodies and by shear stress originating on the surface of endothelium due to blood flow. The experimental and clinical data supporting this immunological hypothesis of atherosclerosis are discussed. PMID:16295529

  9. The Impact of Organokines on Insulin Resistance, Inflammation, and Atherosclerosis

    PubMed Central

    2016-01-01

    Immoderate energy intake, a sedentary lifestyle, and aging have contributed to the increased prevalence of obesity, sarcopenia, metabolic syndrome, type 2 diabetes, and cardiovascular disease. There is an urgent need for the development of novel pharmacological interventions that can target excessive fat accumulation and decreased muscle mass and/or strength. Adipokines, bioactive molecules derived from adipose tissue, are involved in the regulation of appetite and satiety, inflammation, energy expenditure, insulin resistance and secretion, glucose and lipid metabolism, and atherosclerosis. Recently, there is emerging evidence that skeletal muscle and the liver also function as endocrine organs that secrete myokines and hepatokines, respectively. Novel discoveries and research into these organokines (adipokines, myokines, and hepatokines) may lead to the development of promising biomarkers and therapeutics for cardiometabolic disease. In this review, I summarize recent data on these organokines and focus on the role of adipokines, myokines, and hepatokines in the regulation of insulin resistance, inflammation, and atherosclerosis. PMID:26996418

  10. Intravascular multispectral optoacoustic tomography of atherosclerosis: prospects and challenges

    PubMed Central

    Rosenthal, Amir; Jaffer, Farouc A; Ntziachristos, Vasilis

    2012-01-01

    The progression of atherosclerosis involves complex changes in the structure, composition and biology of the artery wall. Currently, only anatomical plaque burden is routinely characterized in living patients, whereas compositional and biological changes are mostly inaccessible. However, anatomical imaging alone has proven to be insufficient for accurate diagnostics of the disease. Multispectral optoacoustic tomography offers complementary data to anatomical methods and is capable of imaging both tissue composition and, via the use of molecular markers, the biological activity therein. In this paper we review recent progress in multispectral optoacoustic tomography imaging of atherosclerosis with specific emphasis on intravascular applications. The potential capabilities of multispectral optoacoustic tomography are compared with those of established intravascular imaging techniques and current challenges on the road towards a clinically viable imaging modality are discussed. PMID:23144663

  11. Immune Effector Mechanisms Implicated in Atherosclerosis: From Mice to Humans

    PubMed Central

    Libby, Peter; Lichtman, Andrew H.; Hansson, Göran K.

    2013-01-01

    According to the traditional view, atherosclerosis results from a passive buildup of cholesterol in the artery wall. Yet, burgeoning evidence implicates inflammation and immune effector mechanisms in the pathogenesis of this disease. Both innate and adaptive immunity operate during atherogenesis and link many traditional risk factors to altered arterial functions. Inflammatory pathways have become targets in the quest for novel preventive and therapeutic strategies against cardiovascular disease, a growing contributor to morbidity and mortality worldwide. Here we review current experimental and clinical knowledge of the pathogenesis of atherosclerosis through an immunological lens and how host defense mechanisms essential for survival of the species actually contribute to this chronic disease but also present new opportunities for its mitigation. PMID:23809160

  12. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis.

    PubMed

    Kojima, Yoko; Volkmer, Jens-Peter; McKenna, Kelly; Civelek, Mete; Lusis, Aldons Jake; Miller, Clint L; Direnzo, Daniel; Nanda, Vivek; Ye, Jianqin; Connolly, Andrew J; Schadt, Eric E; Quertermous, Thomas; Betancur, Paola; Maegdefessel, Lars; Matic, Ljubica Perisic; Hedin, Ulf; Weissman, Irving L; Leeper, Nicholas J

    2016-08-01

    Atherosclerosis is the disease process that underlies heart attack and stroke. Advanced lesions at risk of rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris. Why these cells are not cleared remains unknown. Here we show that atherogenesis is associated with upregulation of CD47, a key anti-phagocytic molecule that is known to render malignant cells resistant to programmed cell removal, or 'efferocytosis'. We find that administration of CD47-blocking antibodies reverses this defect in efferocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis in multiple mouse models. Mechanistic studies implicate the pro-atherosclerotic factor TNF-α as a fundamental driver of impaired programmed cell removal, explaining why this process is compromised in vascular disease. Similar to recent observations in cancer, impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target. PMID:27437576

  13. Lysophospholipids and their G protein-coupled receptors in atherosclerosis.

    PubMed

    Li, Ya-Feng; Li, Rong-Shan; Samuel, Sonia B; Cueto, Ramon; Li, Xin-Yuan; Wang, Hong; Yang, Xiao-Feng

    2016-01-01

    Lysophospholipids (LPLs) are bioactive lipid-derived signaling molecules generated by the enzymatic and chemical processes of regiospecific phospholipases on substrates such as membrane phospholipids (PLs) and sphingolipids (SLs). They play a major role as extracellular mediators by activating G-protein coupled receptors (GPCRs) and stimulating diverse cellular responses from their signaling pathways. LPLs are involved in various pathologies of the vasculature system including coronary heart disease and hypertension. Many studies suggest the importance of LPLs in their association with the development of atherosclerosis, a chronic and severe vascular disease. This paper focuses on the pathophysiological effects of different lysophospholipids on atherosclerosis, which may promote the pathogenesis of myocardial infarction and strokes. Their atherogenic biological activities take place in vascular endothelial cells, vascular smooth muscle cells, fibroblasts, monocytes and macrophages, dendritic cells, T-lymphocytes, platelets, etc. PMID:26709762

  14. Circadian Influence on Metabolism and Inflammation in Atherosclerosis.

    PubMed

    McAlpine, Cameron S; Swirski, Filip K

    2016-06-24

    Many aspects of human health and disease display daily rhythmicity. The brain's suprachiasmic nucleus, which interprets recurring external stimuli, and autonomous molecular networks in peripheral cells together, set our biological circadian clock. Disrupted or misaligned circadian rhythms promote multiple pathologies including chronic inflammatory and metabolic diseases such as atherosclerosis. Here, we discuss studies suggesting that circadian fluctuations in the vessel wall and in the circulation contribute to atherogenesis. Data from humans and mice indicate that an impaired molecular clock, disturbed sleep, and shifting light-dark patterns influence leukocyte and lipid supply in the circulation and alter cellular behavior in atherosclerotic lesions. We propose that a better understanding of both local and systemic circadian rhythms in atherosclerosis will enhance clinical management, treatment, and public health policy. PMID:27340272

  15. Extracellular vesicles as new pharmacological targets to treat atherosclerosis.

    PubMed

    Yin, Min; Loyer, Xavier; Boulanger, Chantal M

    2015-09-15

    Extracellular vesicles released by most cell types, include apoptotic bodies (ABs), microvesicles (MVs) and exosomes. They play a crucial role in physiology and pathology, contributing to "cell-to-cell" communication by modifying the phenotype and the function of target cells. Thus, extracellular vesicles participate in the key processes of atherosclerosis from endothelial dysfunction, vascular wall inflammation to vascular remodeling. The purpose of this review is to summarize recent findings on extracellular vesicle formation, structure, release and clearance. We focus on the deleterious and beneficial effects of extracellular vesicles in the development of atherosclerosis. The potential role of extracellular vesicles as biomarkers and pharmacological targets, their innate therapeutic capacity, or their use for novel drug delivery devices in atherosclerotic cardiovascular diseases will also be discussed. PMID:26142082

  16. Innate immunity and monocyte-macrophage activation in atherosclerosis

    PubMed Central

    2011-01-01

    Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review. PMID:21526997

  17. Angiotensin-(1-7): new perspectives in atherosclerosis treatment

    PubMed Central

    Zhang, Feng; Liu, Jun; Li, Su-Fang; Song, Jun-Xian; Ren, Jing-Yi; Chen, Hong

    2015-01-01

    Angiotensin (Ang)-(1-7) is recognized as a new bioactive peptide in renin-angiotensin system (RAS). Ang-(1-7) is a counter-regulatory mediator of Ang-II which appears to be protective against cardiovascular disease. Recent studies have found that Ang-(1-7) played an important role in reducing smooth muscle cell proliferation and migration, improving endothelial function and regulating lipid metabolism, leading to inhibition of atherosclerotic lesions and increase of plaque stability. Although clinical application of Ang-(1-7) is restricted due to its pharmacokinetic properties, identification of stabilized compounds, including more stable analogues and specific delivery compounds, has enabled clinical application of Ang-(1-7). In this review, we discussed recent findings concerning the biological role of Ang-(1-7) and related mechanism during atherosclerosis development. In addition, we highlighted the perspective to develop therapeutic strategies using Ang-(1-7) to treat atherosclerosis. PMID:26788046

  18. Imaging of coronary atherosclerosis and identification of the vulnerable plaque

    PubMed Central

    de Feyter, P.J.; Serruys, P. W.; Nieman, K.; Mollet, N.; Cademartiri, F.; van Geuns, R. J.; Slager, C.; van der Steen, A.F.W.; Krams, R.; Schaar, J.A.; Wielopolski, P.; Pattynama, P.M.T.; Arampatzis, A.; van der Lugt, A.; Regar, E.; Ligthart, J.; Smits, P.

    2003-01-01

    Identification of the vulnerable plaque responsible for the occurrence of acute coronary syndromes and acute coronary death is a prerequisite for the stabilisation of this vulnerable plaque. Comprehensive coronary atherosclerosis imaging in clinical practice should involve visualisation of the entire coronary artery tree and characterisation of the plaque, including the three-dimensional morphology of the plaque, encroachment of the plaque on the vessel lumen, the major tissue components of the plaque, remodelling of the vessel and presence of inflammation. Obviously, no single diagnostic modality is available that provides such comprehensive imaging and unfortunately no diagnostic tool is available that unequivocally identifies the vulnerable plaque. The objective of this article is to discuss experience with currently available diagnostic modalities for coronary atherosclerosis imaging. In addition, a number of evolving techniques will be briefly discussed. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6Figure 7 PMID:25696244

  19. Inflammation, oxidative stress and renin angiotensin system in atherosclerosis

    PubMed Central

    Husain, Kazim; Hernandez, Wilfredo; Ansari, Rais A; Ferder, Leon

    2015-01-01

    Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin II (Ang II) and a decrease in nitric oxide. The renin-angiotensin system (RAS), and its primary mediator Ang II, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors (angiotensin-converting enzyme inhibitors)], Ang II receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in ApoE-deficient atherosclerotic mice. PMID:26322175

  20. Adropin is associated with hyperhomocysteine and coronary atherosclerosis

    PubMed Central

    ZHAO, LIANG-PING; YOU, TAO; CHAN, SIEW-PANG; CHEN, JIAN-CHANG; XU, WEI-TING

    2016-01-01

    Homocysteine has been recognized as a risk factor for atherosclerosis and cardiovascular diseases. Adropin is a newly-identified energy homeostasis protein with a potential protective effect against coronary artery disease (CAD). This study attempted to measure the correlation between serum homocysteine and adropin levels in patients with CAD, and to ascertain how the two hormones could affect the severity of coronary atherosclerosis. A cohort of CAD patients who had undergone coronary angiography was prospectively recruited. The serum homocysteine and adropin levels of the patients were measured and the severity of coronary atherosclerosis was quantified with the SYNTAX score. The data were analyzed with a generalized structural equation model. In total, 170 consecutive patients were recruited with a mean serum homocysteine level of 15.9±8.3 µmol/l, and 76 (44.7%) patients were identified as hyperhomocysteinemic with a serum homocysteine level >15 µmol/l. Serum homocysteine level was found to be significantly negatively correlated with serum adropin level (r=−0.169, P=0.028). Patients with hyperhomocysteinemia had lower serum adropin levels and higher SYNTAX scores than patients without hyperhomocysteinemia. Further analysis with a generalized structural equation model showed that adropin was significantly associated with hyperhomocysteinemia (adjusted odds ratio: 0.95, 95% confidence interval: 0.93 to 0.98; P=0.002), which in turn was significantly associated with the SYNTAX score (coefficient: 4.71, 95% confidence interval: 1.39 to 8.03; P=0.005). In conclusion, the serum homocysteine level was inversely correlated with the serum adropin level in patients with CAD. A low serum adropin level was associated with hyperhomocysteinemia and more severe coronary atherosclerosis, as reflected by a higher SYNTAX score. PMID:26998038

  1. 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

  2. Bisphenol A exposure enhances atherosclerosis in WHHL rabbits.

    PubMed

    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

  3. 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

  4. Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis.

    PubMed

    Hoeke, Geerte; Kooijman, Sander; Boon, Mariëtte R; Rensen, Patrick C N; Berbée, Jimmy F P

    2016-01-01

    Atherosclerosis, for which hyperlipidemia is a major risk factor, is the leading cause of morbidity and mortality in Western society, and new therapeutic strategies are highly warranted. Brown adipose tissue (BAT) is metabolically active in human adults. Although positron emission tomography-computed tomography using a glucose tracer is the golden standard to visualize and quantify the volume and activity of BAT, it has become clear that activated BAT combusts fatty acids rather than glucose. Here, we review the role of brown and beige adipocytes in lipoprotein metabolism and atherosclerosis, with evidence derived from both animal and human studies. On the basis of mainly data from animal models, we propose a model in which activated brown adipocytes use their intracellular triglyceride stores to generate fatty acids for combustion. BAT rapidly replenishes these stores by internalizing primarily lipoprotein triglyceride-derived fatty acids, generated by lipoprotein lipase-mediated hydrolysis of triglycerides, rather than by holoparticle uptake. As a consequence, BAT activation leads to the generation of lipoprotein remnants that are subsequently cleared via the liver provided that an intact apoE-low-density lipoprotein receptor pathway is present. Through these mechanisms, BAT activation reduces plasma triglyceride and cholesterol levels and attenuates diet-induced atherosclerosis development. Initial studies suggest that BAT activation in humans may also reduce triglyceride and cholesterol levels, but potential antiatherogenic effects should be assessed in future studies. PMID:26837747

  5. Iron overload diminishes atherosclerosis in apoE-deficient mice

    PubMed Central

    Kirk, Elizabeth A.; Heinecke, Jay W.; LeBoeuf, Renée C.

    2001-01-01

    It has been proposed that elevated levels of tissue iron increase the risk for atherosclerosis, perhaps by favoring the formation of pro-atherogenic oxidized LDL. Working with apoE-deficient (apoE–/–) mice, which do not require a high-fat diet to develop atherosclerosis, we compared the effects of standard diet (0.02% iron) or a 2% carbonyl iron diet. After 24 weeks, mice fed the 2% carbonyl iron diet had twice as much iron in their plasma, a ninefold increase in bleomycin-detectable free iron in their plasma, and ten times as much iron in their livers as control mice. Dietary iron overload caused a modest (30%) rise in plasma triglyceride and cholesterol. Nevertheless, this regimen did not exacerbate, but rather reduced the severity of atherosclerosis by 50%, and it failed to elevate hepatic levels of heme oxygenase mRNA, which is induced by many different oxidative insults in vitro. Moreover, hepatic levels of protein-bound dityrosine and ortho-tyrosine, two markers of metal-catalyzed oxidative damage in vitro, failed to rise in iron-overloaded animals. Our observations suggest that elevated serum and tissue levels of iron are not atherogenic in apoE–/– mice. Moreover, they call into question the hypothesis that elevated levels of tissue iron promote LDL oxidation and oxidative stress in vivo. PMID:11413162

  6. Atomic Force Microscopy Study of Atherosclerosis Progression in Arterial Walls.

    PubMed

    Timashev, Peter S; Kotova, Svetlana L; Belkova, Galina V; Gubar'kova, Ekaterina V; Timofeeva, Lidia B; Gladkova, Natalia D; Solovieva, Anna B

    2016-04-01

    Cardiovascular disease remains the leading cause of mortality worldwide. Here we suggest a novel approach for tracking atherosclerosis progression based on the use of atomic force microscopy (AFM). Using AFM, we studied cross-sections of coronary arteries with the following types of lesions: Type II-thickened intima; Type III-thickened intima with a lipid streak; Type IV-fibrotic layer over a lipid core; Type Va-unstable fibrotic layer over a lipid core; Type Vc-very thick fibrotic layer. AFM imaging revealed that the fibrotic layer of an atherosclerotic plaque is represented by a basket-weave network of collagen fibers and a subscale network of fibrils that become looser with atherosclerosis progression. In an unstable plaque (Type Va), packing of the collagen fibers and fibrils becomes even less uniform than that at the previous stages, while a stable fibrotic plaque (Vc) has significantly tighter packing. Such alterations of the collagen network morphology apparently, led to deterioration of the Type Va plaque mechanical properties, that, in turn, resulted in its instability and propensity to rupture. Thus, AFM may serve as a useful tool for tracking atherosclerosis progression in the arterial wall tissue. PMID:26843417

  7. Plasma IL-5 concentration and subclinical carotid atherosclerosis

    PubMed Central

    Silveira, Angela; McLeod, Olga; Strawbridge, Rona J.; Gertow, Karl; Sennblad, Bengt; Baldassarre, Damiano; Veglia, Fabrizio; Deleskog, Anna; Persson, Jonas; Leander, Karin; Gigante, Bruna; Kauhanen, Jussi; Rauramaa, Rainer; Smit, Andries J.; Mannarino, Elmo; Giral, Philippe; Gustafsson, Sven; Söderberg, Stefan; Öhrvik, John; Humphries, Steve E.; Tremoli, Elena; de Faire, Ulf; Hamsten, Anders

    2015-01-01

    Objective Genetic variants robustly associated with coronary artery disease were reported in the vicinity of the interleukin (IL)-5 locus, and animal studies suggested a protective role for IL-5 in atherosclerosis. Therefore, we set this work to explore IL-5 as a plasma biomarker for early subclinical atherosclerosis, as determined by measures of baseline severity and change over time of carotid intima-media thickness (cIMT). Methods We used biobank and databases of IMPROVE, a large European prospective cohort study of high-risk individuals (n = 3534) free of clinically overt cardiovascular disease at enrollment, in whom composite and segment-specific measures of cIMT were recorded at baseline and after 15 and 30 months. IL-5 was measured with an immunoassay in plasma samples taken at baseline. Results IL-5 levels were lower in women than in men, lower in the South than in North of Europe, and showed positive correlations with most established risk factors. IL-5 showed significant inverse relationships with cIMT change over time in the common carotid segment in women, but no significant relationships to baseline cIMT in either men or women. Conclusions Our results suggest that IL-5 may be part of protective mechanisms operating in early atherosclerosis, at least in women. However, the relationships are weak and whereas IL-5 has been proposed as a potential molecular target to treat allergies, it is difficult to envisage such a scenario in coronary artery disease. PMID:25587992

  8. TGF-beta signaling in atherosclerosis and restenosis.

    PubMed

    McCaffrey, Timothy A

    2009-01-01

    Current theories suggest that atherosclerotic and restenotic lesions result from imbalances between systems that are proinflammatory/fibroproliferative versus the endogenous inhibitory systems that normally limit inflammation and vascular wound repair. Abnormalities in one of the major regulatory pathways, the transforming growth factor-beta (TGF-beta) system, has been characterized in both animal models and in human lesions and lesion-derived cells. TGF-beta signaling is capable of regulating many of the key aspects of atherosclerosis and restenosis: inflammation, chemotaxis, fibrosis, proliferation, and apoptosis. There are significant decreases in TGF-beta activity in patients with atherosclerosis, and equally important changes in the way cells respond to TGF-beta during atherogenesis. Evidence from multiple sources indicates that experimental modulation of TGF-beta activity, or TGF-beta responses, changes the course of atherosclerosis and intimal hyperplasia. Cells derived from human lesions produce adequate TGF-beta levels, but are resistant to the antiproliferative and apoptotic effects of TGF-beta. An evolving theory describes TGF-beta as a major orchestrator of the vascular repair process, with observable defects in its production, activation, and cellular responses during the atherosclerotic and restenotic processes. PMID:19482699

  9. SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

    PubMed Central

    Xu, Suowen; Yin, Meimei; Koroleva, Marina; Mastrangelo, Michael A.; Zhang, Wenbo; Bai, Peter; Little, Peter J.; Jin, Zheng Gen

    2016-01-01

    SIRT6 is an important member of sirtuin family that represses inflammation, aging and DNA damage, three of which are causing factors for endothelial dysfunction. SIRT6 expression is decreased in atherosclerotic lesions from ApoE−/− mice and human patients. However, the role of SIRT6 in regulating vascular endothelial function and atherosclerosis is not well understood. Here we show that SIRT6 protects against endothelial dysfunction and atherosclerosis. Global and endothelium-specific SIRT6 knockout mice exhibited impaired endothelium-dependent vasorelaxation. Moreover, SIRT6+/− haploinsufficient mice fed a high-fat diet (HFD) also displayed impaired endothelium-dependent vasorelaxation. Importantly, SIRT6+/−;ApoE−/− mice after HFD feeding exhibited exacerbated atherosclerotic lesion development, concurrent with increased expression of the proinflammatory cytokine VCAM-1. Loss- and gain-of-SIRT6 function studies in cultured human endothelial cells (ECs) showed that SIRT6 attenuated monocyte adhesion to ECs. RNA-sequencing profiling revealed that SIRT6 overexpression decreased the expression of multiple atherosclerosis-related genes, including proatherogenic gene TNFSF4 (tumor necrosis factor superfamily member 4). Chromatin immunoprecipitation assays showed that SIRT6 decreased TNFSF4 gene expression by binding to and deacetylating H3K9 at TNFSF4 gene promoter. Collectively, these findings demonstrate that SIRT6 play a pivotal role in maintaining endothelial function and increased SIRT6 activity could be a new therapeutic strategy to combat atherosclerotic disease. PMID:27249230

  10. Arterial remodeling of basilar atherosclerosis in isolated pontine infarction.

    PubMed

    Feng, Chao; Hua, Ting; Xu, Yu; Liu, Xue-Yuan; Huang, Jing

    2015-04-01

    Isolated pontine infarctions are usually classified as paramedian pontine infarction (PPI) and lacunar pontine infarction (LPI). Although they have different shapes and locations, some recent studies proved that they might both be associated with basilar artery atherosclerosis in pathogenesis. This study aimed to explore the difference of basilar artery remodeling between two subtypes of pontine infarctions. Patients with PPI or LPI were scanned by High-resolution MRI (HR-MRI). The MR images of patients with basilar artery atherosclerosis were further analyzed to measure the vessel, lumen and wall areas at different segments of basilar arteries. Stenosis rate and remodeling index were calculated according to which arterial remodeling was divided into positive, intermediate and negative remodeling. Vascular risk factors and remodeling-related features were compared between PPI and LPI, and also between patients with and without positive remodeling. 34 patients with PPI and 21 patients with LPI had basilar artery atherosclerosis identified by HR-MRI. Positive remodeling was dominant in LPI group while in PPI group, three subtypes of remodeling were equal. Patients with positive remodeling had higher levels of low-density lipoprotein and homocysteine. Positive remodeling of basilar artery might reflect the low stability of basilar atherosclerotic plaques, which was more closely associated with LPI than PPI. PMID:25367406

  11. IKKβ links vascular inflammation to obesity and atherosclerosis

    PubMed Central

    Sui, Yipeng; Park, Se-Hyung; Xu, Jinxian; Monette, Sébastien; Helsley, Robert N.; Han, Seong-Su

    2014-01-01

    IκB kinase β (IKKβ), a central coordinator of inflammatory responses through activation of NF-κB, has been implicated in vascular pathologies, but its role in atherogenesis remains elusive. Here, we demonstrate that IKKβ functions in smooth muscle cells (SMCs) to regulate vascular inflammatory responses and atherosclerosis development. IKKβ deficiency in SMCs driven by a SM22Cre-IKKβ-flox system rendered low density lipoprotein receptor-null mice resistant to vascular inflammation and atherosclerosis induced by high-fat feeding. Unexpectedly, IKKβ-deficient mice were also resistant to diet-induced obesity and metabolic disorders. Cell lineage analysis revealed that SM22Cre is active in primary adipose stromal vascular cells and deficiency of IKKβ diminished the ability of these cells to differentiate, leading to accumulation of adipocyte precursor cells in adipose tissue. Mechanistically, reduction of IKKβ expression or pharmacological inhibition of IKKβ inhibited proteasome-mediated β-catenin ubiquitination and degradation in murine preadipocytes, resulting in elevated β-catenin levels and impaired adipocyte differentiation. Further, chronic treatment of mice with a potent IKKβ inhibitor decreased adipogenesis and ameliorated diet-induced obesity. Our findings demonstrate a pivotal role of IKKβ in linking vascular inflammation to atherosclerosis and adipose tissue development, and provide evidence for using appropriate IKKβ inhibitors in the treatment of obesity and metabolic disorders. PMID:24799533

  12. Curcumin analog L3 alleviates diabetic atherosclerosis by multiple effects.

    PubMed

    Zheng, Bin; Yang, Liu; Wen, Caixia; Huang, Xiuwang; Xu, Chenxia; Lee, Kuan-Han; Xu, Jianhua

    2016-03-15

    L3, an analog of curcumin, is a compound isolated from a traditional Chinese medicine Turmeric. In this paper, we aims to explore the efficacy of L3 on diabetic atherosclerosis and the related mechanism. The effect of L3 was studied on glucose and lipid metabolism, antioxidant status, atherosclerosis-related indexes and pathological changes of main organs in the mice model of diabetes induced by streptozotocin and high-fat diet. The results showed that L3 treatment could meliorate dyslipidemia and hyperglycemia, reduce oxidative stress, enhance the activity of antioxidases, increase the nitric oxide level in plasma and aortic arch, decrease the production of reactive oxygen species in pancreas and lectin-like oxidized low-density lipoprotein receptor-1 expression in aortic arch, and meliorate the fatty and atherosclerotic degeneration in aortic arch, thereby preventing the development of diabetes and its complications. These results suggested that L3 can alleviate the diabetic atherosclerosis by multiple effects. This study provided scientific basis for the further research and clinical application of L3. PMID:26852952

  13. Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis

    PubMed Central

    Moss, Mary E.; Jaffe, Iris Z.

    2015-01-01

    Atherosclerosis is a chronic inflammatory disease of the vasculature that causes significant morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease. Landmark clinical trials revealed that mineralocorticoid receptor (MR) antagonists improve outcomes in cardiovascular patients. Conversely, enhanced MR activation by the hormone aldosterone is associated with increased risk of MI, stroke, and cardiovascular death. This review summarizes recent advances in our understanding of the role of aldosterone and the MR in the pathogenesis of vascular inflammation and atherosclerosis as it proceeds from risk factor-induced endothelial dysfunction and inflammation to plaque formation, progression, and ultimately rupture with thrombosis, the cause of acute ischemia. The role of the MR in converting cardiac risk factors into endothelial dysfunction, in enhancing leukocyte adhesion and infiltration into the vasculature, in promoting systemic inflammation and vascular oxidative stress, and in plaque destabilization and thrombosis are discussed. A greater understanding of the mechanisms by which the MR promotes atherosclerosis has substantial potential to identify novel treatment targets to improve cardiovascular health and decrease mortality. PMID:26441842

  14. SIRT6 protects against endothelial dysfunction and atherosclerosis in mice.

    PubMed

    Xu, Suowen; Yin, Meimei; Koroleva, Marina; Mastrangelo, Michael A; Zhang, Wenbo; Bai, Peter; Little, Peter J; Jin, Zheng Gen

    2016-05-01

    SIRT6 is an important member of sirtuin family that represses inflammation, aging and DNA damage, three of which are causing factors for endothelial dysfunction. SIRT6 expression is decreased in atherosclerotic lesions from ApoE(-/-) mice and human patients. However, the role of SIRT6 in regulating vascular endothelial function and atherosclerosis is not well understood. Here we show that SIRT6 protects against endothelial dysfunction and atherosclerosis. Global and endothelium-specific SIRT6 knockout mice exhibited impaired endothelium-dependent vasorelaxation. Moreover, SIRT6(+/-) haploinsufficient mice fed a high-fat diet (HFD) also displayed impaired endothelium-dependent vasorelaxation. Importantly, SIRT6(+/-); ApoE(-/-) mice after HFD feeding exhibited exacerbated atherosclerotic lesion development, concurrent with increased expression of the proinflammatory cytokine VCAM-1. Loss- and gain-of-SIRT6 function studies in cultured human endothelial cells (ECs) showed that SIRT6 attenuated monocyte adhesion to ECs. RNA-sequencing profiling revealed that SIRT6 overexpression decreased the expression of multiple atherosclerosis-related genes, including proatherogenic gene TNFSF4 (tumor necrosis factor superfamily member 4). Chromatin immunoprecipitation assays showed that SIRT6 decreased TNFSF4 gene expression by binding to and deacetylating H3K9 at TNFSF4 gene promoter. Collectively, these findings demonstrate that SIRT6 play a pivotal role in maintaining endothelial function and increased SIRT6 activity could be a new therapeutic strategy to combat atherosclerotic disease. PMID:27249230

  15. 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

  16. Macrophages in Vascular Inflammation – From Atherosclerosis to Vasculitis

    PubMed Central

    Shirai, Tsuyoshi; Hilhorst, Marc; Harrison, David G.; Goronzy, Jörg J.; Weyand, Cornelia M.

    2015-01-01

    The spectrum of vascular inflammatory disease ranges from atherosclerosis and hypertension, widespread conditions affecting large proportions of the population, to the vasculitides, rare syndromes leading to fast and irreversible organ failure. Atherosclerosis progresses over decades, inevitably proceeding through multiple phases of disease and causes its major complications when the vessel wall lesion ruptures, giving rise to lumen-occlusive atherothrombosis. Vasculitides of medium and large arteries progress rapidly, causing tissue ischemia through lumen-occlusive intimal hyperplasia. In both disease entities, macrophages play a decisive role in pathogenesis, but function in the context of other immune cells that direct their differentiation and their functional commitments. In atherosclerosis, macrophages are involved in the removal of lipids and tissue debris and make a critical contribution to tissue damage and wall remodeling. In several of the vasculitides, macrophages contribute to granuloma formation, a microstructural platform optimizing macrophage-T cell interactions, antigen containment and inflammatory amplification. By virtue of their versatility and plasticity, macrophages are able to promote a series of pathogenic functions, ranging from the release of cytokines and enzymes, the production of reactive oxygen species, presentation of antigen and secretion of tissue remodeling factors. However, as short-lived cells that lack memory, macrophages are also amendable to reprogramming, making them promising targets for anti-inflammatory interventions. PMID:25811915

  17. Biomarkers of Subclinical Atherosclerosis in Patients with Autoimmune Disorders

    PubMed Central

    Profumo, Elisabetta; Di Franco, Manuela; Buttari, Brigitta; Masella, Roberta; Filesi, Carmelina; Tosti, Maria Elena; Scrivo, Rossana; Scarno, Antongiulio; Spadaro, Antonio; Saso, Luciano; Riganò, Rachele

    2012-01-01

    Atherosclerosis is accelerated in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We investigated a possible association of oxidized low-density lipoproteins (ox-LDLs), nitric oxide (NO), 3-nitrotyrosine, vitamin A, vitamin E, and β-carotene serum levels with subclinical atherosclerosis in RA and PsA. By the use of ELISA, we observed higher ox-LDL levels in patients with intima-media thickness (IMT) > 1 than in patients with IMT ≤ 1 and a negative correlation between NO levels and IMT values. By the use of high-performance liquid chromatography, we determined higher levels of vitamin A in patients with PsA and IMT ≤ 1 than in controls and lower levels of β-carotene in patients with RA and PsA than in controls. β-carotene concentrations were negatively correlated to the duration of disease in RA. Our study confirms that ox-LDLs and NO may be markers of accelerated atherosclerosis in RA and PsA whereas vitamins seem to be associated only to the presence of the autoimmune disorders. PMID:22529523

  18. Biomarkers of subclinical atherosclerosis in patients with autoimmune disorders.

    PubMed

    Profumo, Elisabetta; Di Franco, Manuela; Buttari, Brigitta; Masella, Roberta; Filesi, Carmelina; Tosti, Maria Elena; Scrivo, Rossana; Scarno, Antongiulio; Spadaro, Antonio; Saso, Luciano; Riganò, Rachele

    2012-01-01

    Atherosclerosis is accelerated in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We investigated a possible association of oxidized low-density lipoproteins (ox-LDLs), nitric oxide (NO), 3-nitrotyrosine, vitamin A, vitamin E, and β-carotene serum levels with subclinical atherosclerosis in RA and PsA. By the use of ELISA, we observed higher ox-LDL levels in patients with intima-media thickness (IMT) > 1 than in patients with IMT ≤ 1 and a negative correlation between NO levels and IMT values. By the use of high-performance liquid chromatography, we determined higher levels of vitamin A in patients with PsA and IMT ≤ 1 than in controls and lower levels of β-carotene in patients with RA and PsA than in controls. β-carotene concentrations were negatively correlated to the duration of disease in RA. Our study confirms that ox-LDLs and NO may be markers of accelerated atherosclerosis in RA and PsA whereas vitamins seem to be associated only to the presence of the autoimmune disorders. PMID:22529523

  19. Nitric oxide in atherosclerosis: vascular protector or villain?

    PubMed

    Dusting, G J; Fennessy, P; Yin, Z L; Gurevich, V

    1998-11-01

    1. Nitric oxide (NO) has important roles in physiological vasodilatation, cytotoxicity and vascular disease. Nitric oxide and prostacyclin (PGI2), both released from the endothelium, act synergistically to inhibit platelet aggregation and adhesion. These autacoids also inhibit the adhesion and migration of leucocytes and, in some arteries, they synergize in terms of vasodilation. 2. The development of atherosclerosis and hyperlipaemia per se is accompanied by impairment of endothelium-dependent vasodilation. 3. Atherosclerosis is associated with marked changes in the activity of isoforms of NO synthase (NOS) in the artery wall, including increased expression of the NOS2 (inducible) isoform in complex human lesions as well as in the neointima of experimental animal models. 4. Failure of NO release from the endothelium with normal physiological stimuli, which has been attributed to a defect in the operation of the endothelial NOS (NOS3), provides conditions propitious for leucocyte adhesion, vasospasm, thrombosis and, in addition, may promote increased proliferation of intimal cells. 5. Nitric oxide and superoxide anions generated by inflammatory cells in atherosclerosis react to form cytodestructive peroxynitrite radicals, potentially causing injury to the endothelium and myocytes, and this may be a factor in apoptosis of cells leading to plaque rupture. 6. We have been able to reverse these NO defects with therapeutic agents, including angiotensin-converting enzyme inhibitors, antagonists of platelet-activating factor and NO donor compounds, all offering promise in protecting against some manifestations of vascular disease. PMID:9809190

  20. 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.

  1. Adaptive Response of T and B Cells in Atherosclerosis.

    PubMed

    Ketelhuth, Daniel F J; Hansson, Göran K

    2016-02-19

    Atherosclerosis is a chronic inflammatory disease that is initiated by the retention and accumulation of cholesterol-containing lipoproteins, particularly low-density lipoprotein, in the artery wall. In the arterial intima, lipoprotein components that are generated through oxidative, lipolytic, and proteolytic activities lead to the formation of several danger-associated molecular patterns, which can activate innate immune cells as well as vascular cells. Moreover, self- and non-self-antigens, such as apolipoprotein B-100 and heat shock proteins, can contribute to vascular inflammation by triggering the response of T and B cells locally. This process can influence the initiation, progression, and stability of plaques. Substantial clinical and experimental data support that the modulation of adaptive immune system may be used for treating and preventing atherosclerosis. This may lead to the development of more selective and less harmful interventions, while keeping host defense mechanisms against infections and tumors intact. Approaches such as vaccination might become a realistic option for cardiovascular disease, especially if they can elicit regulatory T and B cells and the secretion of atheroprotective antibodies. Nevertheless, difficulties in translating certain experimental data into new clinical therapies remain a challenge. In this review, we discuss important studies on the function of T- and B-cell immunity in atherosclerosis and their manipulation to develop novel therapeutic strategies against cardiovascular disease. PMID:26892965

  2. Bastadins, brominated-tyrosine derivatives, suppress accumulation of cholesterol ester in macrophages.

    PubMed

    Eguchi, Keisuke; Kato, Hikaru; Fujiwara, Yukio; Losung, Fitje; Mangindaan, Remy E P; de Voogd, Nicole J; Takeya, Motohiro; Tsukamoto, Sachiko

    2015-11-15

    The formation of foam cells in macrophages has been suggested to play an essential role in the progression of early atherosclerotic lesions in vivo and, thus, its suppression is considered to be one of the major approaches for the treatment of atherosclerosis. We isolated eight brominated-tyrosine derivatives, bastadins, from the EtOH extract of the marine sponge Ianthella vasta as inhibitors of the formation of foam cells induced by acetylated low-density lipoproteins in human monocyte-derived macrophages. Bastadin 6 was the strongest inhibitor of foam cell formation due to its suppression of acyl-coenzyme A:cholesterol acyltransferase. PMID:26403929

  3. 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

  4. Dietary Cocoa Powder Improves Hyperlipidemia and Reduces Atherosclerosis in apoE Deficient Mice through the Inhibition of Hepatic Endoplasmic Reticulum Stress

    PubMed Central

    Guan, Hua; Lin, Yan; Bai, Liang; An, Yingfeng; Shang, Jianan; Wang, Zhao; Zhao, Sihai; Fan, Jianglin

    2016-01-01

    Cocoa powder is rich in flavonoids, which have many beneficial effects on human health, including antioxidative and anti-inflammatory effects. The aim of our study was to investigate whether the intake of cocoa powder has any influence on hyperlipidemia and atherosclerosis and examine the underlying molecular mechanisms. We fed apoE knockout mice a Western diet supplemented with either 0.2% (low group) or 2% (high group) cocoa powder for 12 weeks. The groups fed dietary cocoa powder showed a significant reduction in both plasma cholesterol levels and aortic atherosclerosis compared to the control group. Analysis of mRNA profiling of aortic atherosclerotic lesions revealed that the expression of several genes related to apoptosis, lipid metabolism, and inflammation was significantly reduced, while the antiapoptotic gene Bcl2 was significantly increased in the cocoa powder group compared to the control. RT-PCR analysis along with Western blotting revealed that a diet containing cocoa powder inhibited the expression of hepatic endoplasmic reticulum stress. These data suggest that cocoa powder intake improves hyperlipidemia and atherosclerosis, and such beneficial effects are possibly mediated through the suppression of hepatic endoplasmic reticulum stress. PMID:26980943

  5. Dietary Cocoa Powder Improves Hyperlipidemia and Reduces Atherosclerosis in apoE Deficient Mice through the Inhibition of Hepatic Endoplasmic Reticulum Stress.

    PubMed

    Guan, Hua; Lin, Yan; Bai, Liang; An, Yingfeng; Shang, Jianan; Wang, Zhao; Zhao, Sihai; Fan, Jianglin; Liu, Enqi

    2016-01-01

    Cocoa powder is rich in flavonoids, which have many beneficial effects on human health, including antioxidative and anti-inflammatory effects. The aim of our study was to investigate whether the intake of cocoa powder has any influence on hyperlipidemia and atherosclerosis and examine the underlying molecular mechanisms. We fed apoE knockout mice a Western diet supplemented with either 0.2% (low group) or 2% (high group) cocoa powder for 12 weeks. The groups fed dietary cocoa powder showed a significant reduction in both plasma cholesterol levels and aortic atherosclerosis compared to the control group. Analysis of mRNA profiling of aortic atherosclerotic lesions revealed that the expression of several genes related to apoptosis, lipid metabolism, and inflammation was significantly reduced, while the antiapoptotic gene Bcl2 was significantly increased in the cocoa powder group compared to the control. RT-PCR analysis along with Western blotting revealed that a diet containing cocoa powder inhibited the expression of hepatic endoplasmic reticulum stress. These data suggest that cocoa powder intake improves hyperlipidemia and atherosclerosis, and such beneficial effects are possibly mediated through the suppression of hepatic endoplasmic reticulum stress. PMID:26980943

  6. A Translational Model for Diet-related Atherosclerosis: Effect of Statins on Hypercholesterolemia and Atherosclerosis in a Minipig.

    PubMed

    Amuzie, Chidozie; Swart, John R; Rogers, Christopher S; Vihtelic, Thomas; Denham, Steven; Mais, Dale E

    2016-04-01

    Models of atherosclerosis are used in preclinical studies but often fail to translate to humans. A model that better reflects human atherosclerosis is necessary. We recently engineered the ExeGen™ low-density lipoprotein receptor (LDLR) miniswine, in which the LDL receptor gene is modified to drive hypercholesterolemia and atherosclerosis, and showed diet-related exacerbation of these phenotypes. Five groups of animals, either wild type (+/+) or heterozygous (+/-), were fed either a normal or high-fat diet for 6 months. One group of heterozygous pigs fed a high-fat diet was also administered atorvastatin at 3 mg/kg/day. Clinical chemistry and anatomic pathology parameters were measured biweekly and at termination. The high-fat diet resulted in increased adiposity and interspersion of adipocytes within the salivary glands. The heterozygous pigs on the high-fat diet gained more weight and had significant increases in total cholesterol, high-density lipoprotein, and LDL compared to wild-type animals or heterozygous animals fed a normal diet. Atorvastatin attenuated these parameters, indicating the statin had a beneficial effect, even in a high-fat diet scenario. Atorvastatin treatment also reduced the intensity of Oil Red O staining in pigs on high-fat diet. Atorvastatin-related amelioration of several indices of cardiovascular pathophysiology in this model underscores its utility for drug discovery. PMID:26883155

  7. Detailed analysis of association between common single nucleotide polymorphisms and subclinical atherosclerosis: The Multi-ethnic Study of Atherosclerosis.

    PubMed

    Vargas, Jose D; Manichaikul, Ani; Wang, Xin-Qun; Rich, Stephen S; Rotter, Jerome I; Post, Wendy S; Polak, Joseph F; Budoff, Matthew J; Bluemke, David A

    2016-06-01

    Previously identified single nucleotide polymorphisms (SNPs) in genome wide association studies (GWAS) of cardiovascular disease (CVD) in participants of mostly European descent were tested for association with subclinical cardiovascular disease (sCVD), coronary artery calcium score (CAC) and carotid intima media thickness (CIMT) in the Multi-Ethnic Study of Atherosclerosis (MESA). The data in this data in brief article correspond to the article Common Genetic Variants and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis [1]. This article includes the demographic information of the participants analyzed in the article as well as graphical displays and data tables of the association of the selected SNPs with CAC and of the meta-analysis across ethnicities of the association of CIMT-c (common carotid), CIMT-I (internal carotid), CAC-d (CAC as dichotomous variable with CAC>0) and CAC-c (CAC as continuous variable, the log of the raw CAC score plus one) and CVD. The data tables corresponding to the 9p21 fine mapping experiment as well as the power calculations referenced in the article are also included. PMID:26958643

  8. Detailed analysis of association between common single nucleotide polymorphisms and subclinical atherosclerosis: The Multi-ethnic Study of Atherosclerosis

    PubMed Central

    Vargas, Jose D.; Manichaikul, Ani; Wang, Xin-Qun; Rich, Stephen S.; Rotter, Jerome I.; Post, Wendy S.; Polak, Joseph F.; Budoff, Matthew J.; Bluemke, David A.

    2016-01-01

    Previously identified single nucleotide polymorphisms (SNPs) in genome wide association studies (GWAS) of cardiovascular disease (CVD) in participants of mostly European descent were tested for association with subclinical cardiovascular disease (sCVD), coronary artery calcium score (CAC) and carotid intima media thickness (CIMT) in the Multi-Ethnic Study of Atherosclerosis (MESA). The data in this data in brief article correspond to the article Common Genetic Variants and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis [1]. This article includes the demographic information of the participants analyzed in the article as well as graphical displays and data tables of the association of the selected SNPs with CAC and of the meta-analysis across ethnicities of the association of CIMT-c (common carotid), CIMT-I (internal carotid), CAC-d (CAC as dichotomous variable with CAC>0) and CAC-c (CAC as continuous variable, the log of the raw CAC score plus one) and CVD. The data tables corresponding to the 9p21 fine mapping experiment as well as the power calculations referenced in the article are also included. PMID:26958643

  9. "State-of-Art" paper of the Italian Working Group on Atherosclerosis: Preclinical assessment of early coronary atherosclerosis.

    PubMed

    Madonna, Rosalinda; Selvaggio, Stefano; Selvaggio, Giancarlo; Coronelli, Maurizio; Cocco, Nino

    2016-07-01

    Although the early diagnosis and treatment for acute myocardial infarction have improved over the past decades, the morbidity and mortality from coronary artery disease (CAD) remain significant in Europe and worldwide. It is estimated that the majority of people in the developed countries who die suddenly from CAD, have no prior manifestation of disease, and the majority of these individuals are not considered to be at high risk. Accurate identification of individuals at risk of such events before the clinical manifestations is therefore required. This "State-of-Art" paper of the Italian Working Group on Atherosclerosis aims to i. provide an overview of both the traditional and emerging non-invasive imaging techniques used to detect early atherosclerosis in the general population with moderate cardiovascular risk; ii. identify the rationale for screening asymptomatic patients with preclinical atherosclerotic lesions and the optimal algorithm that should be used to detect them; iii. discuss the future directions of atherosclerosis research, with special focus on nanotechnology, aimed at early identification and treatment of low- and intermediate-risk patients. PMID:27093681

  10. Pterostilbene, a novel natural plant conduct, inhibits high fat-induced atherosclerosis inflammation via NF-κB signaling pathway in Toll-like receptor 5 (TLR5) deficient mice.

    PubMed

    Zhang, Yuan; Zhang, Yi

    2016-07-01

    Atherosclerosis is a specific form of an artery wall thickens, a syndrome affecting arterial blood vessels due to a chronic inflammatory response in the walls of arteries, which is promoted by fat accumulation. Toll-like receptors (TLRs) play prominent roles in inflammatory responses. And TLR5 is overexpressed in several diseases. Here in our study, we investigated the effect of TLR5 in high fat-induced atherosclerosis via NF-κB signaling pathway modulating pro-inflammatory cytokines releasing. Our results found that high fat induced atherosclerosis in wild type mice with fat accumulation and inflammatory response through NF-κB activation. Contrastly, TLR5 knockout mice displayed lower fat accumulation and ameliorated inflammation after high fat feeding with NF-κB inactivation. In addition, pterostilbene, as a natural dimethyl ether derivative of resveratrol mainly from blueberries, has diverse pharmacological activities, especially anti-inflammation. Our study also found that pterostilbene displayed inhibited role in suppressing inflammatory response through inactivating NF-κB signaling pathway regulated by TLR5 down-regulation in high fat-induced mice. Moreover, in vitro experiments of vascular smooth muscle cells (VSMCs) challenged with LPS or TNF-α, further indicated that NF-κB was involved in atherosclerosis progression, leading to high secretion of pro-inflammatory cytokines. However, VSMCs from TLR5 deficient mice inhibited phosphorylated levels of NF-κB signalilng pathway, finally resulting in down-regulation of inflammatory cytokines. Notably, pterostilbene also displayed suppressed role in inflammatory response via NF-κB inactivity in LPS or TNF-α-induced VSMCs by decreasing TLR5 expression. The results above indicated a novel therapeutic strategy of pterostilbene to protect against atherosclerosis via TLR5 regulation for clinic treatment in the future. PMID:27261612

  11. 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. PMID:20807945

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

    PubMed Central

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

    2009-01-01

    Background 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. Methods 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. Results 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. Conclusion 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. PMID:19754940

  13. Fire Suppression and Response

    NASA Technical Reports Server (NTRS)

    Ruff, Gary A.

    2004-01-01

    This report is concerned with the following topics regarding fire suppression:What is the relative effectiveness of candidate suppressants to extinguish a representative fire in reduced gravity, including high-O2 mole fraction, low -pressure environments? What are the relative advantages and disadvantages of physically acting and chemically-acting agents in spacecraft fire suppression? What are the O2 mole fraction and absolute pressure below which a fire cannot exist? What effect does gas-phase radiation play in the overall fire and post-fire environments? Are the candidate suppressants effective to extinguish fires on practical solid fuels? What is required to suppress non-flaming fires (smoldering and deep seated fires) in reduced gravity? How can idealized space experiment results be applied to a practical fire scenario? What is the optimal agent deployment strategy for space fire suppression?

  14. 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. PMID:25667093

  15. 75 FR 46945 - Proposed Collection; Comment Request; Multi-Ethnic Study of Atherosclerosis (MESA) Event...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-04

    ... and progression of subclinical cardiovascular disease (CVD)-- that is, atherosclerosis and other forms..., Division of Cardiovascular Sciences, NHLBI, NIH, II Rockledge Centre, 6701 Rockledge Drive, Suite...

  16. ARG2 impairs endothelial autophagy through regulation of MTOR and PRKAA/AMPK signaling in advanced atherosclerosis

    PubMed Central

    Xiong, Yuyan; Yepuri, Gautham; Forbiteh, Michael; Yu, Yi; Montani, Jean-Pierre; Yang, Zhihong; Ming, Xiu-Fen

    2015-01-01

    Impaired autophagy function and enhanced ARG2 (arginase 2)-MTOR (mechanistic target of rapamycin) crosstalk are implicated in vascular aging and atherosclerosis. We are interested in the role of ARG2 and the potential underlying mechanism(s) in modulation of endothelial autophagy. Using human nonsenescent “young” and replicative senescent endothelial cells as well as Apolipoprotein E-deficient (apoe−/−Arg2+/+) and Arg2-deficient apoe−/− (apoe−/−arg2−/−) mice fed a high-fat diet for 10 wk as the atherosclerotic animal model, we show here that overexpression of ARG2 in the young cells suppresses endothelial autophagy with concomitant enhanced expression of RICTOR, the essential component of the MTORC2 complex, leading to activation of the AKT-MTORC1-RPS6KB1/S6K1 (ribosomal protein S6 kinase, 70kDa, polypeptide 1) cascade and inhibition of PRKAA/AMPK (protein kinase, AMP-activated, α catalytic subunit). Expression of an inactive ARG2 mutant (H160F) had the same effect. Moreover, silencing RPS6KB1 or expression of a constitutively active PRKAA prevented autophagy suppression by ARG2 or H160F. In senescent cells, enhanced ARG2-RICTOR-AKT-MTORC1-RPS6KB1 and decreased PRKAA signaling and autophagy were observed, which was reversed by silencing ARG2 but not by arginase inhibitors. In line with the above observations, genetic ablation of Arg2 in apoe−/− mice reduced RPS6KB1, enhanced PRKAA signaling and endothelial autophagy in aortas, which was associated with reduced atherosclerosis lesion formation. Taken together, the results demonstrate that ARG2 impairs endothelial autophagy independently of the L-arginine ureahydrolase activity through activation of RPS6KB1 and inhibition of PRKAA, which is implicated in atherogenesis. PMID:25484082

  17. Kv1.3 potassium channel mediates macrophage migration in atherosclerosis by regulating ERK activity.

    PubMed

    Kan, Xiao-Hong; Gao, Hai-Qing; Ma, Zhi-Yong; Liu, Lin; Ling, Ming-Ying; Wang, Yuan-Yuan

    2016-02-01

    Ion channels expressed in macrophages have been tightly related to atherosclerosis by coupling cellular function. How the voltage-gated potassium channels (Kv) affect macrophage migration remain unknown. The aim of our study is to investigate whether Kv1.3-ERK signaling pathway plays an important role in the process. We explored the expression of Kv1.3 in coronary atherosclerotic heart disease and found Kv1.3 channel was increased in acute coronary syndrome patients. Treatment of RAW264.7 cells with Kv1.3 small interfering RNA, suppressed cell migration. The expression of phosphorylated ERK1/2 also decreased after knockdown of Kv1.3. On the other hand, overexpression of Kv1.3 channel promoted cell migration and ERK1/2 phosphorylation. U-0126, the mitogen-activated protein kinase inhibitors, could reverse macrophage migration induced by Kv1.3 channel overexpression. Downregulation of Kv1.3 channel by siRNA could not further inhibit cell migration when cells were treated with U-0126. It means that ERK is downstream signal of Kv1.3 channel. We concluded that Kv1.3 may stimulate macrophage migration through the activation of ERK. PMID:26748289

  18. Akt3 Deficiency in Macrophages Promotes Foam Cell Formation and Atherosclerosis in Mice

    PubMed Central

    Ding, Liang; Biswas, Sudipta; Morton, Richard E.; Smith, Jonathan D.; Hay, Nissim; Byzova, Tatiana; Febbraio, Maria; Podrez, Eugene

    2012-01-01

    Summary Akt, a serine-threonine protein kinase, exists as three isoforms. The Akt signaling pathway controls multiple cellular functions in the cardiovascular system, and the atheroprotective endothelial cell dependent role of Akt1 has been recently demonstrated. The role of Akt3 isoform in cardiovascular pathophysiology is not known. We explored the role of Akt3 in atherosclerosis using mice with a genetic ablation of the Akt3 gene. Using hyperlipidemic ApoE−/− mice, we demonstrated a macrophage dependent, atheroprotective role for Akt3. In vitro experiments demonstrated differential subcellular localization of Akt1 and Akt3 in macrophages, and showed that Akt3 specifically inhibits macrophage cholesteryl ester accumulation and foam cell formation, a critical early event in atherogenesis. Mechanistically, Akt3 suppresses foam cell formation by reducing lipoprotein uptake and promoting ACAT-1 degradation via the ubiquitin-proteasome pathway. These studies demonstrate the non-redundant atheroprotective role for Akt3 exerted via the previously unknown link between the Akt signaling pathway and cholesterol metabolism. PMID:22632897

  19. MafB promotes atherosclerosis by inhibiting foam-cell apoptosis

    NASA Astrophysics Data System (ADS)

    Hamada, Michito; Nakamura, Megumi; Tran, Mai Thi Nhu; Moriguchi, Takashi; Hong, Cynthia; Ohsumi, Takayuki; Dinh, Tra Thi Huong; Kusakabe, Manabu; Hattori, Motochika; Katsumata, Tokio; Arai, Satoko; Nakashima, Katsuhiko; Kudo, Takashi; Kuroda, Etsushi; Wu, Chien-Hui; Kao, Pei-Han; Sakai, Masaharu; Shimano, Hitoshi; Miyazaki, Toru; Tontonoz, Peter; Takahashi, Satoru

    2014-01-01

    MafB is a transcription factor that induces myelomonocytic differentiation. However, the precise role of MafB in the pathogenic function of macrophages has never been clarified. Here we demonstrate that MafB promotes hyperlipidemic atherosclerosis by suppressing foam-cell apoptosis. Our data show that MafB is predominantly expressed in foam cells found within atherosclerotic lesions, where MafB mediates the oxidized LDL-activated LXR/RXR-induced expression of apoptosis inhibitor of macrophages (AIM). In the absence of MafB, activated LXR/RXR fails to induce the expression of AIM, a protein that is normally responsible for protecting macrophages from apoptosis; thus, Mafb-deficient macrophages are prone to apoptosis. Haematopoietic reconstitution with Mafb-deficient fetal liver cells in recipient LDL receptor-deficient hyperlipidemic mice revealed accelerated foam-cell apoptosis, which subsequently led to the attenuation of the early atherogenic lesion. These findings represent the first evidence that the macrophage-affiliated MafB transcription factor participates in the acceleration of atherogenesis.

  20. Prevalence of atherosclerosis in patients with inactive rheumatoid arthritis.

    PubMed

    Dehghan, Pooneh; Rajaei, Alireza; Moeineddin, Reza; Alizadeh, Afshin Mohammad

    2015-08-01

    Patients with rheumatoid arthritis (RA) exhibit higher cardiovascular morbidity and mortality than the general population. The common carotid artery intima-media thickness (CCA-IMT) measured by ultrasound is a validated surrogate marker of atherosclerosis. We studied the prevalence of subclinical atherosclerosis in patients with inactive RA. CCA-IMT was measured at the level of the carotid bifurcation in 35 patients with RA and 35 age- and sex-matched controls. CCA-IMT measurements more than two standard deviations above the mean measurement of the control group were defined as abnormal. Patients and controls with known cardiovascular risk factors were excluded from the study. The following data were taken into consideration for each patient: age, sex, duration of RA, and medication received by the patient. These variables were adjusted in data analysis. The patients were required to have had normal C-reactive protein levels for at least 1 year and no clinical signs or symptoms of active disease. An independent t test and chi-squared test were used for statistical analysis. Nine patients with RA (25.7 %) and two controls (5.7 %) had an abnormal IMT. Patients showed more carotid atherosclerotic plaques and a higher mean CCA-IMT than did controls (48.6 vs. 14.3 % and 0.705 ± 0.140 vs. 0.580 ± 0.125, respectively). An abnormal CCA-IMT was more prevalent in patients >50 years of age with >5 years of involvement (P = 0.001). These results support the theory that chronic inflammation in patients with inactive RA is associated with atherosclerosis and suggest the use of carotid ultrasonography as a useful tool with which to establish the risk of cardiovascular disease. PMID:26122966

  1. Influence of chronic exercise on carotid atherosclerosis in marathon runners

    PubMed Central

    Taylor, Beth A; Zaleski, Amanda L; Capizzi, Jeffrey A; Ballard, Kevin D; Troyanos, Christopher; Baggish, Aaron L; D'Hemecourt, Pierre A; Dada, Marcin R; Thompson, Paul D

    2014-01-01

    Objectives The effect of habitual, high-intensity exercise training on the progression of atherosclerosis is unclear. We assessed indices of vascular health (central systolic blood pressure (SBP) and arterial stiffness as well as carotid intima-medial thickness (cIMT)) in addition to cardiovascular risk factors of trained runners versus their untrained spouses or partners to evaluate the impact of exercise on the development of carotid atherosclerosis. Setting field study at Boston Marathon. Participants 42 qualifiers (mean age±SD: 46±13 years, 21 women) for the 2012 Boston Marathon and their sedentary domestic controls (46±12 years, n=21 women). Outcomes We measured medical and running history, vital signs, anthropometrics, blood lipids, C reactive protein (CRP), 10 years Framingham risk, central arterial stiffness and SBP and cIMT. Results Multiple cardiovascular risk factors, including CRP, non-high-density lipoprotein cholesterol, triglycerides, heart rate, body weight and body mass index (all p<0.05), were reduced in the runners. The left and right cIMT, as well as central SBP, were not different between the two groups (all p>0.31) and were associated with age (all r≥0.41; p<0.01) and Framingham risk score (all r≥0.44; p<0.01) independent of exercise group (all p>0.08 for interactions). The amplification of the central pressure waveform (augmentation pressure at heart rate 75 bpm) was also not different between the two groups (p=0.07) but was related to age (p<0.01) and group (p=0.02) in a multiple linear regression model. Conclusions Habitual endurance exercise improves the cardiovascular risk profile, but does not reduce the magnitude of carotid atherosclerosis associated with age and cardiovascular risk factors. PMID:24531453

  2. The association between periodontal disease parameters and severity of atherosclerosis

    PubMed Central

    Ketabi, Mohammad; Meybodi, Fatemeh Rashidi; Asgari, Mohammad Reza

    2016-01-01

    Background: Atherosclerosis is the most common cause for heart attack and stroke. In the last decade, several epidemiological studies have found an association between periodontal infection and atherosclerosis. The aim of this research was to determine the possible association between chronic periodontal disease and severity of atherosclerosis. Materials and Methods: Eighty-two subjects that were referred to Chamran Heart Hospital in Isfahan for angiography were involved in this study. Fifty-nine subjects had coronary artery obstruction (CAO) and 23 showed no obstruction after angiography. The severity of CAO was assessed. Periodontal parameters including pocket depth (PD), gingival recession (R), clinical attachment level (CAL), and bleeding on probing (BOP) of all subjects were recorded. The decayed-missing-filled (DMF) index of all subjects was also measured. For statistical analysis, Pearson correlation test, Chi-square, and independent t-test were used. Results: There were significant positive correlation between variables R, PD, CAL, decayed (D), missing (M), DMF, BOP, and degree of CAO. However, there were no significant differences between filling variable degree of CAO (left anterior descending, left circumflex, and right coronary artery). Independent t-test showed that the mean of variables R, PD, AL, D, M, and DMF in patients with obstructed arteries were significantly higher than subjects without CAO. But there were no significant differences between variable F in two groups. Conclusion: The results of this cross-section analytical study showed an association between periodontal disease and dental parameters with the severity of CAO measured by angiography. However, this association must not interpret as a cause and effect relationship. PMID:27274346

  3. 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. PMID:23696447

  4. Risk Factors for Subclinical Atherosclerosis in Diabetic and Obese Children

    PubMed Central

    Faienza, Maria Felicia; Acquafredda, Angelo; Tesse, Riccardina; Luce, Vincenza; Ventura, Annamaria; Maggialetti, Nicola; Monteduro, Mariantonietta; Giordano, Paola; Cavallo, Luciano

    2013-01-01

    Background. Increased carotid intima-media thickness (cIMT) is considered a marker of early-onset atherosclerosis and it seems to predict cardiovascular events both in obese and diabetic subjects. We aimed to evaluate early signs of atherosclerosis and investigate for predisposing factors in children and adolescents affected by type 1 diabetes (T1DM) or obesity, comparing them with healthy controls. Methods. Out of 71 enrolled subjects (mean age 12.8 ± 2.3 years), 26 had T1DM and 24 were obese, while 21 age- and sex-matched subjects acted as controls. cIMT was measured using standardized methods. Serum glucose, insulin, cholesterol, triglycerides and C-reactive protein levels were evaluated. An oral glucose tolerance test (OGTT) was performed in obese subjects. Results. Diabetic and obese individuals showed higher cIMT mean values than healthy controls (p<0.005). cIMT of the three examined segments correlated positively with fasting glucose levels and negatively with units of insulin/kg/day administered in T1DM individuals. A positive correlation between insulin levels (basal and after oral glucose load) and cIMT of common, internal and external carotid artery was found in obese subjects (p<0.03). High density cholesterol levels represented a protective factor for cIMT in this latter group of the study population. Conclusions. Our findings show that cIMT correlates with high insulin levels (a sign of insulin resistance) in obese patients and with high fasting glucose levels (a sign of relative insulin deficiency) in T1DM subjects, confirming the need of reducing hyperinsulinism and monitoring blood glucose levels in these subjects to prevent atherosclerosis. PMID:23423872

  5. Peroxiredoxin1 Prevents Excessive Endothelial Activation and Early Atherosclerosis

    PubMed Central

    Kisucka, Janka; Chauhan, Anil K.; Patten, Ian S.; Yesilaltay, Ayce; Neumann, Carola; Van Etten, Richard A.; Krieger, Monty; Wagner, Denisa D.

    2016-01-01

    The peroxiredoxin (Prdx) family of antioxidant enzymes uses redox-active cysteines to reduce peroxides, lipid hydroperoxides, and peroxynitrites. Prdx1 is known to be important to protect red blood cells against reactive oxygen species and in tumor prevention. In this study, the role of Prdx1 in inflammation, thrombosis, and atherosclerosis was investigated. Using intravital microscopy, we showed that the number of leukocytes rolling per minute in unstimulated veins was increased by 2.5-fold in Prdx1−/− compared to Prdx1+/+ mice. In Prdx1−/− mice, 50% of leukocytes rolled at a velocity <10 μm/sec compared with 10% in Prdx1+/+ mice, suggesting that adhesion molecule density on the endothelium may have been increased by Prdx1 deficiency. Indeed, endothelial P-selectin, soluble P-selectin, and von Willebrand factor in plasma were increased in Prdx1−/− mice compared to Prdx1+/+ mice, indicating elevated Weibel–Palade body release. In contrast to this excessive endothelial activation, Prdx1−/− platelets showed no sign of hyperreactivity, and their aggregation both in vitro and in vivo was normal. We also examined the role of Prdx1 in the apoE−/− murine spontaneous model of atherosclerosis. Prdx1−/−/apoE−/− mice fed normal chow developed larger, more macrophage-rich aortic sinus lesions than Prdx1+/+/apoE−/− mice, despite similar amounts and size distributions of cholesterol in their plasma lipoproteins. Thus, Prdx1 protects against excessive endothelial activation and atherosclerosis, and the Prdx1−/− mice could serve as an animal model susceptible to chronic inflammation. PMID:18689572

  6. The pigeon (Columba livia) model of spontaneous atherosclerosis

    PubMed Central

    Anderson, J. L.; Smith, S. C.; Taylor, R. L.

    2014-01-01

    Multiple animal models have been employed to study human atherosclerosis, the principal cause of mortality in the United States. Each model has individual advantages related to specific pathologies. Initiation, the earliest disease phase, is best modeled by the White Carneau (WC-As) pigeon. Atherosclerosis develops spontaneously in the WC-As without either external manipulation or known risk factors. Furthermore, susceptibility is caused by a single gene defect inherited in an autosomal recessive manner. The Show Racer (SR-Ar) pigeon is resistant to atherosclerosis. Breed differences in the biochemistry and metabolism of celiac foci cells have been described. For example, WC-As have lower oxidative metabolism but higher amounts of chondroitin-6-sulfate and nonesterified fatty acids compared with SR-Ar. Gene expression in aortic smooth muscle cells was compared between breeds using representational difference analysis and microarray analysis. Energy metabolism and cellular phenotype were the chief gene expression differences. Glycolysis and synthetic cell types were related to the WC-As but oxidative metabolism and contractile cell types were related to the SR-Ar. Rosiglitazone, a PPARγ agonist, blocked RNA binding motif (RBMS1) expression in WC-As cells. The drug may act through the c-myc oncogene as RBMS1 is a c-myc target. Proteomic tests of aortic smooth muscle cells supported greater glycosylation in the WC-As and a transforming growth factor β effect in SR-Ar. Unoxidized fatty acids build up in WC-As cells because of their metabolic deficiency, ultimately preventing the contractile phenotype in these cells. The single gene responsible for the disease is likely regulatory in nature. PMID:25214557

  7. In vitro experimental photodynamic diagnosis of artery atherosclerosis

    NASA Astrophysics Data System (ADS)

    Bialy, Dariusz; Derkacz, Arkadiusz; Wawrzynska, M.; Kwasny, Miroslaw; Strek, Wieslaw; Protasiewicz, Marcin

    2004-07-01

    Background: Although there are several methods for atherosclerosis detection available, none of them seems to be accurate enough to identify the vulnerable atheroscleroitc plaque. Photodynamic diagnosis (PDD) and therapy (PDT) -- a new method evaluated for neoplasms treatment is a modern approach to detecting and treating atherosclerosis. Aim: The purpose of this study was to assess in vitro the capability of PDD with use of chlorin e6 to recognize atherosclerotic plaque and its usefulness as a feedback system for photoangioplasty treatment. Methods: 30 specimens of human aorta. The samples were soaked with chlorin e6 and then washed out. The luminescence spectra were then collected. All samples were examined with light microscopy. Results: Tissue fluorescence is seen as green light. We noted a very strong red fluorescence of chlorin e6 originating from lipid reach plaque. We established a quantitative factor which would be the ratio R of chlorin e6 red intensity in its 660 nm maximum compared to the area of green luminescence centered at 515 nm. The highest value of the ratio was reached at atheromatous samples, then calcified and normal ones R2 = 3.51 +/- 0.62, R3 = 1.63 +/- 0.31, R1 = 1.51 +/- 0.15 respectively. Statistically significant difference was noted between group two and one and between group two and three R2 = 3.51 +/- 0.62 vs R3 = 1.63 +/- 0.31 (p < 0,05); R2 = 3.51 +/- 0.62 vs. R1 = 1.51 +/- 0.15 (p<0.05) respectively. Conclusions: the following in vitro study confirms that photosensitizer chlorin e6 accumulates within atheromatous plaque. It may be a specific tool for atheromatous and normal or calcified segments discrimination. The advantage of the above method is a possibility of a real time imaging followed by targeted therapy of various forms and stages of atherosclerosis.

  8. Aortic Root Calcification: A Possible Imaging Biomarker of Coronary Atherosclerosis.

    PubMed

    Nafakhi, Hussein; Al-Nafakh, Hasan A; Al-Mosawi, Abdulameer A

    2016-04-01

    It has been reported that coronary atherosclerosis risk assessment using coronary artery calcium and thoracic aorta calcium quantification may improve risk stratification as it can lead to the reclassification of persons at increased risk. The aortic root has been characterized by its close anatomical proximity to the ostial origins of the right and left coronary arteries, and it can be evaluated using multi-detector computed tomography without additional radiation exposure and the use of contrast. The correlations between aortic root calcification and coronary atherosclerotic markers as well as cardiac risk factors have been analyzed. PMID:27195236

  9. Current siRNA targets in atherosclerosis and aortic aneurysm.

    PubMed

    Pradhan-Nabzdyk, Leena; Huang, Chenyu; LoGerfo, Frank W; Nabzdyk, Christoph S

    2014-05-01

    Atherosclerosis (ATH) and aortic aneurysms (AA) remain challenging chronic diseases that confer high morbidity and mortality despite advances in medical, interventional, and surgical care. RNA interference represents a promising technology that may be utilized to silence genes contributing to ATH and AA. Despite positive results in preclinical and some clinical feasibility studies, challenges such as target/sequence validation, tissue specificity, transfection efficiency, and mitigation of unwanted off-target effects remain to be addressed. In this review the most current targets and some novel approaches in siRNA delivery are being discussed. Due to the plethora of investigated targets, only studies published between 2010 and 2014 were included. PMID:24882715

  10. Mechanistic similarities between trauma, atherosclerosis, and other inflammatory processes.

    PubMed

    Scalea, Joseph R; Bromberg, Jonathan; Bartlett, Stephen T; Scalea, Thomas M

    2015-12-01

    Most human diseases, including trauma, atherosclerosis, and malignancy, can be characterized by either an overexuberant inflammatory response or an inadequate immunologic response. As our understanding of the mechanisms underlying these inflammatory aberrations improves, so should our approach to the patient. The development of novel technologies capable of exploiting inflammatory mediators will undoubtedly play a role in future patient-directed therapies. Trauma surgeons are uniquely positioned to usher in a new era of patient diagnostics and patient-directed therapies based on an understanding of the immune system's response to stimuli. These improvements are likely to affect not only trauma care but all aspects of medicine. PMID:26304513

  11. Periodontal Disease-Induced Atherosclerosis and Oxidative Stress

    PubMed Central

    Kurita-Ochiai, Tomoko; Jia, Ru; Cai, Yu; Yamaguchi, Yohei; Yamamoto, Masafumi

    2015-01-01

    Periodontal disease is a highly prevalent disorder affecting up to 80% of the global population. Recent epidemiological studies have shown an association between periodontal disease and cardiovascular disease, as oxidative stress plays an important role in chronic inflammatory diseases such as periodontal disease and cardiovascular disease. In this review, we focus on the mechanisms by which periodontopathic bacteria cause chronic inflammation through the enhancement of oxidative stress and accelerate cardiovascular disease. Furthermore, we comment on the antioxidative activity of catechin in atherosclerosis accelerated by periodontitis. PMID:26783845

  12. Aortic Root Calcification: A Possible Imaging Biomarker of Coronary Atherosclerosis

    PubMed Central

    Nafakhi, Hussein; Al-Nafakh, Hasan A.; Al-Mosawi, Abdulameer A.

    2016-01-01

    It has been reported that coronary atherosclerosis risk assessment using coronary artery calcium and thoracic aorta calcium quantification may improve risk stratification as it can lead to the reclassification of persons at increased risk. The aortic root has been characterized by its close anatomical proximity to the ostial origins of the right and left coronary arteries, and it can be evaluated using multi-detector computed tomography without additional radiation exposure and the use of contrast. The correlations between aortic root calcification and coronary atherosclerotic markers as well as cardiac risk factors have been analyzed. PMID:27195236

  13. Bone marrow NR4A expression is not a dominant factor in the development of atherosclerosis or macrophage polarization in mice.

    PubMed

    Chao, Lily C; Soto, Erin; Hong, Cynthia; Ito, Ayaka; Pei, Liming; Chawla, Ajay; Conneely, Orla M; Tangirala, Rajendra K; Evans, Ronald M; Tontonoz, Peter

    2013-03-01

    The formation of the atherosclerotic lesion is a complex process influenced by an array of inflammatory and lipid metabolism pathways. We previously demonstrated that NR4A nuclear receptors are highly induced in macrophages in response to inflammatory stimuli and modulate the expression of genes linked to inflammation in vitro. Here we used mouse genetic models to assess the impact of NR4A expression on atherosclerosis development and macrophage polarization. Transplantation of wild-type, Nur77⁻/⁻, or Nor1⁻/⁻ null hematopoetic precursors into LDL receptor (LDLR)⁻/⁻ recipient mice led to comparable development of atherosclerotic lesions after high-cholesterol diet. We also observed comparable induction of genes linked to M1 and M2 responses in wild-type and Nur77-null macrophages in response to lipopolysaccharides and interleukin (IL)-4, respectively. In contrast, activation of the nuclear receptor liver X receptor (LXR) strongly suppressed M1 responses, and ablation of signal transductor and activator of transcription 6 (STAT6) strongly suppressed M2 responses. Recent studies have suggested that alterations in levels of Ly6C(lo) monocytes may be a contributor to inflammation and atherosclerosis. In our study, loss of Nur77, but not Nor1, was associated with decreased abundance of Ly6C(lo) monocytes, but this change was not correlated with atherosclerotic lesion development. Collectively, our results suggest that alterations in the Ly6C(lo) monocyte population and bone marrow NR4A expression do not play dominant roles in macrophage polarization or the development of atherosclerosis in mice. PMID:23288947

  14. Piperlongumine inhibits atherosclerotic plaque formation and vascular smooth muscle cell proliferation by suppressing PDGF receptor signaling

    PubMed Central

    Son, Dong Ju; Kim, Soo Yeon; Han, Seong Su; Kim, Chan Woo; Kumar, Sandeep; Park, Byeoung Soo; Lee, Sung Eun; Yun, Yeo Pyo; Jo, Hanjoong; Park, Young Hyun

    2012-01-01

    Piperlongumine (piplartine, PL) is an alkaloid found in the long pepper (Piper longum L.) and has well-documented anti-platelet aggregation, anti-inflammatory, and anti-cancer properties; however, the role of PL in prevention of atherosclerosis is unknown. We evaluated the anti-atherosclerotic potential of PL in an in vivo murine model of accelerated atherosclerosis and defined its mechanism of action in aortic vascular smooth muscle cells (VSMCs) in vitro. Local treatment with PL significantly reduced atherosclerotic plaque formation as well as proliferation and nuclear factor-kappa B (NF-κB) activation in an in vivo setting. PL treatment in VSMCs in vitro showed inhibition of migration and platelet-derived growth factor BB (PDGF-BB)-induced proliferation to the in vivo findings. We further identified that PL inhibited PDGF-BB-induced PDGF receptor beta activation and suppressed downstream signaling molecules such as phospholipase C1, extracellular signal-regulated kinases 1 and 2 and Akt. Lastly, PL significantly attenuated activation of NF-κB—a downstream transcriptional regulator in PDGF receptor signaling, in response to PDGF-BB stimulation. In conclusion, our findings demonstrate a novel, therapeutic mechanism by which PL suppresses atherosclerosis plaque formation in vivo. PMID:22995306

  15. Caveolae and Caveolin-1 Integrate Reverse Cholesterol Transport and Inflammation in Atherosclerosis

    PubMed Central

    Qin, Li; Zhu, Neng; Ao, Bao-Xue; Liu, Chan; Shi, Ya-Ning; Du, Ke; Chen, Jian-Xiong; Zheng, Xi-Long; Liao, Duan-Fang

    2016-01-01

    Lipid disorder and inflammation play critical roles in the development of atherosclerosis. Reverse cholesterol transport is a key event in lipid metabolism. Caveolae and caveolin-1 are in the center stage of cholesterol transportation and inflammation in macrophages. Here, we propose that reverse cholesterol transport and inflammation in atherosclerosis can be integrated by caveolae and caveolin-1. PMID:27011179

  16. Atherosclerosis and ischemic cardiomyopathy in a captive, adult red-tailed hawk (Buteo jamaicensis).

    PubMed

    Shrubsole-Cockwill, Alana; Wojnarowicz, Chris; Parker, Dennilyn

    2008-09-01

    An adult, male, captive red-tailed hawk (Buteo jamaicensis) of at least 19 years of age presented in dorsal recumbency. The hawk was nonresponsive, and despite initial supportive care, died shortly after presentation. Gross postmortem revealed no abnormal findings. Histologic examination demonstrated atherosclerosis and ischemic cardiomyopathy. This is the first reported case of atherosclerosis in a red-tailed hawk. PMID:18939649

  17. 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…

  18. Tissue Factor Pathway Inhibitor-2 Gene Polymorphisms Associate With Coronary Atherosclerosis in Chinese Population

    PubMed Central

    Yu, Jia; Liu, Rong-Le; Luo, Xin-Ping; Shi, Hai-ming; Ma, Duan; Pan, Jun-Jie; Ni, Huan-Chun

    2015-01-01

    Abstract Tissue factor pathway inhibitor-2 (TFPI-2) may play critical roles in the pathogenesis of atherosclerosis. In this study, we aimed to investigate the association between TFPI-2 gene polymorphisms and coronary atherosclerosis. Four hundred and seven patients with coronary atherosclerosis and 306 individuals with normal coronary artery were enrolled in the present study. Nine single-nucleotide polymorphisms (SNPs) (rs3763473, rs59805398, rs60215632, rs59999573, rs59740167, rs34489123, rs4517, rs4264, and rs4271) were detected with polymerase chain reaction-direct sequencing method. Severity of coronary atherosclerosis was assessed by Gensini score. After the baseline investigation, patients with coronary atherosclerosis were followed up for incidence of cardiovascular events (CVEs). Eight SNPs were in accordance with the Hardy–Weinberg equilibrium, and 8 haplotypes were constructed based on rs59999573, rs59740167, and rs34489123 after linkage disequilibrium and haplotype analysis. Two SNPs (rs59805398 and rs34489123) and 5 haplotypes correlated with coronary atherosclerosis even after adjustment by Gensini score. At follow-up (median 53 months, range 1–60 months), 85 patients experienced CVE. However, there was no strong association between the gene polymorphisms and the occurrence of CVE. Tissue factor pathway inhibitor-2 gene polymorphisms were associated with coronary atherosclerosis in the Chinese population, suggesting that the information about TFPI-2 gene polymorphisms was useful for assessing the risk of developing coronary atherosclerosis, but there was not enough evidence showing it could predict occurrence of CVE. PMID:26496276

  19. Preliminary and early stages of atherosclerosis in childhood.

    PubMed

    Pesonen, E

    1989-01-01

    According to the unified theory of atherosclerosis, endothelial cell injury and lipid infiltration play an important role in atherogenesis. Newborn babies may suffer endothelial cell damage, as may be detected by electron microscopy. Connective tissue elements are occasionally abundant already in newborns. Chondroitin sulfate A and C increase with age. The children may exhibit continuous accumulation of cholesterol esters in the intima of coronary arteries. Cholesteryl ester fatty acid composition, along with age, tends to approach that of serum low-density lipoproteins. Fatty streaks appear in coronary arteries in puberty, and fibrous plaques are recordable beyond the age of 20 years. The topography of myo-intimal thickenings, fatty streaks, and fibrous plaques is similar to complicated atherosclerotic lesions. Even newborn babies have obstructive myo-intimal thickenings in their coronary arteries. One fifth of all infants under one week of age suffer 20% stenosis, with percentile manifestation of stenosis in the arterial cross-section being established as ratio of intimal area to luminal area of a dilated coronary artery multiplied by 100. Occasionally, the intima is very thick, in our series initiating up to 57% of all narrowing. There are probably noxious factors which temporarily damage the endothelial cells and initiate a rapid, partially reversible thickening reaction. Some of this response of the intima to exogenous stimuli might be genetically determined. A thickened intima is susceptible to lipid deposition and atherosclerosis. PMID:2683501

  20. Macrophage Heterogeneity and Plasticity: Impact of Macrophage Biomarkers on Atherosclerosis

    PubMed Central

    Rojas, Joselyn; Salazar, Juan; 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

  1. Coronary Atherosclerosis The Implications of Being a Woman.

    PubMed

    Morales-Villegas, E

    2014-07-01

    The profile of ischemic heart disease by coronary atherosclerosis has been developed based on clinical, paraclinical and angiographic grounds inherent to the male gender. A man in his 40s - 50s with "classical" cardiovascular risk factors, angina pectoris and hemodynamically significant myocardial ischemia associated with angiographic stenosis (≥ 50% endovascular diameter reduction equivalent to ≥ 75% endovascular area reduction and determining a trans-stenotic pressure gradient) is the prototype over which guidelines for prevention, diagnosis and treatment of this disease are structured. However, this "male" pattern of coronary atherosclerosis is not the rule in female gender. Therefore, in women, the frequent lack of a clinical, paraclinical and angiographic profile, classically masculine, results in a suboptimal medical approach, characterized by low implementation of the guidelines for prevention, diagnosis and treatment of ischemic heart disease. The final consequence of this cycle, favored by other gender, social and environmental circumstances, is a high morbidity and mortality caused by this pathology in the female gender. In this chapter, which concludes with a review of the state-of-the-art knowledge of atheroma in females, the current concepts on the physiological level of c-LDL, oxidized c-LDL "a mimicked pathogen" and atherogenesis will be reviewed in sequence for didactic purposes. PMID:24993280

  2. Imaging of coronary atherosclerosis in various susceptible groups

    PubMed Central

    Nerlekar, Nitesh; Wong, Dennis T. L.

    2016-01-01

    Coronary artery disease (CAD) is the leading cause of death and disability worldwide. Atherosclerosis, which is the primary pathophysiologic mechanism for the development of plaque leading to CAD, is a multifactorial process resulting from a complex interplay between genetic susceptibility and various risk factors such as hypertension (HT), dyslipidaemia, diabetes mellitus (DM) and smoking. In addition, influences from other disease states such as chronic kidney disease (CKD), obesity and the metabolic syndrome as well as gender and ethnic diversity also contribute to the disease process. Insights from pathological observations and advances in cellular and molecular biology have helped us understand the process of plaque formation, progression and rupture leading to events. Several intravascular imaging techniques such as intravascular ultrasound (IVUS), Virtual histology IVUS (VH-IVUS) and optical coherence tomography (OCT) allow in vivo assessment of plaque burden, plaque morphology and response to therapy. In addition, non invasive assessment using coronary artery calcium (CAC) score allows risk stratification and plaque burden assessment whilst computed tomography coronary angiography (CTCA) allows evaluation of luminal stenosis, plaque characterisation and quantification. This review aims to summarise the results of invasive and non-invasive imaging studies of coronary atherosclerosis seen in various high-risk populations including DM, metabolic syndrome, obesity, CKD and, gender differences and ethnicity. Understanding the phenotype of plaques in various susceptible groups may allow potential development of personalised therapies. PMID:27500095

  3. Telomere Length and the Cancer–Atherosclerosis Trade-Off

    PubMed Central

    Stone, Rivka C.; Horvath, Kent; Kark, Jeremy D.; Susser, Ezra; Tishkoff, Sarah A.; Aviv, Abraham

    2016-01-01

    Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a) the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b) how cancer might have played a role in the evolution of telomere biology across mammals, (c) evidence that in modern humans telomere length is a determinant (rather than only a biomarker) of cancer and atherosclerosis, and (d) the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan. PMID:27386863

  4. Telomere Length and the Cancer-Atherosclerosis Trade-Off.

    PubMed

    Stone, Rivka C; Horvath, Kent; Kark, Jeremy D; Susser, Ezra; Tishkoff, Sarah A; Aviv, Abraham

    2016-07-01

    Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a) the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b) how cancer might have played a role in the evolution of telomere biology across mammals, (c) evidence that in modern humans telomere length is a determinant (rather than only a biomarker) of cancer and atherosclerosis, and (d) the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan. PMID:27386863

  5. Role of apoptosis in atherosclerosis and its therapeutic implications.

    PubMed

    Stoneman, Victoria E A; Bennett, Martin R

    2004-10-01

    Atherosclerotic plaques develop as a consequence of the accumulation of circulating lipid and the subsequent migration of inflammatory cells (macrophages and T-lymphocytes) and VSMCs (vascular smooth muscle cells). Advanced plaques consist of a lipid-rich core, separated from the lumen by a fibrous cap composed of VSMCs, collagen and extracellular matrix. Plaque enlargement ultimately narrows the lumen (stenosis) causing angina. However, recent studies have emphasized that acute coronary syndromes (unstable angina/myocardial infarction) are caused by lesion erosion/rupture with superimposed thrombus formation on often small non-stenotic plaques. Thus current therapies work predominantly on stabilization of plaques rather than plaque regression. Apoptosis (programmed cell death) is increasingly observed as plaques develop, although the exact mechanisms and consequences of apoptosis in the development and progression of atherosclerosis are still controversial. Increased endothelial cell apoptosis may initiate atherosclerosis, whereas apoptosis of VSMCs and macrophages localizes in 'vulnerable' lesions, i.e. those most likely to rupture, and at sites of rupture. This review will focus on the regulation of apoptosis of cells within the vasculature, concentrating on the relevance of apoptosis to plaque progression and clinical consequences of vascular cell apoptosis. PMID:15230690

  6. Imaging of coronary atherosclerosis - evolution towards new treatment strategies.

    PubMed

    Dweck, Marc R; Doris, Mhairi K; Motwani, Manish; Adamson, Philip D; Slomka, Piotr; Dey, Damini; Fayad, Zahi A; Newby, David E; Berman, Daniel

    2016-09-01

    Coronary atherosclerosis and the precipitation of acute myocardial infarction are highly complex processes, which makes accurate risk prediction challenging. Rapid developments in invasive and noninvasive imaging technologies now provide us with detailed, exquisite images of the coronary vasculature that allow direct investigation of a wide range of these processes. These modalities include sophisticated assessments of luminal stenoses and myocardial perfusion, complemented by novel measures of the atherosclerotic plaque burden, adverse plaque characteristics, and disease activity. Together, they can provide comprehensive, individualized assessments of coronary atherosclerosis as it occurs in patients. Not only can this information provide important pathological insights, but it can also potentially be used to guide personalized treatment decisions. In this Review, we describe the latest advances in both established and emerging imaging techniques, focusing on the strengths and weakness of each approach. Moreover, we discuss how these technological advances might be translated from attractive images into novel imaging strategies and definite improvements in clinical risk prediction and patient outcomes. This process will not be easy, and the many potential barriers and difficulties are also reviewed. PMID:27226154

  7. 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. PMID:25174928

  8. Periodontitis-atherosclerosis syndrome: an expanded model of pathogenesis.

    PubMed

    Offenbacher, S; Madianos, P N; Champagne, C M; Southerland, J H; Paquette, D W; Williams, R C; Slade, G; Beck, J D

    1999-10-01

    The early reports of a linkage between periodontitis and atherosclerosis have garnered further support by additional data generated by several investigative teams in many different countries. The evidence continues to suggest that periodontitis may be an important risk factor or risk indicator for cardiovascular pathology for some individuals. The term periodontitis-atherosclerosis syndrome (PAS) is proposed as a new diagnostic term to describe this condition in these individuals. Current evidence, albeit preliminary in nature, which describes a cluster of clinical signs and symptoms that are associated with this condition, is presented. It is clear that this syndrome will require considerable study and refinement before a definitive diagnosis and treatment plan can be formulated. Potential mechanisms by which systemic inflammation and infectious challenge of periodontal origin may serve as a potential modifier of cardiovascular disease are discussed in the context of a detailed working model of pathogenesis. This hypothetical model embraces many cellular and molecular components of atherogenesis and thromboembolic diseases from the perspective of periodontitis pathogenesis. Many aspects of the hypothetical model remain unproved; however, it is our opinion that only through the clarification of the mechanisms of pathogenesis can we ultimately construct a knowledge framework for accurate diagnoses and successful therapies. The concept of diagnosing and treating a periodontal patient to minimize the deleterious effects of this chronic infectious and inflammatory condition on the cardiovascular system represents an unprecedented challenge to our profession. PMID:10685359

  9. Molecular chaperones and heat shock proteins in atherosclerosis

    PubMed Central

    Xu, Qingbo; Metzler, Bernhard; Jahangiri, Marjan

    2012-01-01

    In response to stress stimuli, mammalian cells activate an ancient signaling pathway leading to the transient expression of heat shock proteins (HSPs). HSPs are a family of proteins serving as molecular chaperones that prevent the formation of nonspecific protein aggregates and assist proteins in the acquisition of their native structures. Physiologically, HSPs play a protective role in the homeostasis of the vessel wall but have an impact on immunoinflammatory processes in pathological conditions involved in the development of atherosclerosis. For instance, some members of HSPs have been shown to have immunoregulatory properties and modification of innate and adaptive response to HSPs, and can protect the vessel wall from the disease. On the other hand, a high degree of sequence homology between microbial and mammalian HSPs, due to evolutionary conservation, carries a risk of misdirected autoimmunity against HSPs expressed on the stressed cells of vascular endothelium. Furthermore, HSPs and anti-HSP antibodies have been shown to elicit production of proinflammatory cytokines. Potential therapeutic use of HSP in prevention of atherosclerosis involves achieving optimal balance between protective and immunogenic effects of HSPs and in the progress of research on vaccination. In this review, we update the progress of studies on HSPs and the integrity of the vessel wall, discuss the mechanism by which HSPs exert their role in the disease development, and highlight the potential clinic translation in the research field. PMID:22058161

  10. Lipid droplet-associated proteins in atherosclerosis (Review).

    PubMed

    Plakkal Ayyappan, Janeesh; Paul, Antoni; Goo, Young-Hwa

    2016-06-01

    Accumulation of atherosclerotic plaques in arterial walls leads to major cardiovascular diseases and stroke. Macrophages/foam cells are central components of atherosclerotic plaques, which populate the arterial wall in order to remove harmful modified low‑density lipoprotein (LDL) particles, resulting in the accumulation of lipids, mostly LDL‑derived cholesterol ester, in cytosolic lipid droplets (LDs). At present, LDs are recognized as dynamic organelles that govern cellular metabolic processes. LDs consist of an inner core of neutral lipids surrounded by a monolayer of phospholipids and free cholesterol, and contain LD‑associated proteins (LDAPs) that regulate LD functions. Foam cells are characterized by an aberrant accumulation of cytosolic LDs, and are considered a hallmark of atherosclerotic lesions through all stages of development. Previous studies have investigated the mechanisms underlying foam cell formation, aiming to discover therapeutic strategies that target foam cells and intervene against atherosclerosis. It is well established that LDAPs have a major role in the pathogenesis of metabolic diseases caused by dysfunction of lipid metabolism, and several studies have linked LDAPs to the development of atherosclerosis. In this review, several foam cell‑targeting pathways have been described, with an emphasis on the role of LDAPs in cholesterol mobilization from macrophages. In addition, the potential of LDAPs as therapeutic targets to prevent the progression and/or facilitate the regression of the disease has been discussed. PMID:27082419

  11. Circulating Endothelial Microparticles: A Key Hallmark of Atherosclerosis Progression

    PubMed Central

    Panth, Nisha; Kim, Dong-Wook

    2016-01-01

    The levels of circulating microparticles (MPs) are raised in various cardiovascular diseases. Their increased level in plasma is regarded as a biomarker of alteration in vascular function. The prominent MPs present in blood are endothelial microparticles (EMPs) described as complex submicron (0.1 to 1.0 μm) vesicles like structure, released in response to endothelium cell activation or apoptosis. EMPs possess both physiological and pathological effects and may promote oxidative stress and vascular inflammation. EMPs release is triggered by inducer like angiotensin II, lipopolysaccharide, and hydrogen peroxide leading to the progression of atherosclerosis. However, there are multiple physiological pathways for EMPs generation like NADPH oxidase derived endothelial ROS formation, Rho kinase pathway, and mitogen-activated protein kinases. Endothelial dysfunction is a key initiating event in atherosclerotic plaque formation. Atheroemboli, resulting from ruptured carotid plaques, is a major cause of stroke. Increasing evidence suggests that EMPs play an important role in the pathogenesis of cardiovascular disease, acting as a marker of damage, either exacerbating disease progression or triggering a repair response. In this regard, it has been suggested that EMPs have the potential to act as biomarkers of disease status. This review aims to provide updated information of EMPs in relation to atherosclerosis pathogenesis. PMID:27066292

  12. Lipid droplet-associated proteins in atherosclerosis (Review)

    PubMed Central

    AYYAPPAN, JANEESH PLAKKAL; PAUL, ANTONI; GOO, YOUNG-HWA

    2016-01-01

    Accumulation of atherosclerotic plaques in arterial walls leads to major cardiovascular diseases and stroke. Macrophages/foam cells are central components of atherosclerotic plaques, which populate the arterial wall in order to remove harmful modified low-density lipoprotein (LDL) particles, resulting in the accumulation of lipids, mostly LDL-derived cholesterol ester, in cytosolic lipid droplets (LDs). At present, LDs are recognized as dynamic organelles that govern cellular metabolic processes. LDs consist of an inner core of neutral lipids surrounded by a monolayer of phospholipids and free cholesterol, and contain LD-associated proteins (LDAPs) that regulate LD functions. Foam cells are characterized by an aberrant accumulation of cytosolic LDs, and are considered a hallmark of atherosclerotic lesions through all stages of development. Previous studies have investigated the mechanisms underlying foam cell formation, aiming to discover therapeutic strategies that target foam cells and intervene against atherosclerosis. It is well established that LDAPs have a major role in the pathogenesis of metabolic diseases caused by dysfunction of lipid metabolism, and several studies have linked LDAPs to the development of atherosclerosis. In this review, several foam cell-targeting pathways have been described, with an emphasis on the role of LDAPs in cholesterol mobilization from macrophages. In addition, the potential of LDAPs as therapeutic targets to prevent the progression and/or facilitate the regression of the disease has been discussed. PMID:27082419

  13. Medical therapy for patients with subclinical and clinical carotid atherosclerosis.

    PubMed

    Corrado, E; Bacarella, D; Coppola, G; Rizzo, M; Muratori, I; Dell'oglio, S; Nugara, C; Ferrara, F; Novo, S

    2012-02-01

    The management of carotid artery disease includes both modifications in life style as well treatment of vascular risk factors. However, strict risk factor modification, including improved antihypertensive therapy, lipid management, smoking cessation, and antiplatelet therapy, promise for reducing the vascular event rate in patients with carotid atherosclerosis. The best medical management for stroke prevention was highlighted in clinical practice guidelines issued jointly in 2006 by the American Heart Association and the American Stroke Association, and co-sponsored by the Council on Cardiovascular Radiology and Intervention and the American Academy of Neurology. Lowering blood pressure to a target below 120/80 mm Hg by life style interventions and antihypertensive treatment. Glucose control to near-normoglycemic levels (target hemoglobin A1C ≤7%) is recommended among diabetics to reduce micro-vascular complications and, with lesser certainty, macrovascular complications. The primary objective of this review is to summarize the current evidence and standards for the advanced diagnostic and management strategies used in asymptomatic and symptomatic patients with carotid atherosclerosis. PMID:22330618

  14. Atherosclerosis in Alaska Natives and non-natives.

    PubMed

    Newman, W P; Middaugh, J P; Propst, M T; Rogers, D R

    1993-04-24

    Low mortality from coronary heart disease (CHD) among Eskimos has been attributed to less atherosclerosis in the coronary arteries because of a high dietary intake of omega-3 fatty acids. Other investigators attribute this low mortality to the fact that Eskimos have a high mortality from other causes before middle age, when CHD is common. However, most studies have been epidemiological, either by death-certificate review or risk-factor evaluation. We evaluated the extent of atherosclerotic lesions in the coronary arteries and aortas from Alaska Natives. Standardised comparisons between samples from 103 Native and 101 non-native residents show that the extent of raised lesions increases with age in both groups, but the prevalence of raised lesions in native specimens was consistently lower than in those from non-natives. This difference was statistically significant. The data suggest that the differences in CHD mortality between Alaska Natives and non-natives are, at least in part, the result of less atherosclerosis in natives. PMID:8096960

  15. Imaging of coronary atherosclerosis in various susceptible groups.

    PubMed

    Munnur, Ravi Kiran; Nerlekar, Nitesh; Wong, Dennis T L

    2016-08-01

    Coronary artery disease (CAD) is the leading cause of death and disability worldwide. Atherosclerosis, which is the primary pathophysiologic mechanism for the development of plaque leading to CAD, is a multifactorial process resulting from a complex interplay between genetic susceptibility and various risk factors such as hypertension (HT), dyslipidaemia, diabetes mellitus (DM) and smoking. In addition, influences from other disease states such as chronic kidney disease (CKD), obesity and the metabolic syndrome as well as gender and ethnic diversity also contribute to the disease process. Insights from pathological observations and advances in cellular and molecular biology have helped us understand the process of plaque formation, progression and rupture leading to events. Several intravascular imaging techniques such as intravascular ultrasound (IVUS), Virtual histology IVUS (VH-IVUS) and optical coherence tomography (OCT) allow in vivo assessment of plaque burden, plaque morphology and response to therapy. In addition, non invasive assessment using coronary artery calcium (CAC) score allows risk stratification and plaque burden assessment whilst computed tomography coronary angiography (CTCA) allows evaluation of luminal stenosis, plaque characterisation and quantification. This review aims to summarise the results of invasive and non-invasive imaging studies of coronary atherosclerosis seen in various high-risk populations including DM, metabolic syndrome, obesity, CKD and, gender differences and ethnicity. Understanding the phenotype of plaques in various susceptible groups may allow potential development of personalised therapies. PMID:27500095

  16. Atherosclerosis: Recent trials, new targets and future directions.

    PubMed

    Ladeiras-Lopes, Ricardo; Agewall, Stefan; Tawakol, Ahmed; Staels, Bart; Stein, Evan; Mentz, Robert J; Leite-Moreira, Adelino; Zannad, Faiez; Koenig, Wolfgang

    2015-08-01

    Mortality from cardiovascular diseases (CVD) represents the primary cause of death worldwide. Prevention or treatment of atherosclerosis and its clinical sequelae is a central goal in the management of patients with established vascular disease or those at high-risk for vascular events. This paper provides a review of the contemporary pharmacological armamentarium targeting atherosclerosis and also highlights strategies to support future clinical trial design. Powering future trials targeting LDL-cholesterol to its absolute reduction and including patients with a higher LDL-C despite optimal medical therapy (or unable to tolerate statins) will increase the odds of meaningful results. Mendelian randomization studies may identify new causal risk factors for CVD that would help in the selection of the patients most likely to benefit from a specific new compound. Furthermore, imaging techniques integrating a morphological and functional assessment such as IVUS, OCT, PET/CT and PET/MRI may represent in a near future robust "soft" endpoints to support successful translation of early research into meaningful phase III clinical outcome trials. PMID:26002254

  17. Anti-inflammatory and anti-atherogenic role of BMP receptor II in atherosclerosis.

    PubMed

    Simic, Tatjana

    2013-09-01

    Evaluation of: Kim CW, Song H, Kumar S et al. Anti-inflammatory and anti-atherogenic role of BMP receptor II in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 33, 1350-1359 (2013). Increased expression of BMPs in atherosclerosis suggested that the knockdown of the receptor mediating BMP action would prevent endothelial inflammation and atherosclerosis. Based on this hypothesis, Kim et al. performed a series of experiments in which the effect of BMP receptor type II (BMPRII) knockout was tested in in vitro and in vivo models of atherogenesis. Unexpectedly, they found that the loss of BMPRII induces endothelial inflammation and atherosclerosis. Knockdown of BMPRII in endothelial cells induced monocyte adhesion through the expression of ICAM-1 and VCAM-1. The loss of BMPRII induced endothelial inflammation and atherosclerosis in apoE-deficient mice. Besides, BMPRII expression was gradually lost over the course of atherosclerosis progression in human coronary arteries. PMID:24020661

  18. Myeloid cells in atherosclerosis: a delicate balance of anti-inflammatory and proinflammatory mechanisms

    PubMed Central

    Koltsova, Ekaterina K.; Hedrick, Catherine C.; Ley, Klaus

    2016-01-01

    Purpose of review Atherosclerosis is chronic disease, whose progression is orchestrated by the balance between proinflammatory and anti-inflammatory mechanisms. Various myeloid cells, including monocytes, macrophages, dendritic cells and neutrophils can be found in normal and atherosclerotic aortas, in which they regulate inflammation and progression of atherosclerosis. The lineage relationship between blood monocyte subsets and the various phenotypes and functions of myeloid cells in diseased aortas is under active investigation. Recent findings Various subsets of myeloid cells play diverse roles in atherosclerosis. This review discusses new findings in phenotypic and functional characterization of different subsets of macrophages, in part determined by the transcription factors IRF5 and Trib1, and dendritic cells, characterized by the transcription factor Zbtb46, in atherosclerosis. Summary Improved understanding proinflammatory and anti-inflammatory mechanisms of macrophages and dendritic cell functions is needed for better preventive and therapeutic measures in atherosclerosis. PMID:24005215

  19. Cough suppression disorders spectrum.

    PubMed

    Reich, Jerome M

    2014-02-01

    Volitional cough suppression, identified exclusively in females, is an unusual causal mechanism for instances of lobar atalectasis and bronchiectasis. It is a postulated mechanism for the genesis of Lady Windermere Syndrome. PMID:24462261

  20. Jet Noise Suppression

    NASA Technical Reports Server (NTRS)

    Gliebe, P. R.; Brausch, J. F.; Majjigi, R. K.; Lee, R.

    1991-01-01

    The objectives of this chapter are to review and summarize the jet noise suppression technology, to provide a physical and theoretical model to explain the measured jet noise suppression characteristics of different concepts, and to provide a set of guidelines for evolving jet noise suppression designs. The underlying principle for all jet noise suppression devices is to enhance rapid mixing (i.e., diffusion) of the jet plume by geometric and aerothermodynamic means. In the case of supersonic jets, the shock-cell broadband noise reduction is effectively accomplished by the elimination or mitigation of the shock-cell structure. So far, the diffusion concepts have predominantly concentrated on jet momentum and energy (kinetic and thermal) diffusion, in that order, and have yielded better noise reduction than the simple conical nozzles. A critical technology issue that needs resolution is the effect of flight on the noise suppression potential of mechanical suppressor nozzles. A more thorough investigation of this mechanism is necessary for the successful development and design of an acceptable noise suppression device for future high-speed civil transports.

  1. Piperlongumine inhibits atherosclerotic plaque formation and vascular smooth muscle cell proliferation by suppressing PDGF receptor signaling

    SciTech Connect

    Son, Dong Ju; Kim, Soo Yeon; Han, Seong Su; Kim, Chan Woo; Kumar, Sandeep; Park, Byeoung Soo; Lee, Sung Eun; Yun, Yeo Pyo; Jo, Hanjoong; Park, Young Hyun

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer Anti-atherogenic effect of PL was examined using partial carotid ligation model in ApoE KO mice. Black-Right-Pointing-Pointer PL prevented atherosclerotic plaque development, VSMCs proliferation, and NF-{kappa}B activation. Black-Right-Pointing-Pointer Piperlongumine reduced vascular smooth muscle cell activation through PDGF-R{beta} and NF-{kappa}B-signaling. Black-Right-Pointing-Pointer PL may serve as a new therapeutic molecule for atherosclerosis treatment. -- Abstract: Piperlongumine (piplartine, PL) is an alkaloid found in the long pepper (Piper longum L.) and has well-documented anti-platelet aggregation, anti-inflammatory, and anti-cancer properties; however, the role of PL in prevention of atherosclerosis is unknown. We evaluated the anti-atherosclerotic potential of PL in an in vivo murine model of accelerated atherosclerosis and defined its mechanism of action in aortic vascular smooth muscle cells (VSMCs) in vitro. Local treatment with PL significantly reduced atherosclerotic plaque formation as well as proliferation and nuclear factor-kappa B (NF-{kappa}B) activation in an in vivo setting. PL treatment in VSMCs in vitro showed inhibition of migration and platelet-derived growth factor BB (PDGF-BB)-induced proliferation to the in vivo findings. We further identified that PL inhibited PDGF-BB-induced PDGF receptor beta activation and suppressed downstream signaling molecules such as phospholipase C{gamma}1, extracellular signal-regulated kinases 1 and 2 and Akt. Lastly, PL significantly attenuated activation of NF-{kappa}B-a downstream transcriptional regulator in PDGF receptor signaling, in response to PDGF-BB stimulation. In conclusion, our findings demonstrate a novel, therapeutic mechanism by which PL suppresses atherosclerosis plaque formation in vivo.

  2. Prospects for prevention of atherosclerosis in the young.

    PubMed

    Kannel, W B

    1976-10-01

    There appears to be a need to protect our young from an atherogenic way of life. The average male child today has one chance in three of a cardiovascular catastrophe before age 60. Atherosclerosis and the conditions which predispose appear to have their onset in childhood. Correctable precursors of cardiovascular disease have been identified, and their contribution to risk has been estimated not only for adults but for college students as well. An analysis of the combined impact of atherogenic risk factors indicates that they exert greater force early in life than later. Although the optimal time to begin prophylaxis is not established, there is evidence to suggest that measures instituted late in life when lesions are advanced is of only limited value. Prevention of atherosclerosis is best viewed as a family affair since the propensity to disease and contributing factors tend to be shared by family members. It is also difficult to implement effectively preventive measures which include dietary changes, weight control, exercise and restriction of cigarettes for one family member without involving the rest of the family. Optimal levels of the correctable precursors of cardiovascular disease are not established for children. However, the rise in serum lipids, blood pressure, weight and blood sugar observed in transition from childhood to adult life is not inevitable, or desirable. Paediatricians can alter the appalling cardiovascular mortality statistics by not allowing the process or the habits and conditions which promote it to reach an irreversible stage. Cardiovascular disease may well begin in childhood with "medical trivia" such as a tendency to obesity, moderate cholesterol and blood pressure elevations, lack of exercise and the cigarette habit. In some respects a heart attack at age 45 can be regarded as a failure of the paediatrician. Awaiting proof of the efficacy of the indicated prophylactic measures is not acceptable since this will be a long time in

  3. Establishment and ultrasound characteristics of atherosclerosis in rhesus monkey

    PubMed Central

    2015-01-01

    Background Atherosclerosis is one of the main risk factors cause acute cerebral-cardio vascular diseases. It's of great significance to establish an atherosclerosis animal model that can mimic the characteristics and nature course of human patients. Therefore, a rhesus monkey model was induced by high-fat diet to monitor their lipid profile and intima-media thickness (IMT) of artery walls and study atherosclerosis progression. Methods Fifty male rhesus monkeys were enrolled in this study. All of these monkeys were aged 7 to 14 years with BMI >30 kg/m2. They were fed with high-fat diet containing 10% of fat for the first 48 weeks. Use ultrasound to measure the IMT at bilateral common carotid arteries and their bifurcations and aorta (AO) of the monkeys, and screen out the individuals with thickened IMT for the next phase. In the next 48 weeks, some of these monkeys (n = 4) were fed with standard diet containing 3% fat. Meanwhile the other monkeys (n = 5) were fed with high-fat diet for another 48 weeks. Their serum lipid level was monitored and arterial IMT was also determined periodically. Results Serum lipid level of all 50 monkeys elevated after fed with high-fat diet for the first 48 weeks. IMT thickening at right common carotid bifurcation and aorta (AO) was thickened in 9 monkeys. Furthermore, 4 of these 9 monkeys were fed with standard diet and other 5 monkeys were fed with high-fat diet in the following 48 weeks. The serum lipid level of the 4 monkeys recovered and their IMT at RBIF and AO did not progress. However, the lipid level of other 5 monkeys remained high, and their IMT thickening of AO progressed, and plaques and calcification focuses were found at the anterior wall of aorta near the bifurcation of common iliac artery. Conclusions After high-fat diet induction for 96 weeks, serum lipid levels of rhesus monkeys elevated significantly, which subsequently caused IMT thickening and plaques formation. When IMT thickening occurred, further vascular

  4. Atherosclerosis in coronary artery and aorta in a semi-urban population by applying modified American Heart Association classification of atherosclerosis: An autopsy study

    PubMed Central

    Thej, Mothakapalli Jagadish; Kalyani, Raju; Kiran, Jayaramaiah

    2012-01-01

    Background: Ischemic heart disease (IHD) following atherosclerosis is a giant killer and the incidence of atherosclerosis in coronary arteries is rapidly increasing among Indians. The study was formulated to assess the histomorphological atherosclerotic changes in aorta and coronary arteries at autopsy by applying the modified American Heart Association classification of atherosclerosis based on morphological descriptions to find out the age and sex related prevalence of atherosclerosis in the semi-urban population of Kolar, a district in Southern India. Materials and Methods: Autopsy was conducted on 113 cases whose age ranged from 8-85 years. Autopsy was conducted by the conventional technique; heart and the aorta were removed and fixed in 10% formalin. The heart was dissected along the direction of flow of blood and aorta along the posterior surface. Microscopic assessment of the three main coronary arteries and aorta was done using the modified American Heart Association classification of atherosclerosis. Proportions were analyzed using Chi-square test. Results: The number of males was 78 (69%) and number of females was 35 (31%). Mean age was 37.11 ± 15.69 years. Increased incidence of intermediate lesions was noted in young individuals (15-34 yrs). Atherosclerotic lesions were more in left anterior descending artery compared to other coronary arteries and in abdominal aorta compared to thoracic and ascending aorta. Vulnerable plaques were more in right coronary artery. Conclusion: With cardiovascular disease attaining pandemic proportions, the study of subclinical atherosclerosis is the need of the hour to estimate the disease burden in the asymptomatic population. The increased amount of atherosclerosis (advanced and intermediate lesions) found in the young population in this study gives an indication that anti-atherogenic preventive measures need to be implemented in young individuals, so as to prevent coronary artery disease from causing premature death

  5. Human neutrophil elastase: mediator and therapeutic target in atherosclerosis.

    PubMed

    Henriksen, Peter A; Sallenave, Jean-Michel

    2008-01-01

    Human neutrophil elastase (HNE) is present within atherosclerotic plaques where it contributes to matrix degradation and weakening of the vessel wall associated with the complications of aneurysm formation and plaque rupture. It is joined by other extracellular proteases in these actions but the broad range of substrates and potency of HNE coupled with the potential for rapid increases in HNE activity associated with neutrophil degranulation in acute coronary syndromes single this disruptive protease out as therapeutic target in atherosclerotic disease. This review summarises the role of HNE in neutrophil-mediated endothelial injury and the evidence for HNE as a mediator of atherosclerotic plaque development. The therapeutic potential of HNE neutralising antiproteases, alpha-1-antitrypsin and elafin, in atherosclerosis, is discussed. PMID:18289916

  6. Prediction of cardiovascular outcomes by imaging coronary atherosclerosis

    PubMed Central

    Pathan, Faraz

    2016-01-01

    Over the last two decades, several invasive and non-invasive coronary atherosclerosis imaging modalities have emerged as predictors of cardiovascular outcomes in at-risk population. These modalities have demonstrated independent or incremental prognostic information over existing/standard risk stratification schemes, such as the Framingham risk score (FRS), by identifying characteristics of coronary artery diseases (CADs). In this review, we begin with discussing the importance of pre-test probability and quality of outcome measure, followed by specific findings of each modality in relation to prognosis. We focused on both short and long term prognostic aspects of coronary computed tomography (CT) (including coronary calcium score and coronary angiography) and magnetic resonance imaging as non-invasive tools, as well as invasive modalities including intravascular ultrasound (IVUS), optical coherence tomography (OCT), near infrared spectroscopy and Angioscopy. PMID:27500091

  7. LOX-1-Mediated Effects on Vascular Cells in Atherosclerosis.

    PubMed

    Chistiakov, Dimitry A; Orekhov, Alexander N; Bobryshev, Yuri V

    2016-01-01

    In healthy arteries, expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is almost undetectable. However, in proatherogenic conditions, LOX-1 is markedly up-regulated in vascular cells. In atherosclerosis, LOX-1 appears to be the key scavenger receptor for binding oxidized LDL (oxLDL). Notably, a positive feedback exists between LOX-1 and oxLDL. LOX-1 is involved in mediating of proatherosclerotic effects of oxLDL which result in endothelial dysfunction, proinflammatory recruitment of monocytes into the arterial intima, formation of foam cells, apoptosis of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), as well as in plaque destabilization and rupture. In this review, we consider effects of the LOX-1/oxLDL axis on several types of vascular cells such as ECs, VSMCs, and macrophages. PMID:27160316

  8. Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis.

    PubMed

    Dweck, Marc R; Aikawa, Elena; Newby, David E; Tarkin, Jason M; Rudd, James H F; Narula, Jagat; Fayad, Zahi A

    2016-07-01

    Major focus has been placed on the identification of vulnerable plaques as a means of improving the prediction of myocardial infarction. However, this strategy has recently been questioned on the basis that the majority of these individual coronary lesions do not in fact go on to cause clinical events. Attention is, therefore, shifting to alternative imaging modalities that might provide a more complete pan-coronary assessment of the atherosclerotic disease process. These include markers of disease activity with the potential to discriminate between patients with stable burnt-out disease that is no longer metabolically active and those with active atheroma, faster disease progression, and increased risk of infarction. This review will examine how novel molecular imaging approaches can provide such assessments, focusing on inflammation and microcalcification activity, the importance of these processes to coronary atherosclerosis, and the advantages and challenges posed by these techniques. PMID:27390335

  9. Cathepsins and cystatin C in atherosclerosis and obesity.

    PubMed

    Lafarge, Jean-Charles; Naour, Nadia; Clément, Karine; Guerre-Millo, Michèle

    2010-11-01

    Given the increasing prevalence of human obesity worldwide, there is an urgent need for a better understanding of the molecular mechanisms linking obesity to metabolic and cardiovascular diseases. Our knowledge is nevertheless limited regarding molecules linking adipose tissue to downstream complications. The importance of cathepsins was brought to light in this context. Through a large scale transcriptomic analysis, our group recently identified the gene encoding cathepsin S as one of the most deregulated gene in the adipose tissue of obese subjects and positively correlated with body mass index. Other members of the cathepsin family are expressed in the adipose tissue, including cathepsin K and cathepsin L. Given their implication in atherogenesis, these proteases could participate into the well established deleterious relationship between enlarged adipose tissue and increased cardiovascular risk. Here, we review the clinical and experimental evidence relevant to the role of cathepsins K, L and S and their most abundant endogenous inhibitor, cystatin C, in atherosclerosis and in obesity. PMID:20417681

  10. Venous thromboembolism has the same risk factors as atherosclerosis

    PubMed Central

    Mi, Yuhong; Yan, Shufeng; Lu, Yanhui; Liang, Ying; Li, Chunsheng

    2016-01-01

    Abstract Background: Previous studies have shown that idiopathic pulmonary embolism is positively associated with other cardiovascular events, such as myocardial infarction and stroke, suggesting a potentially important association between atherosclerosis risk factors and venous thromboembolism (VTE). We performed a meta-analysis to evaluate the correlation between risk factors for atherosclerosis and VTE. Methods: In December 2014, we searched MEDLINE and EMBASE for studies evaluating the associations between VTE and risk factors for atherosclerosis and pooled outcome data using random-effects meta-analysis. In addition, we analyzed publication bias. Results: Thirty-three case-control and cohort studies with a total of 185,124 patients met the inclusion criteria. We found that participants with body mass index (BMI) ≥30 kg/m2 had a significantly higher prevalence of VTE than those with BMI <30 kg/m2 in both case-control studies (odds ratio [OR] = 2.45, 95% confidence interval [CI]: 1.78–3.35) and cohort studies (relative risk [RR] = 2.39, 95% CI: 1.79–3.17). VTE was more prevalent in patients with hypertension than without hypertension (OR = 1.40, 95% CI: 1.06–1.84; RR = 1.36, 95% CI: 1.11–1.67). The findings were similar for VTE prevalence between patients with and without diabetes (OR = 1.78, 95% CI: 1.17–2.69; RR = 1.41, 95% CI: 1.20–1.66). Current smoking was significantly associated with VTE prevalence in case-control studies (OR = 1.34, 95% CI: 1.01–1.77), but not in cohort studies (RR = 1.29, 95% CI: 0.96–1.72). In addition, we found that total cholesterol and triglyceride concentrations were significantly higher in patients with VTE than without VTE (weighted mean differences [WMD] = 8.94 mg/dL, 95% CI: 3.52–14.35 mg/dL, and WMD = 14.00 mg/dL, 95% CI: 8.85–19.16 mg/dL, respectively). High-density lipoprotein cholesterol concentrations were significantly lower in patients with VTE

  11. [Fatty acid and lipid peroxidation in human atherosclerosis].

    PubMed

    Loeper, J; Goy, J; Emerit, J; Rozensztajn, L; Jeny, C; Bedu, O

    1983-06-01

    Plasma fatty acids and lipid peroxidation were studied in human atherosclerosis. Analysis of fatty acids in 16 controls and 32 hyperlipidemic patients showed, in the latter, a decrease in saturated fatty acids, especially palmitic and stearic acids, and an increase in unsaturated fatty acids, especially arachidonic acid. Compared to hyperlipidemic patients without arterial injury, patients with arterial injury exhibit a significant increase in malonaldehyde (MDA). In the former, MDA concentrations are significantly increased compared to controls. Therefore, peroxidation of unsaturated fatty acids may have a deleterious effect on arteries in atheroma, through the release of toxic endoperoxydes and the metabolization of arachidonic acid into thromboxane, which is a platelet aggregator. Lipid peroxidation can also be demonstrated in other diseases: we found very high MDA concentration in 11 alcoholic patients (alcoholic hepatitis, cirrhosis) and 6 patients with inflammatory conditions such as Crohn disease. PMID:6308785

  12. Cystatin C deficiency in human atherosclerosis and aortic aneurysms

    PubMed Central

    Shi, Guo-Ping; Sukhova, Galina K.; Grubb, Anders; Ducharme, Anique; Rhode, Luis H.; Lee, Richard T.; Ridker, Paul M.; Libby, Peter; Chapman, Harold A.

    1999-01-01

    The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves breakdown of the elastic laminae. Elastolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage, but whether endogenous local inhibitors counterbalance these proteases is unknown. We show here that, whereas cystatin C is normally expressed in vascular wall smooth muscle cells (SMCs), this cysteine protease inhibitor is severely reduced in both atherosclerotic and aneurysmal aortic lesions. Furthermore, increased abdominal aortic diameter among 122 patients screened by ultrasonography correlated inversely with serum cystatin C levels. In vitro, cytokine-stimulated vascular SMCs secrete cathepsins, whose elastolytic activity could be blocked when cystatin C secretion was induced by treatment with TGF-β1. The findings highlight a potentially important role for imbalance between cysteine proteases and cystatin C in arterial wall remodeling and establish that cystatin C deficiency occurs in vascular disease. PMID:10545518

  13. Emerging Roles of GPER in Diabetes and Atherosclerosis

    PubMed Central

    Barton, Matthias; Prossnitz, Eric R.

    2015-01-01

    G protein-coupled estrogen receptor (GPER) is a 7-transmembrane receptor implicated in rapid estrogen signaling. Originally cloned from vascular endothelial cells, GPER plays a central role in the regulation of vascular tone and cell growth, as well as lipid and glucose homeostasis. This review highlights our knowledge of the physiological and pathophysiological functions of GPER in the pancreas, peripheral and immune tissues, and the arterial vasculature. Recent findings of its roles in obesity, diabetes, and atherosclerosis, including the GPER-dependent regulation of lipid metabolism and inflammation, are presented. The therapeutic potential of targeting GPER-dependent pathways in chronic diseases such as coronary artery disease and diabetes and in the context of menopause is also discussed. PMID:25767029

  14. Solid Lipid Nanoparticles for Image-Guided Therapy of Atherosclerosis.

    PubMed

    Oumzil, Khalid; Ramin, Michael A; Lorenzato, Cyril; Hémadou, Audrey; Laroche, Jeanny; Jacobin-Valat, Marie Josée; Mornet, Stephane; Roy, Claude-Eric; Kauss, Tina; Gaudin, Karen; Clofent-Sanchez, Gisèle; Barthélémy, Philippe

    2016-03-16

    Although the application of nanotechnologies to atherosclerosis remains a young field, novel strategies are needed to address this public health issue. In this context, the magnetic resonance imaging (MRI) approach has been gradually investigated in order to enable image-guided treatments. In this contribution, we report a new approach based on nucleoside-lipids allowing the synthesis of solid lipid nanoparticles (SLN) loaded with iron oxide particles and therapeutic agents. The insertion of nucleoside-lipids allows the formation of stable SLNs loaded with prostacycline (PGI2) able to inhibit platelet aggregation. The new SLNs feature better relaxivity properties in comparison to the clinically used contrast agent Feridex, indicating that SLNs are suitable for image-guided therapy. PMID:26751997

  15. Extracellular matrix synthesis in vascular disease: hypertension, and atherosclerosis

    PubMed Central

    Ponticos, Markella; Smith, Barbara D.

    2014-01-01

    Extracellular matrix (ECM) within the vascular network provides both a structural and regulatory role. The ECM is a dynamic composite of multiple proteins that form structures connecting cells within the network. Blood vessels are distended by blood pressure and, therefore, require ECM components with elasticity yet with enough tensile strength to resist rupture. The ECM is involved in conducting mechanical signals to cells. Most importantly, ECM regulates cellular function through chemical signaling by controlling activation and bioavailability of the growth factors. Cells respond to ECM by remodeling their microenvironment which becomes dysregulated in vascular diseases such hypertension, restenosis and atherosclerosis. This review examines the cellular and ECM components of vessels, with specific emphasis on the regulation of collagen type I and implications in vascular disease. PMID:24474961

  16. Atherosclerosis in psoriatic disease: latest evidence and clinical implications

    PubMed Central

    Eder, Lihi; Gladman, Dafna D.

    2015-01-01

    It is widely accepted that atherosclerosis is caused by chronic low-grade inflammation that results from an interaction between immune mechanisms and metabolic abnormalities within the vessel wall. Population-based studies have found an increased cardiovascular risk in patients with psoriasis and psoriatic arthritis (PsA). This risk is higher in patients with severe disease phenotypes, such as those with severe psoriasis and with musculoskeletal inflammation. Higher levels of inflammatory biomarkers also predict the development of clinical cardiovascular events in these patients. The effect of medications used for PsA on cardiovascular risk is limited to observational studies. Antitumor necrosis factor agents and methotrexate have been associated with reduced cardiovascular risk. These data highlight the importance of screening for cardiovascular risk factors in these patients. PMID:26425147

  17. Flow Shear Stress and Atherosclerosis: A Matter of Site Specificity

    PubMed Central

    Nigro, Patrizia; Abe, Jun-ichi

    2011-01-01

    Abstract It is well accepted that atherosclerosis occurs in a site-specific manner especially at branch points where disturbed blood flow (d-flow) predisposes to the development of plaques. Investigations both in vivo and in vitro have shown that d-flow is pro-atherogenic by promoting oxidative and inflammatory states in the artery wall. In contrast, steady laminar blood flow (s-flow) is atheroprotective by inhibition of oxidative stress and inflammation in the vessel wall. The mechanism for inflammation in endothelial cells (ECs) exposed to d-flow has been well studied and includes redox-dependent activation of apoptosis signal-regulating kinase 1 (ASK1) and Jun NH2-terminal kinase (JNK) that ultimately lead to the expression of adhesive molecules. In contrast, s-flow leads to the activation of the mitogen extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) pathway that prevents pro-inflammatory signaling. Important transcriptional events that reflect the pro-oxidant and pro-inflammatory condition of ECs in d-flow include the activation of activator protein 1 (AP-1) and nuclear factor kappaB (NFκB), whereas in s-flow, activation of Krüppel-like factor 2 (KLF2) and nuclear factor erythroid 2-like 2 (Nrf2) are dominant. Recent studies have shown that protein kinase c zeta (PKCζ) is highly activated under d-flow conditions and may represent a molecular switch for EC signaling and gene expression. The targeted modulation of proteins activated in a site-specific manner holds the promise for a new approach to limit atherosclerosis. Antioxid. Redox Signal. 15, 1405–1414. PMID:21050140

  18. Association Between Psoriasis and Subclinical Atherosclerosis: A Meta-Analysis.

    PubMed

    Fang, Na; Jiang, Menglin; Fan, Yu

    2016-05-01

    The association between psoriasis and carotid intima-media thickness (CIMT) or impaired flow-mediated dilation (FMD) remains controversial. We aimed to evaluate the extent of subclinical atherosclerosis as measured by CIMT and FMD in patients with psoriasis by conducting a meta-analysis.A systematic literature search was performed using PubMed, Embase, Cochrane databases, China National Knowledge Infrastructure, and VIP databases up to February 2015. Observational studies investigating CIMT or FMD in patients with psoriasis and controls were eligible. Psoriatic patients and controls were at least age- and sex-matched. Random-effects analysis was used to estimate the weighted mean difference (WMD) and 95% confidence interval (CI) between psoriatic patients and controls.A total of 20 studies were identified and analyzed. Meta-analysis showed that psoriatic patients had a significantly thicker CIMT (WMD 0.11 mm; 95% CI 0.08-0.15) and lower FMD (WMD -2.79%; -4.14% to -1.43%) than those in controls. Subgroup analysis indicated that psoriatic arthritis appeared to have less impaired FMD (WMD -2.45%) and thinner CIMT (WMD 0.10 mm). Psoriatic patients with mean age >45 years had much thicker CIMT (WMD 0.13 mm). The impaired FMD (WMD -3.99%) seemed more pronounced in psoriatic patients with mean age <45 years.This meta-analysis suggests that patients with psoriasis are associated with excessive risk of subclinical atherosclerosis. Screening and monitoring CIMT and brachial artery FMD may be recommended to identify a subgroup of psoriatic patients at higher risk for cardiovascular events. PMID:27196459

  19. Subclinical Atherosclerosis Measures for Cardiovascular Prediction in CKD

    PubMed Central

    Sang, Yingying; Ballew, Shoshana H.; Shlipak, Michael; Katz, Ronit; Rosas, Sylvia E.; Peralta, Carmen A.; Woodward, Mark; Kramer, Holly J.; Jacobs, David R.; Sarnak, Mark J.; Coresh, Josef

    2015-01-01

    Whether inclusion of the coronary artery calcium score improves cardiovascular risk prediction in individuals with CKD, a population with unique calcium-phosphate homeostasis, is unknown. Among 6553 participants ages 45–84 years without prior cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis, coronary artery calcium score was assessed for cardiovascular risk prediction beyond the Framingham predictors in those with (n=1284) and without CKD and contrasted with carotid intima-media thickness and ankle-brachial index (two other measures of subclinical atherosclerosis). During a median follow-up of 8.4 years, 650 cardiovascular events (coronary heart disease, stroke, heart failure, and peripheral artery disease) occurred (236 events in subjects with CKD). In Cox proportional hazards models adjusted for Framingham predictors, each subclinical measure was independently associated with cardiovascular outcomes, with larger adjusted hazard ratios (HRs; per 1 SD) for coronary artery calcium score than carotid intima-media thickness or ankle-brachial index in subjects without and with CKD (HR, 1.69; 95% confidence interval [95% CI], 1.45 to 1.97 versus HR, 1.12; 95% CI, 1.00 to 1.25 and HR, 1.20; 95% CI, 1.08 to 1.32, respectively). Compared with inclusion of carotid intima-media thickness or ankle-brachial index, inclusion of the coronary artery calcium score led to greater increases in C statistic for predicting cardiovascular disease and net reclassification improvement. Coronary artery calcium score performed best for the prediction of coronary heart disease and heart failure, regardless of CKD status. In conclusion, each measure improved cardiovascular risk prediction in subjects with CKD, with the greatest improvement observed with coronary artery calcium score. PMID:25145930

  20. Recent advances in pathogenesis, assessment, and treatment of atherosclerosis

    PubMed Central

    Spence, J. David

    2016-01-01

    In recent years, there have been a number of advances in the pathogenesis and treatment of atherosclerosis and in assessing prognosis in carotid atherosclerosis. Risk stratification to improve vascular prevention by identifying patients most likely to benefit from intensive therapy is much improved by measuring carotid plaque burden. In patients with asymptomatic carotid stenosis, a number of modalities can be used to identify the 10-15% who could benefit from endarterectomy or stenting. Transcranial Doppler embolus detection, echolucency and ulceration on 3D ultrasound, intraplaque hemorrhage on magnetic resonance imaging (MRI), and reduced cerebrovascular reserve are useful already; new approaches including plaque texture on ultrasound and imaging of plaque inflammation and early calcification on positron emission tomography/computed tomography (PET/CT) are in development. The discovery that the intestinal microbiome produces vasculotoxic metabolites from dietary constituents such as carnitine in meat (particularly red meat) and phosphatidylcholine from egg yolk and other sources has revolutionized nutritional aspects of vascular prevention. Because many of these vasculotoxic metabolites are removed by the kidney, it is particularly important in patients with renal failure to limit their intake of red meat and egg yolk. A new approach to lowering low-density lipoprotein (LDL) cholesterol by blocking the action of an enzyme that destroys LDL receptors promises to revolutionize vascular prevention once less costly treatments are developed, and a new approach to vascular prevention—“treating arteries instead of risk factors”—shows promise but requires randomized trials. These advances all promise to help in the quest to prevent strokes in high-risk patients. PMID:27540477

  1. Losartan alleviates hyperuricemia-induced atherosclerosis in a rabbit model

    PubMed Central

    Zheng, Hongchao; Li, Ning; Ding, Yueyou; Miao, Peizhi

    2015-01-01

    Objective: To investigate the mechanisms underlying the therapeutic effects of losartan on hyperuricemia-induced aortic atherosclerosis, in an experimental rabbit model. Methods: Male rabbits (n = 48) were divided into control, hyperuricemia (HU), hypercholesterolemia + hyperuricemia (HC + HU) and high-purine with 30-mg/kg/d losartan (HU + losartan) groups. Serum uric acid (UA) and plasma renin and angiotensin II activities were determined. Aortic tissue specimens were analyzed for histological changes and proliferating cell nuclear antigen (PCNA). Liver tissues were sampled for quantitative analyses of liver low-density lipoprotein receptor (LDLR) mRNA and protein via reverse transcription polymerase chain reaction and western blotting. Results: After 12 weeks, serum UA and plasma renin and plasma angiotensin II activities were enhanced in the HU and HU + HC groups (P < 0.001) compared to the control, whereas in the HU + losartan group plasma renin activity was not different and serum UA concentrations as well as plasma angiotensin II activity were moderately enhanced (P < 0.05). Smooth muscle cell (SMC) PCNA expression increased strongly in the HU and HU + HC groups (P < 0.001), but was less pronounced in the HU + losartan group. In contrast, transcription and expression of LDLR mRNA and protein were significantly higher in the control and HU + losartan groups compared to the HU and HU + HC groups. Both the HU and HU + HC groups had elevated intima thickness and intima areas compared to the control and HU + losartan groups. Conclusions: Losartan can alleviate experimental atherosclerosis induced by hyperuricemia. PMID:26617751

  2. Recent advances in pathogenesis, assessment, and treatment of atherosclerosis.

    PubMed

    Spence, J David

    2016-01-01

    In recent years, there have been a number of advances in the pathogenesis and treatment of atherosclerosis and in assessing prognosis in carotid atherosclerosis. Risk stratification to improve vascular prevention by identifying patients most likely to benefit from intensive therapy is much improved by measuring carotid plaque burden. In patients with asymptomatic carotid stenosis, a number of modalities can be used to identify the 10-15% who could benefit from endarterectomy or stenting. Transcranial Doppler embolus detection, echolucency and ulceration on 3D ultrasound, intraplaque hemorrhage on magnetic resonance imaging (MRI), and reduced cerebrovascular reserve are useful already; new approaches including plaque texture on ultrasound and imaging of plaque inflammation and early calcification on positron emission tomography/computed tomography (PET/CT) are in development. The discovery that the intestinal microbiome produces vasculotoxic metabolites from dietary constituents such as carnitine in meat (particularly red meat) and phosphatidylcholine from egg yolk and other sources has revolutionized nutritional aspects of vascular prevention. Because many of these vasculotoxic metabolites are removed by the kidney, it is particularly important in patients with renal failure to limit their intake of red meat and egg yolk. A new approach to lowering low-density lipoprotein (LDL) cholesterol by blocking the action of an enzyme that destroys LDL receptors promises to revolutionize vascular prevention once less costly treatments are developed, and a new approach to vascular prevention-"treating arteries instead of risk factors"-shows promise but requires randomized trials. These advances all promise to help in the quest to prevent strokes in high-risk patients. PMID:27540477

  3. Characterization of the europium tetracycline complex as a biomarker for atherosclerosis

    NASA Astrophysics Data System (ADS)

    Courrol, Lilia C.; da Silva, Mônica N.; Sicchieri, Leticia B.

    2016-04-01

    Atherosclerosis is a narrowing of the arteries caused by an increase of atheromatous plaque: material formed by macrophage cells containing cholesterol and fatty acids, calcium and a variable amount of fibrous connective tissue. The elation between vulnerable plaques and cardiovascular events can be determined using plaque biomarkers. In this work, atherosclerotic plaques stained with different molar ratios of europium, in a potential plaque biomarker, europium tetracycline complex, were studied by fluorescence microscopy. The tetracycline antibiotic used was chlortetracycline. The growth of atherosclerotic plaque was followed during 60 days in New Zealand rabbits divided in two groups: an experimental group (EG), with nine animals and a control group (CG) with three animals. The animals in the EG received a diet with 1% of cholesterol and the animals of GC received a normal diet. The aortic arch of the animals with 60 days were cut in the vertical plane in 6 μm thick slices, which were mounted on glass slides and stained with hematoxylin an eosin and europium chlortetracycline complex (EuCTc). The fluorescence images were obtained exciting the EuCTc absorption band with a filter cube D (BP 355 - 425) and the emission was collected with a LP 470 suppression filter. Light intensity, detector gain and acquisition time were fixed for comparisons. The 20× magnified images were collected with 12 bit (or 4096 gray tones) resolution. The mean value of gray scale for each molar ratio of EuCTc was different, indicating that the complex interacts with the components of atherosclerotic plaque and the best molar ratio was 1.5 EuCTc. These results indicate the potential use of the EuCTc biomarker for atherosclerotic plaque characterization.

  4. Sulforaphane attenuates the development of atherosclerosis and improves endothelial dysfunction in hypercholesterolemic rabbits.

    PubMed

    Shehatou, George S G; Suddek, Ghada M

    2016-02-01

    The aim of the present work was to explore possible protective effects of sulforaphane (SFN) against atherosclerosis development and endothelial dysfunction in hypercholesterolemic rabbits. Rabbits were assigned to three groups of five: group I fed normal chow diet for four weeks, group II fed 1% high cholesterol diet (HCD) and group III fed HCD + SFN (0.25 mg/kg/day). Blood samples were collected for measurement of serum triglycerides (TGs), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), lactate dehydrogenase (LDH) and C-reactive protein (CRP). Aortic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and total nitrite/nitrate (NOx) were measured. Vascular reactivity and intima/media (I/M) ratio were analyzed. Nuclear factor-kappa B (NF-κB) activation in aortic endothelial cells was identified immunohistochemically. HCD induced significant increases in serum TGs, TC, LDL-C, LDH, and CRP, and aortic MDA and SOD. Moreover, HCD caused significant reductions in serum HDL-C, aortic GSH and NOx. SFN administration significantly decreased HCD-induced elevations in serum TC, LDL-C, CRP, and LDH. while significantly increased HDL-C and GSH levels and normalized aortic SOD and NOx. Additionally, SFN significantly improved rabbit aortic endothelium-dependent relaxation to acetylcholine. Moreover, SFN significantly reduced the elevation in I/M ratio. This effect was confirmed by aortic histopathologic examination. The expression of NF-κB in aortic tissue showed a marked reduction upon treatment with SFN. In conclusion, this study reveals that SFN has the ability to ameliorate HCD-induced atherosclerotic lesions progression and vascular dysfunction, possibly via its lipid-lowering and antioxidant effects and suppression of NF-κB-mediated inflammation. PMID:26490346

  5. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis.

    PubMed

    Ouimet, Mireille; Ediriweera, Hasini N; Gundra, U Mahesh; Sheedy, Frederick J; Ramkhelawon, Bhama; Hutchison, Susan B; Rinehold, Kaitlyn; van Solingen, Coen; Fullerton, Morgan D; Cecchini, Katharine; Rayner, Katey J; Steinberg, Gregory R; Zamore, Phillip D; Fisher, Edward A; Loke, P'ng; Moore, Kathryn J

    2015-12-01

    Cellular metabolism is increasingly recognized as a controller of immune cell fate and function. MicroRNA-33 (miR-33) regulates cellular lipid metabolism and represses genes involved in cholesterol efflux, HDL biogenesis, and fatty acid oxidation. Here, we determined that miR-33-mediated disruption of the balance of aerobic glycolysis and mitochondrial oxidative phosphorylation instructs macrophage inflammatory polarization and shapes innate and adaptive immune responses. Macrophage-specific Mir33 deletion increased oxidative respiration, enhanced spare respiratory capacity, and induced an M2 macrophage polarization-associated gene profile. Furthermore, miR-33-mediated M2 polarization required miR-33 targeting of the energy sensor AMP-activated protein kinase (AMPK), but not cholesterol efflux. Notably, miR-33 inhibition increased macrophage expression of the retinoic acid-producing enzyme aldehyde dehydrogenase family 1, subfamily A2 (ALDH1A2) and retinal dehydrogenase activity both in vitro and in a mouse model. Consistent with the ability of retinoic acid to foster inducible Tregs, miR-33-depleted macrophages had an enhanced capacity to induce forkhead box P3 (FOXP3) expression in naive CD4(+) T cells. Finally, treatment of hypercholesterolemic mice with miR-33 inhibitors for 8 weeks resulted in accumulation of inflammation-suppressing M2 macrophages and FOXP3(+) Tregs in plaques and reduced atherosclerosis progression. Collectively, these results reveal that miR-33 regulates macrophage inflammation and demonstrate that miR-33 antagonism is atheroprotective, in part, by reducing plaque inflammation by promoting M2 macrophage polarization and Treg induction. PMID:26517695

  6. [Fibrinogen--acute phase protein as a marker of immunological process as atherosclerosis].

    PubMed

    Rajtari, Renata; Kloch, Małgorzata; Kiec-Wilk, Beata; Kolasińska-Kloch, Władysława

    2005-01-01

    The most important CAD risk factors are: smoking, high level of LDL-cholesterol and low level of HDL-cholesterol, hypertriglyceridemia, diabetes, obesity, hypertension, men sex, age over 45 in men and over 55 in women. Carl von Rokitański was the first who suggested the role of thrombosis and fibrynolisis in the development of atherosclerosis and was the author of thrombolic theory. The recently studies show that atherosclerosis is an immuno-inflamatory process. Fibrinogen as an acute phase protein is a new marker of ischemic heart disease and its role in atherosclerosis needs further investigations. PMID:17037285

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

    SciTech Connect

    Hsieh, Yi-Chen; Lien, Li-Ming; Chung, Wen-Ting; Hsieh, Fang-I; Hsieh, Pei-Fan; Wu, Meei-Maan; Tseng, Hung-Pin; Chiou, Hung-Yi; Chen, Chien-Jen

    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. 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. {yields

  8. Explosion suppression system

    DOEpatents

    Sapko, Michael J.; Cortese, Robert A.

    1992-01-01

    An explosion suppression system and triggering apparatus therefor are provided for quenching gas and dust explosions. An electrically actuated suppression mechanism which dispenses an extinguishing agent into the path ahead of the propagating flame is actuated by a triggering device which is light powered. This triggering device is located upstream of the propagating flame and converts light from the flame to an electrical actuation signal. A pressure arming device electrically connects the triggering device to the suppression device only when the explosion is sensed by a further characteristic thereof beside the flame such as the pioneer pressure wave. The light powered triggering device includes a solar panel which is disposed in the path of the explosion and oriented between horizontally downward and vertical. Testing mechanisms are also preferably provided to test the operation of the solar panel and detonator as well as the pressure arming mechanism.

  9. mTOR Enhances Foam Cell Formation by Suppressing the Autophagy Pathway

    PubMed Central

    Li, Lingxia; Niu, Xiaolin; Dang, Xiaoyan; Li, Ping; Qu, Li; Bi, Xiaoju; Gao, Yanxia; Hu, Yanfen; Li, Manxiang; Qiao, Wanhai; Peng, Zhuo; Pan, Longfei

    2014-01-01

    Recently, autophagy has drawn more attention in cardiovascular disease as it has important roles in lipid metabolism. Mammalian target of rapamycin (mTOR) is a key regulator of autophagy; however, its effect on atherosclerosis and the underlying mechanism remains undefined. In this study, an obvious upregulation of mTOR and p-mTOR protein was observed in macrophage-derived foam cells. Blocking mTOR expression with specific small interference RNA (siRNA) dramatically suppressed foam cell formation, accompanied by a decrease of lipid deposition. Further mechanistic analysis indicated that suppressing mTOR expression significantly upregulated autophagic marker LC3 expression and downregulated autophagy substrate p62 levels, indicating that mTOR silencing triggered autophagosome formation. Moreover, blocking mTOR expression obviously accelerated neutral lipid delivery to lysosome and cholesterol efflux from foam cells, implying that mTOR could induce macrophage foam cell formation by suppressing autophagic pathway. Further, mTOR silencing significantly upregulated ULK1 expression, which was accounted for mTOR-induced foam cell formation via autophagic pathway as treatment with ULK1 siRNA dampened LC3-II levels and increased p62 expression, concomitant with lipid accumulation and decreased cholesterol efflux from foam cells. Together, our data provide an insight into how mTOR accelerates the pathological process of atherosclerosis. Accordingly, blocking mTOR levels may be a promising therapeutic agent against atherosclerotic complications. PMID:24512183

  10. Photoimmune suppression and photocarcinogenesis.

    PubMed

    Ullrich, Stephen E

    2002-03-01

    The primary cause of non-melanoma skin cancer, the most prevalent form of human neoplasia, is the ultraviolet (UV) radiation found in sunlight. Exposing mice to UV radiation induces skin cancers that are highly antigenic. Upon transfer of an UV-induced skin cancer to a normal syngeneic mouse, the tumor cells are recognized and rapidly destroyed by the immune system of the recipient. This raises the question of how these cancers avoided immune destruction during their development in the UV-irradiated host. This question was answered when it was discovered that in addition to being carcinogenic, UV radiation was also immunosuppressive. Studies with immune suppressed transplantation recipients, and biopsy proven skin cancer patients have confirmed that UV-induced immune suppression is a risk factor for skin cancer development in humans. It is of great importance, therefore, to understand the mechanisms underlying UV-induced immune suppression. The focus of this manuscript will be to use some examples from the more recent scientific literature to review the mechanisms by which UV radiation suppresses the immune response and allows for the progressive outgrowth of antigenic skin tumors. PMID:11861222

  11. Parasitic suppressing circuit

    NASA Technical Reports Server (NTRS)

    Fowler, J. T.; Raposa, F. L. (Inventor)

    1973-01-01

    A circuit for suppressing parasitic oscillations across an inductor operating in a resonant mode is described. The circuit includes a switch means and resistive means connected serially across the inductor. A unidirectional resistive-capacitive network is also connected across the inductor and to the switch means to automatically render the switch means conducting when inductive current through the inductor ceases to flow.

  12. Apple Polyphenols Decrease Atherosclerosis and Hepatic Steatosis in ApoE−/− Mice through the ROS/MAPK/NF-κB Pathway

    PubMed Central

    Xu, Zhe-Rong; Li, Jin-You; Dong, Xin-Wei; Tan, Zhong-Ju; Wu, Wei-Zhen; Xie, Qiang-Min; Yang, Yun-Mei

    2015-01-01

    In this study, we examined the effects of apple polyphenols (APs) on hyperlipidemia, atherosclerosis, hepatic steatosis and endothelial function and investigated the potential mechanisms. ApoE−/− mice were fed a western-type diet and orally treated with APs (100 mg/kg) or atorvastatin (10 mg/kg) for 12 weeks. Hyperlipidemia and atherosclerosis in the aortic sinuses and, and hepatic lipidosis were measured. The treatment with APs or atorvastatin induced a remarkable reduction in the atherosclerotic lesions and hepatic steatosis and decreased the levels of low-density lipoprotein, triglyceride, CCL-2 and VCAM-1 levels in the plasma. Conversely, the APs significantly increased the plasma levels of high-density lipoprotein (HDL) cholesterol and markedly up-regulated the glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) levels in liver tissues. Moreover, the APs treatment modulated lipid metabolism by up-regulating the transcription of associated hepatic genes including PPARα, while down-regulating the transcription of SCAP and its downstream genes associated with lipid synthesis in the liver. Histological assessment showed that the APs treatment also reduced the macrophage infiltration in the aortic root plaque and the inflammatory cells infiltrations to the liver tissues. Moreover, we confirmed that the APs treatment greatly reduced the ox-LDL-induced endothelial dysfunction and monocyte adhesion to rat aortic endothelial cells (RAECs). Mechanistically, the APs treatment suppressed the ROS/MAPK/NF-κB signaling pathway, and consequently, reduced CCL-2, ICAM-1 and VCAM-1 expression. Our results suggest that the APs are a beneficial nutritional supplement for the attenuation of atherosclerosis. PMID:26305254

  13. Atherosclerosis in Sjögren's syndrome: evidence, possible mechanisms and knowledge gaps.

    PubMed

    Valim, Valéria; Gerdts, Eva; Jonsson, Roland; Ferreira, Gilda Aparecida; Brokstad, Karl Albert; Brun, Johan G; Midtbø, Helga; Mydel, Piotr Mateusz

    2016-01-01

    Inflammation has been associated with higher cardiovascular risk in rheumatic autoimmune diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus. More recently, primary Sjögren's syndrome (pSS) was also demonstrated as an independent risk factor for cardiovascular disease, emerging as a new interesting model to study atherosclerosis in autoimmune diseases. Patients with pSS have a higher prevalence of developing traditional cardiovascular risk factors like hypertension and dyslipidaemia predisposing for endothelial dysfunction and premature atherosclerosis. However, the disease-specific mechanisms for premature atherosclerosis in pSS are not fully understood. The aim of this review was to critically analyse the current literature on cardiovascular risks in pSS and to discuss the traditional and disease-associated risk factors. We also suggest possible new mechanisms that should be explored in future research to close the current knowledge gaps on the association of pSS, premature atherosclerosis, and clinical cardiovascular disease. PMID:26812164

  14. Promotion of atherosclerosis by Helicobacter cinaedi infection that involves macrophage-driven proinflammatory responses

    PubMed Central

    Khan, Shahzada; Rahman, H. N. Ashiqur; Okamoto, Tatsuya; Matsunaga, Tetsuro; Fujiwara, Yukio; Sawa, Tomohiro; Yoshitake, Jun; Ono, Katsuhiko; Ahmed, Khandaker Ahtesham; Rahaman, Md Mizanur; Oyama, Kohta; Takeya, Motohiro; Ida, Tomoaki; Kawamura, Yoshiaki; Fujii, Shigemoto; Akaike, Takaaki

    2014-01-01

    Helicobacter cinaedi is the most common enterohepatic Helicobacter species that causes bacteremia in humans, but its pathogenicity is unclear. Here, we investigated the possible association of H. cinaedi with atherosclerosis in vivo and in vitro. We found that H. cinaedi infection significantly enhanced atherosclerosis in hyperlipidaemic mice. Aortic root lesions in infected mice showed increased accumulation of neutrophils and F4/80+ foam cells, which was due, at least partly, to bacteria-mediated increased expression of proinflammatory genes. Although infection was asymptomatic, detection of cytolethal distending toxin RNA of H. cinaedi indicated aorta infection. H. cinaedi infection altered expression of cholesterol receptors and transporters in cultured macrophages and caused foam cell formation. Also, infection induced differentiation of THP-1 monocytes. These data provide the first evidence of a pathogenic role of H. cinaedi in atherosclerosis in experimental models, thereby justifying additional investigations of the possible role of enterohepatic Helicobacter spp. in atherosclerosis and cardiovascular disease. PMID:24732347

  15. Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery

    PubMed Central

    2014-01-01

    Background Atherosclerosis, the underlying cause of cardiovascular disease, results from both genetic and environmental factors. Methods In the current study we take a systems-based approach using weighted gene co-expression analysis to identify a candidate pathway of genes related to atherosclerosis. Bioinformatic analyses are performed to identify candidate genes and interactions and several novel genes are characterized using in-vitro studies. Results We identify 1 coexpression module associated with innominate artery atherosclerosis that is also enriched for inflammatory and macrophage gene signatures. Using a series of bioinformatics analysis, we further prioritize the genes in this pathway and identify Cd44 as a critical mediator of the atherosclerosis. We validate our predictions generated by the network analysis using Cd44 knockout mice. Conclusion These results indicate that alterations in Cd44 expression mediate inflammation through a complex transcriptional network involving a number of previously uncharacterized genes. PMID:25115202

  16. Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis.

    PubMed

    Ait-Oufella, Hafid; Sage, Andrew P; Mallat, Ziad; Tedgui, Alain

    2014-05-01

    Chronic inflammation in response to lipoprotein accumulation in the arterial wall is central in the development of atherosclerosis. Both innate and adaptive immunity are involved in this process. Adaptive immune responses develop against an array of potential antigens presented to effector T lymphocytes by antigen-presenting cells, especially dendritic cells. Functional analysis of the role of different T-cell subsets identified the Th1 responses as proatherogenic, whereas regulatory T-cell responses exert antiatherogenic activities. The effect of Th2 and Th17 responses is still debated. Atherosclerosis is also associated with B-cell activation. Recent evidence established that conventional B-2 cells promote atherosclerosis. In contrast, innate B-1 B cells offer protection through secretion of natural IgM antibodies. This review discusses the recent development in our understanding of the role of T- and B-cell subsets in atherosclerosis and addresses the role of dendritic cell subpopulations in the control of adaptive immunity. PMID:24812352

  17. 2015 Russell Ross Memorial Lecture in Vascular Biology: Protective Autoimmunity in Atherosclerosis.

    PubMed

    Ley, Klaus

    2016-03-01

    Atherosclerosis is an inflammatory disease of the arterial wall. It is accompanied by an autoimmune response against apolipoprotein B-100, the core protein of low-density lipoprotein, which manifests as CD4 T cell and antibody responses. To assess the role of the autoimmune response in atherosclerosis, the nature of the CD4 T cell response against apolipoprotein B-100 was studied with and without vaccination with major histocompatibility complex-II-restricted apolipoprotein B-100 peptides. The immunologic basis of autoimmunity in atherosclerosis is discussed in the framework of theories of adaptive immunity. Older vaccination approaches are also discussed. Vaccinating Apoe(-/-) mice with major histocompatibility complex-II-restricted apolipoprotein B-100 peptides reduces atheroma burden in the aorta by ≈40%. The protective mechanism likely includes secretion of interleukin-10. Protective autoimmunity limits atherosclerosis in mice and suggests potential for developing preventative and therapeutic vaccines for humans. PMID:26821946

  18. New therapy via targeting androgen receptor in monocytes/macrophages to battle atherosclerosis.

    PubMed

    Huang, Chiung-Kuei; Pang, Haiyan; Wang, Lin; Niu, Yuanjie; Luo, Jie; Chang, Eugene; Sparks, Janet D; Lee, Soo Ok; Chang, Chawnshang

    2014-06-01

    The male sex has a higher risk to develop coronary artery diseases, including atherosclerosis. The androgen receptor (AR) is expressed in several atherosclerosis-associated cell types, including monocytes/macrophages, endothelial cells (ECs), and smooth muscle cells (SMCs), but its pathophysiological role in each cell type during the development of atherosclerotic lesions remains unclear. Using the Cre-loxP system, we selectively knocked out AR in these 3 cell types and the resultant AR knockout (ARKO) mice, monocyte/macrophage ARKO, EC-ARKO, and SMC-ARKO, were then crossed with the low-density lipoprotein receptor (LDLR) deficient (LDLR(-/-)) mice to develop monocyte/macrophage ARKO-LDLR(-/-), EC-ARKO-LDLR(-/-), and SMC-ARKO-LDLR(-/-) mice for the study of atherosclerosis. The results showed that the monocyte/macrophage ARKO-LDLR(-/-) mice had reduced atherosclerosis compared with the wild-type-LDLR(-/-) control mice. However, no significant difference was detected in EC-ARKO-LDLR(-/-) and SMC-ARKO-LDLR(-/-) mice compared with wild-type-LDLR(-/-) mice, suggesting that the AR in monocytes/macrophages, and not in ECs and SMCs, plays a major role to promote atherosclerosis. Molecular mechanism dissection suggested that AR in monocytes/macrophages upregulated the tumor necrosis factor-α, integrin β2, and lectin-type oxidized LDL receptor 1 molecules that are involved in 3 major inflammation-related processes in atherosclerosis, including monocytes/macrophages migration and adhesion to human umbilical vein ECs, and subsequent foam cell formation. Targeting AR via the AR degradation enhancer, ASC-J9, in wild-type-LDLR(-/-) mice showed similar effects as seen in monocyte/macrophage ARKO-LDLR(-/-) mice with little influence on lipid profile. In conclusion, the AR in monocytes/macrophages plays key roles in atherosclerosis and targeting AR with ASC-J9 may represent a new potential therapeutic approach to battle atherosclerosis. PMID:24688120

  19. TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis

    PubMed Central

    Mahmoud, Marwa M.; Kim, Hyejeong Rosemary; Xing, Rouyu; Hsiao, Sarah; Mammoto, Akiko; Chen, Jing; Serbanovic-Canic, Jovana; Feng, Shuang; Bowden, Neil P.; Maguire, Richard; Ariaans, Markus; Francis, Sheila E.; Weinberg, Peter D.; van der Heiden, Kim; Jones, Elizabeth A.; Chico, Timothy J.A.; Ridger, Victoria

    2016-01-01

    Rationale: Blood flow–induced shear stress controls endothelial cell (EC) physiology during atherosclerosis via transcriptional mechanisms that are incompletely understood. The mechanosensitive transcription factor TWIST is expressed during embryogenesis, but its role in EC responses to shear stress and focal atherosclerosis is unknown. Objective: To investigate whether TWIST regulates endothelial responses to shear stress during vascular dysfunction and atherosclerosis and compare TWIST function in vascular development and disease. Methods and Results: The expression and function of TWIST1 was studied in EC in both developing vasculature and during the initiation of atherosclerosis. In zebrafish, twist was expressed in early embryonic vasculature where it promoted angiogenesis by inducing EC proliferation and migration. In adult porcine and murine arteries, TWIST1 was expressed preferentially at low shear stress regions as evidenced by quantitative polymerase chain reaction and en face staining. Moreover, studies of experimental murine carotid arteries and cultured EC revealed that TWIST1 was induced by low shear stress via a GATA4-dependent transcriptional mechanism. Gene silencing in cultured EC and EC-specific genetic deletion in mice demonstrated that TWIST1 promoted atherosclerosis by inducing inflammation and enhancing EC proliferation associated with vascular leakiness. Conclusions: TWIST expression promotes developmental angiogenesis by inducing EC proliferation and migration. In addition to its role in development, TWIST is expressed preferentially at low shear stress regions of adult arteries where it promotes atherosclerosis by inducing EC proliferation and inflammation. Thus, pleiotropic functions of TWIST control vascular disease and development. PMID:27245171

  20. Pdcd4 deficiency enhances macrophage lipoautophagy and attenuates foam cell formation and atherosclerosis in mice

    PubMed Central

    Wang, L; Jiang, Y; Song, X; Guo, C; Zhu, F; Wang, X; Wang, Q; Shi, Y; Wang, J; Gao, F; Zhao, W; Chen, Y H; Zhang, L

    2016-01-01

    Macrophage foam cells, a major component of the atherosclerotic lesion, have vital roles in the development of atherosclerosis. Lipoautophagy, a type of autophagy characterized by selective delivery of lipid droplet for lysosomal degradation, may impact atherosclerosis by regulating macrophage foam cell formation. Previously, we reported that programmed cell death 4 (PDCD4), a tumor suppressor, negatively regulated autophagy in tumor cells. However, its roles in macrophage lipoautophagy, foam cell formation and atherosclerosis remain to be established. Here we found that Pdcd4 deficiency clearly improved oxidized low-density lipoproteins-impaired autophagy efflux, promoted autophagy-mediated lipid breakdown in murine macrophages and thus prevented macrophage conversion into foam cells. Importantly, Pdcd4 deficiency in mice significantly upregulated macrophage autophagy in local plaques along with attenuated lipid accumulation and atherosclerotic lesions in high-fat-fed Apolipoprotein E knockout mice. Bone marrow transplantation experiment demonstrated that PDCD4-mediated autophagy in hematopoietic cells contributed to the development of atherosclerosis. These results indicate that endogenous PDCD4 promotes for macrophage foam cell formation and atherosclerosis development via inhibiting autophagy and provides new insights into atherogenesis, suggesting that promoting macrophage autophagy through downregulating PDCD4 expression may be beneficial for treating atherosclerosis. PMID:26775706

  1. Endothelial Dysfunction: The Role of SREBP-Induced NLRP3 Inflammasome in Atherosclerosis

    PubMed Central

    Chen, Zhen; Martin, Marcy; Li, Zhao; Shyy, John Y-J.

    2014-01-01

    Purpose of review Great effort has been devoted to elucidate the molecular mechanisms by which inflammasome in macrophages contributes to atherosclerosis. Inflammasome in vascular endothelial cells (ECs) and its causal relationship with endothelial dysfunction in atherosclerosis are less understood. Here we review recent studies of inflammasome and its activation in ECs, and highlight such endothelial inflammatory response in atherosclerosis. Recent findings Inflammasomes are critical effectors in innate immunity, and their activation in macrophages and the arterial wall contributes to atherogenesis. Sterol regulatory element-binding protein 2 (SREBP2), a master regulator in cholesterol biosynthesis, can be activated in a non-canonical manner, which leads to activation of the inflammasome NOD-like receptor family pyrin domain-containing protein (NLRP) in macrophages and ECs. Results from in vitro and in vivo models suggest that SREBP2 is a key molecule in aggravating pro-inflammatory responses in ECs, and promoting atherosclerosis. Summary The SREBP-induced NLRP inflammasome and its instigation of innate immunity is an important contributor to atherosclerosis. Elucidating the underlying mechanisms will expand our understanding of endothelial dysfunction and its dynamic interaction with vascular inflammation. Furthermore, targeting SREBP-inflammasome pathways can be a therapeutic strategy for attenuating atherosclerosis. PMID:25188917

  2. Omics-based approaches to understand mechanosensitive endothelial biology and atherosclerosis.

    PubMed

    Simmons, Rachel D; Kumar, Sandeep; Thabet, Salim Raid; Sur, Sanjoli; Jo, Hanjoong

    2016-09-01

    Atherosclerosis is a multifactorial disease that preferentially occurs in arterial regions exposed to d-flow can be used to indicate disturbed flow or disturbed blood flow. The mechanisms by which d-flow induces atherosclerosis involve changes in the transcriptome, methylome, proteome, and metabolome of multiple vascular cells, especially endothelial cells. Initially, we begin with the pathogenesis of atherosclerosis and the changes that occur at multiple levels owing to d-flow, especially in the endothelium. Also, there are a variety of strategies used for the global profiling of the genome, transcriptome, miRNA-ome, DNA methylome, and metabolome that are important to define the biological and pathophysiological mechanisms of endothelial dysfunction and atherosclerosis. Finally, systems biology can be used to integrate these 'omics' datasets, especially those that derive data based on a single animal model, in order to better understand the pathophysiology of atherosclerosis development in a holistic manner and how this integrative approach could be used to identify novel molecular diagnostics and therapeutic targets to prevent or treat atherosclerosis. WIREs Syst Biol Med 2016, 8:378-401. doi: 10.1002/wsbm.1344 For further resources related to this article, please visit the WIREs website. PMID:27341633

  3. Decreased bone mineral density is associated with coronary atherosclerosis in healthy postmenopausal women

    PubMed Central

    Seo, Seok Kyo; Yun, Bo Hyon; Noe, Eun Bee; Suh, Jong Wook; Choi, Young Sik

    2015-01-01

    Objective This study aimed to assess the association between bone mineral density (BMD) and coronary atherosclerosis in healthy postmenopausal women. Methods We performed a retrospective review of 252 postmenopausal women who had visited a health promotion center for a routine checkup. BMD of the lumbar spine (L1-L4) and femoral neck was evaluated using dual-energy X-ray absorptiometry, and coronary atherosclerosis was assessed using 64-row multidetector computed tomography. Participants were divided into normal BMD and osteopenia-osteoporosis groups, according to the T-scores of their lumbar spine or femoral neck. Results Participants with osteopenia-osteoporosis had a significantly higher proportion of coronary atherosclerosis than did those with normal BMD at the lumbar spine (P=0.003) and femoral neck (P=0.004). Osteopenia-osteoporosis at the lumbar spine (odds ratio [OR], 2.86; 95% confidence interval [CI], 1.12 to 7.27) or femoral neck (OR, 3.35; 95% CI, 1.07 to 10.57) was associated with coronary atherosclerosis, after controlling for age and cardiovascular risk factors. Conclusion Decreased BMD is associated with coronary atherosclerosis in healthy postmenopausal women, independent of age and cardiovascular risk factors. Postmenopausal women with decreased BMD may have a higher risk of developing coronary atherosclerosis. PMID:25798428

  4. Tetrahydrobiopterin Deficiency and Nitric Oxide Synthase Uncoupling Contribute to Atherosclerosis Induced by Disturbed Flow

    PubMed Central

    Li, Li; Chen, Wei; Rezvan, Amir; Jo, Hanjoong; Harrison, David G.

    2011-01-01

    Objective Tetrahydrobiopterin (BH4) is a critical cofactor for Nitric Oxide (NO) synthesis by NO synthase (NOS). Recently, we demonstrated that disturbed flow produced by partial carotid ligation decreases BH4 levels in vivo. We therefore aimed to determine whether atherosclerosis induced by disturbed flow is due to BH4 deficiency and NOS uncoupling and whether increasing BH4 would prevent endothelial dysfunction, plaque inflammation and atherosclerosis. Methods and Results We produced a region of disturbed flow in ApoE−/− mice using partial carotid ligation and fed these animals a high-fat diet. This caused eNOS uncoupling as characterized by increased vascular superoxide production, altered vascular reactivity and a change in eNOS migration on low-temperature gel. These perturbations were accompanied by severe atherosclerosis, infiltration of T cells and macrophages, and an increase in cytokine production. Treatment with BH4 recoupled NOS, decreased superoxide production, imporoved endothelium-dependent vasodilatation and virtually eliminated atherosclerosis. BH4 treatment also markedly reduced vascular inflammation and improved the cytokine milieu induced by disturbed flow. Conclusions Our results highlight a key role of BH4 deficiency and NOS uncoupling in atherosclerosis induced by disturbed flow, and provide insight into the effect of modulating vascular BH4 levels on atherosclerosis and inflammation at these sites of the circulation. PMID:21512164

  5. Pdcd4 deficiency enhances macrophage lipoautophagy and attenuates foam cell formation and atherosclerosis in mice.

    PubMed

    Wang, L; Jiang, Y; Song, X; Guo, C; Zhu, F; Wang, X; Wang, Q; Shi, Y; Wang, J; Gao, F; Zhao, W; Chen, Y H; Zhang, L

    2016-01-01

    Macrophage foam cells, a major component of the atherosclerotic lesion, have vital roles in the development of atherosclerosis. Lipoautophagy, a type of autophagy characterized by selective delivery of lipid droplet for lysosomal degradation, may impact atherosclerosis by regulating macrophage foam cell formation. Previously, we reported that programmed cell death 4 (PDCD4), a tumor suppressor, negatively regulated autophagy in tumor cells. However, its roles in macrophage lipoautophagy, foam cell formation and atherosclerosis remain to be established. Here we found that Pdcd4 deficiency clearly improved oxidized low-density lipoproteins-impaired autophagy efflux, promoted autophagy-mediated lipid breakdown in murine macrophages and thus prevented macrophage conversion into foam cells. Importantly, Pdcd4 deficiency in mice significantly upregulated macrophage autophagy in local plaques along with attenuated lipid accumulation and atherosclerotic lesions in high-fat-fed Apolipoprotein E knockout mice. Bone marrow transplantation experiment demonstrated that PDCD4-mediated autophagy in hematopoietic cells contributed to the development of atherosclerosis. These results indicate that endogenous PDCD4 promotes for macrophage foam cell formation and atherosclerosis development via inhibiting autophagy and provides new insights into atherogenesis, suggesting that promoting macrophage autophagy through downregulating PDCD4 expression may be beneficial for treating atherosclerosis. PMID:26775706

  6. Asymptomatic Atherosclerosis in Egyptian Rheumatoid Arthritis Patients and Its Relation to Disease Activity

    PubMed Central

    Elshereef, Rawhya R.; Darwish, Aymen; Ali, Amal; Abdel-kadar, Mohammed; Hamdy, Lamiaa

    2015-01-01

    Aim. To detect the frequency of subclinical atherosclerosis in rheumatoid arthritis patients without clinically evident atherosclerosis and to correlate its presence with the disease activity. Patients and Methods. Our study includes 112 RA patients (group 1) and 40 healthy controls (group 11). All patients and controls were subjected to full history taking, clinical examination, and laboratory investigations. Carotid intima media wall thickness (IMT) and carotid plaques were measured in both groups by B-mode ultrasonography; also color duplex Doppler ultrasound of the brachial artery was done to detect endothelial function. Results. There is atherosclerosis in 31.3% of asymptomatic RA patients compared with only 5% in controls (P = 0.003**). A significant difference was detected in patients with and without atherosclerosis regarding duration of the disease (P = 0.0001***) and patient's age (P = 0.01*). There is highly statistical significant correlation between atherosclerosis and disease activity index. Conclusion. The frequency of subclinical atherosclerosis was high in long-term active RA patients. PMID:25737726

  7. Allergic lung inflammation promotes atherosclerosis in apolipoprotein E-deficient mice.

    PubMed

    Liu, Cong-Lin; Wang, Yi; Liao, Mengyang; Santos, Marcela M; Fernandes, Cleverson; Sukhova, Galina K; Zhang, Jin-Ying; Cheng, Xiang; Yang, Chongzhe; Huang, Xiaozhu; Levy, Bruce; Libby, Peter; Wu, Gongxiong; Shi, Guo-Ping

    2016-05-01

    Inflammation drives asthma and atherosclerosis. Clinical studies suggest that asthmatic patients have a high risk of atherosclerosis. Yet this hypothesis remains uncertain, given that Th2 imbalance causes asthma whereas Th1 immunity promotes atherosclerosis. In this study, chronic allergic lung inflammation (ALI) was induced in mice by ovalbumin sensitization and challenge. Acute ALI was induced in mice by ovalbumin and aluminum sensitization and ovalbumin challenge. Atherosclerosis was produced in apolipoprotein E-deficient (Apoe(-/-)) mice with a Western diet. When chronic ALI and atherosclerosis were produced simultaneously, ALI increased atherosclerotic lesion size, lesion inflammatory cell content, elastin fragmentation, smooth muscle cell (SMC) loss, lesion cell proliferation, and apoptosis. Production of acute ALI before atherogenesis did not affect lesion size, but increased atherosclerotic lesion CD4(+) T cells, lesion SMC loss, angiogenesis, and apoptosis. Production of acute ALI after atherogenesis also did not change atherosclerotic lesion area, but increased lesion elastin fragmentation, cell proliferation, and apoptosis. In mice with chronic ALI and diet-induced atherosclerosis, daily inhalation of a mast cell inhibitor or corticosteroid significantly reduced atherosclerotic lesion T-cell and mast cell contents, SMC loss, angiogenesis, and cell proliferation and apoptosis, although these drugs did not affect lesion area, compared with those that received vehicle treatment. In conclusion, both chronic and acute ALI promote atherogenesis or aortic lesion pathology, regardless whether ALI occurred before, after, or at the same time as atherogenesis. Antiasthmatic medication can efficiently mitigate atherosclerotic lesion pathology. PMID:26898714

  8. Myeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis

    PubMed Central

    Baumgartl, Julia; Baudler, Stephanie; Scherner, Maximilian; Babaev, Vladimir; Makowski, Liza; Suttles, Jill; McDuffie, Marcia; Fazio, Sergio; Kahn, C. Ronald; Hotamisligil, Gökhan S.; Krone, Wilhelm; Linton, MacRae; Brüning, Jens C.

    2014-01-01

    Summary Inflammatory processes play an important role in the pathogenesis of vascular diseases, and insulin-resistant diabetes mellitus type 2 represents an important risk factor for the development of atherosclerosis. To directly address the role of insulin resistance in myeloid lineage cells in the development of atherosclerosis, we have created mice with myeloid lineagespecific inactivation of the insulin receptor gene. On an ApoE-deficient background, MphIRKO mice developed smaller atherosclerotic lesions. There was a dramatic decrease in LPS-stimulated IL-6 and IL-1β expression in the presence of macrophage autonomous insulin resistance. Consistently, while insulin-resistant IRS-2-deficient mice on an ApoE-deficient background display aggravated atherosclerosis, fetal liver cell transplantation of IRS-2–/–ApoE–/– cells ameliorated atherosclerosis in Apo-E-deficient mice. Thus, systemic versus myeloid cell-restricted insulin resistance has opposing effects on the development of atherosclerosis, providing direct evidence that myeloid lineage autonomous insulin signaling provides proinflammatory signals predisposing to the development of atherosclerosis. PMID:16581002

  9. Mutation in KERA Identified by Linkage Analysis and Targeted Resequencing in a Pedigree with Premature Atherosclerosis

    PubMed Central

    van Capelleveen, Julian C.; Bot, Ilze; de Jager, Saskia C.; van Eck, Miranda; Jolley, Jennifer; Kuiper, Johan; Stephens, Jonathon; Albers, Cornelius A.; Vosmeer, C. Ruben; Kruize, Heleen; Geerke, Daan P.; van der Wal, Allard C.; van der Loos, Chris M.; Kastelein, John J. P.; Trip, Mieke D.

    2014-01-01

    Aims Genetic factors explain a proportion of the inter-individual variation in the risk for atherosclerotic events, but the genetic basis of atherosclerosis and atherothrombosis in families with Mendelian forms of premature atherosclerosis is incompletely understood. We set out to unravel the molecular pathology in a large kindred with an autosomal dominant inherited form of premature atherosclerosis. Methods and Results Parametric linkage analysis was performed in a pedigree comprising 4 generations, of which a total of 11 members suffered from premature vascular events. A parametric LOD-score of 3.31 was observed for a 4.4 Mb interval on chromosome 12. Upon sequencing, a non-synonymous variant in KERA (c.920C>G; p.Ser307Cys) was identified. The variant was absent from nearly 28,000 individuals, including 2,571 patients with premature atherosclerosis. KERA, a proteoglycan protein, was expressed in lipid-rich areas of human atherosclerotic lesions, but not in healthy arterial specimens. Moreover, KERA expression in plaques was significantly associated with plaque size in a carotid-collar Apoe−/− mice (r2 = 0.69; p<0.0001). Conclusion A rare variant in KERA was identified in a large kindred with premature atherosclerosis. The identification of KERA in atherosclerotic plaque specimen in humans and mice lends support to its potential role in atherosclerosis. PMID:24879339

  10. [Risk factors for coronary atherosclerosis. Comparison between two Argentine regions].

    PubMed

    Coniglio, R I; Castillo, S; Dahinten, E; Doubnia, M I; Vasquez, L A; Colombo, O; Estevez, S; Duffard, M C; Lopez Torres, J; Rodriguez, M D

    1994-01-01

    The prevalence of risk factors for coronary atherosclerosis were studied in two population samples, Northeast (Posadas, n = 498) and South (Viedma, C. Rivadavia and Cipolletti, n = 652) of 20 years and older, males and females. The diet in the Northeast (n = 102) contained more monounsaturated acids and polyunsaturated acids than the one in the South (n = 62), 9.5 +/- 4.1 vs. 8.1 +/- 3.5% TCV (Total Caloric Value) (P < 0.02) and 8.1 +/- 4.1 vs. 6.2 +/- 3.0% TCV (P < 0.001) respectively. The P/S relationship was greater in the Northeast, 1.02 +/- 0.44 vs. 0.85 +/- 0.50 (P < 0.001). Total cholesterol (TC) in the Northeast was less than in the South, in males 176 +/- 41 vs. 213 +/- 43 mg/dl (P < 0.001); CLDL (LDL cholesterol) 109 +/- 37 vs. 141 +/- 41 mg/dl (P < 0.001). The most frequent risk factors in the South vs. Northeast (males) were: TC > or = 240 mg/dl, 26.7% vs. 9.5% (P < 0.001); LDL-C > or = 160 mg/dl, 30.3% vs. 10.9% (P < 0.001); Cig > or = 10/d (equal or more than 10 cigarettes per day), 30.0% vs. 16.4% (P < 0.001). The hypertension prevalence (HTA, 160/95), in males, was higher in the Northeast than in the South, 23.7% vs. 11.5% (P < 0.001). BMI > 27 Kg/m2 was higher in the women of Northeast than in the South, 38.4% vs. 24.2% (P < 0.001). In the males of the Northeast, the combination Cig > or = 10/d and HTA, 4.1 vs 0.9% was more common; in the South Cig > or = 10/d and LDL-C > or = 160 mg/d, 8.2% vs. 1.8% (P < 0.001) was more common. The differences in the prevalence of the risk factors between the population samples indicate the need to plan the prevention of coronary atherosclerosis locally. PMID:7997127

  11. Alleviation of high-fat diet-induced atherosclerosis and glucose intolerance by a novel GLP-1 fusion protein in ApoE(-/-) mice.

    PubMed

    Kong, Yuelin; Tong, Yue; Chen, Chen; Gao, Mingming; Gao, Xiangdong; Yao, Wenbing

    2016-07-01

    We have previously constructed an engineered anti-diabetic fusion protein using glucagon-like peptide-1 and the globular domain of adiponectin. Herein, we evaluated the therapeutic effects of this fusion protein (GAD) on high-fat diet (HFD)-fed ApoE(-/-) mice. The lipid-lowering effect of GAD was determined in C57BL/6 mice using a lipid tolerance test. The effects of GAD on HFD-induced glucose intolerance, atherosclerosis, and hepatic steatosis were evaluated in HFD-fed ApoE(-/-) mice using glucose tolerance test, histological examinations and real-time quantitative PCR. The anti-inflammation activity of GAD was assessed in vitro on macrophages. GAD improved lipid metabolism in C57BL/6 mice. GAD treatment alleviated glucose intolerance, reduced blood lipid level, and attenuated atherosclerotic lesion in HFD-fed ApoE(-/-) mice, which was associated with a repressed macrophage infiltration in the vessel wall. GAD treatment also blocked hepatic macrophage infiltration and prevented hepatic inflammation. GAD suppressed lipopolysaccharide-triggered inflammation responses on macrophages, which can be abolished by H89, an inhibitor of protein kinase A. These findings demonstrate that GAD is able to generate a variety of metabolic benefits in HFD-fed ApoE(-/-) mice and indicate that this engineered fusion protein is a promising lead structure for anti-atherosclerosis drug discovery. PMID:26832342

  12. Pressure suppression containment system

    DOEpatents

    Gluntz, Douglas M.; Townsend, Harold E.

    1994-03-15

    A pressure suppression containment system includes a containment vessel surrounding a reactor pressure vessel and defining a drywell therein containing a non-condensable gas. An enclosed wetwell pool is disposed inside the containment vessel, and a gravity driven cooling system (GDCS) pool is disposed above the wetwell pool in the containment vessel. The wetwell pool includes a plenum for receiving the non-condensable gas carried with steam from the drywell following a loss-of coolant-accident (LOCA). The wetwell plenum is vented to a plenum above the GDCS pool following the LOCA for suppressing pressure rise within the containment vessel. A method of operation includes channeling steam released into the drywell following the LOCA into the wetwell pool for cooling along with the non-condensable gas carried therewith. The GDCS pool is then drained by gravity, and the wetwell plenum is vented into the GDCS plenum for channeling the non-condensable gas thereto.

  13. Pressure suppression containment system

    DOEpatents

    Gluntz, D.M.; Townsend, H.E.

    1994-03-15

    A pressure suppression containment system includes a containment vessel surrounding a reactor pressure vessel and defining a drywell therein containing a non-condensable gas. An enclosed wetwell pool is disposed inside the containment vessel, and a gravity driven cooling system (GDCS) pool is disposed above the wetwell pool in the containment vessel. The wetwell pool includes a plenum for receiving the non-condensable gas carried with steam from the drywell following a loss-of-coolant-accident (LOCA). The wetwell plenum is vented to a plenum above the GDCS pool following the LOCA for suppressing pressure rise within the containment vessel. A method of operation includes channeling steam released into the drywell following the LOCA into the wetwell pool for cooling along with the non-condensable gas carried therewith. The GDCS pool is then drained by gravity, and the wetwell plenum is vented into the GDCS plenum for channeling the non-condensable gas thereto. 6 figures.

  14. Multi-Ethnic Study of Atherosclerosis: objectives and design.

    PubMed

    Bild, Diane E; Bluemke, David A; Burke, Gregory L; Detrano, Robert; Diez Roux, Ana V; Folsom, Aaron R; Greenland, Philip; Jacob, David R; Kronmal, Richard; Liu, Kiang; Nelson, Jennifer Clark; O'Leary, Daniel; Saad, Mohammed F; Shea, Steven; Szklo, Moyses; Tracy, Russell P

    2002-11-01

    The Multi-Ethnic Study of Atherosclerosis was initiated in July 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease (CVD) in a population-based sample of 6,500 men and women aged 45-84 years. The cohort will be selected from six US field centers. Approximately 38% of the cohort will be White, 28% African-American, 23% Hispanic, and 11% Asian (of Chinese descent). Baseline measurements will include measurement of coronary calcium using computed tomography; measurement of ventricular mass and function using cardiac magnetic resonance imaging; measurement of flow-mediated brachial artery endothelial vasodilation, carotid intimal-medial wall thickness, and distensibility of the carotid arteries using ultrasonography; measurement of peripheral vascular disease using ankle and brachial blood pressures; electrocardiography; and assessments of microalbuminuria, standard CVD risk factors, sociodemographic factors, life habits, and psychosocial factors. Blood samples will be assayed for putative biochemical risk factors and stored for use in nested case-control studies. DNA will be extracted and lymphocytes will be immortalized for genetic studies. Measurement of selected subclinical disease indicators and risk factors will be repeated for the study of progression over 7 years. Participants will be followed through 2008 for identification and characterization of CVD events, including acute myocardial infarction and other coronary heart disease, stroke, peripheral vascular disease, and congestive heart failure; therapeutic interventions for CVD; and mortality. PMID:12397006

  15. Signaling through LRP1: Protection from atherosclerosis and beyond

    PubMed Central

    Boucher, Philippe; Herz, Joachim

    2010-01-01

    The low-density lipoprotein receptor-related protein (LRP1) is a multifunctional cell surface receptor that belongs to the LDL receptor (LDLR) gene family and that is widely expressed in several tissues. LRP1 consists of an 85-KDa membrane-bound carboxyl fragment (β chain) and a non-covalently attached 515-KDa (α chain) amino-terminal fragment. Through its extracellular domain, LRP1 binds at least 40 different ligands ranging from lipoprotein and protease inhibitor complex to growth factors and extracellular matrix proteins. LRP-1 has also been shown to interact with scaffolding and signaling proteins via its intracellular domain in a phosphorylation-dependent manner and to function as a co-receptor partnering with other cell surface or integral membrane proteins. LRP-1 is thus implicated in two major physiological processes: endocytosis and regulation of signaling pathways, which are both involved in diverse biological roles including lipid metabolism, cell growth/differentiation processes, degradation of proteases, and tissue invasion. The embryonic lethal phenotype obtained after target disruption of the LRP-1 gene in the mouse highlights the biological importance of this receptor and revealed a critical, but yet undefined role in development. Tissue-specific gene deletion studies also reveal an important contribution of LRP1 in vascular remodeling, foam cell biology, the central nervous system, and in the molecular mechanisms of atherosclerosis. PMID:20920479

  16. The simulation of magnetic resonance elastography through atherosclerosis.

    PubMed

    Thomas-Seale, L E J; Hollis, L; Klatt, D; Sack, I; Roberts, N; Pankaj, P; Hoskins, P R

    2016-06-14

    The clinical diagnosis of atherosclerosis via the measurement of stenosis size is widely acknowledged as an imperfect criterion. The vulnerability of an atherosclerotic plaque to rupture is associated with its mechanical properties. The potential to image these mechanical properties using magnetic resonance elastography (MRE) was investigated through synthetic datasets. An image of the steady state wave propagation, equivalent to the first harmonic, can be extracted directly from finite element analysis. Inversion of this displacement data yields a map of the shear modulus, known as an elastogram. The variation of plaque composition, stenosis size, Gaussian noise, filter thresholds and excitation frequency were explored. A decreasing mean shear modulus with an increasing lipid composition was identified through all stenosis sizes. However the inversion algorithm showed sensitivity to parameter variation leading to artefacts which disrupted both the elastograms and quantitative trends. As noise was increased up to a realistic level, the contrast was maintained between the fully fibrous and lipid plaques but lost between the interim compositions. Although incorporating a Butterworth filter improved the performance of the algorithm, restrictive filter thresholds resulted in a reduction of the sensitivity of the algorithm to composition and noise variation. Increasing the excitation frequency improved the techniques ability to image the magnitude of the shear modulus and identify a contrast between compositions. In conclusion, whilst the technique has the potential to image the shear modulus of atherosclerotic plaques, future research will require the integration of a heterogeneous inversion algorithm. PMID:27130475

  17. An Early-Stage Atherosclerosis Research Model Based on Microfluidics.

    PubMed

    Zheng, Wenfu; Huang, Rong; Jiang, Bo; Zhao, Yuyun; Zhang, Wei; Jiang, Xingyu

    2016-04-01

    The arterial microenvironment plays a vital role in the pathology of atherosclerosis (AS). However, the interplay between the arterial microenvironment and atherogenesis remains unclear, partially due to the gap between cell culture and animal experiments. Addressing this problem, the present study reports a microfluidic AS model reconstituting early-stage AS. Physiological or AS-prone hemodynamic conditions are recapitulated on the model. The on-chip model recaptures the atherogenic responses of endothelial cells (ECs) in ways that the Petri dish could not. Significant cytotoxicity of a clinical anti-atherosclerotic drug probucol is discovered on the model, which does not appear on Petri dish but is supported by previous clinical evidence. Moreover, the anti-AS efficiency of platinum-nanoparticles (Pt-NPs) on the model shows excellent consistency with animal experiments. The early-stage AS model shows an excellent connection between Petri dish and animal experiments and highlights its promising role in bridging fundamental AS research, drug screening, and clinical trials. PMID:26890624

  18. Pulp Stone, Haemodialysis, End-stage Renal Disease, Carotid Atherosclerosis

    PubMed Central

    Patil, Santosh; Sinha, Nidhi

    2013-01-01

    Objectives: The aim of this study was to determine the relationship between the presence of pulp calcification and carotid artery calcification on the dental panoramic radiographs in End Stage Renal Disease (ESRD) patients who were on haemodialysis. Methods: A total of 112 End Stage Renal Disease (ESRD) patients on who were haemodialysis participated in this study. The periapical and the panoramic radiographs for all the patients were evaluated for the presence or absence of the narrowing of the dental pulps and for pulp stones in the pulp chambers and the pulp canals. The panoramic radiographs were also evaluated to determine the carotid calcification. Results: Carotid calcifications were detected in none of the patients. 84 (74.99%) patients had dental pulp narrowing, and 38 (33.92%) patients had pulp stones. There was no statistical correlation between pulp narrowing and Carotid Artery Calcification (CAC) in the haemodialysis patient group. There was also no statistical correlation between pulp stones and CAC in the haemodialysis patients. Conclusion: However, the incidental finding of CAC on a panoramic radiograph can provide life-saving information for the vascular disease patients, but in the present study, no significant relationship was found between the presence of the pulpal calcification and CAC in the ESRD patients who were on haemodialysis. Therefore, the presence of pulp calcification does not seem to serve as a diagnostic marker for carotid atherosclerosis. PMID:23905147

  19. ABCG5/ABCG8 in cholesterol excretion and atherosclerosis.

    PubMed

    Yu, Xiao-Hua; Qian, Kun; Jiang, Na; Zheng, Xi-Long; Cayabyab, Francisco S; Tang, Chao-Ke

    2014-01-20

    Cholesterol is essential for the growth and function of all mammalian cells, but abnormally increased blood cholesterol is a major risk factor for atherosclerotic cardiovascular disease. ATP-binding cassette (ABC) transporters G5 (ABCG5) and G8 (ABCG8) form an obligate heterodimer that limits intestinal absorption and facilitates biliary secretion of cholesterol and phytosterols. Consistent with their function, ABCG5 and ABCG8 are located on the apical membrane of enterocytes and hepatocytes. Liver X receptor is the major positive regulator of ABCG5 and ABCG8 expression. Mutations in either of the two genes cause sitosterolemia, a condition in which cholesterol and plant sterols accumulate in the circulation leading to premature cardiovascular disease. Overexpression of ABCG5 and ABCG8 in mice retards diet-induced atherosclerosis because of reduced circulating and hepatic cholesterol. In the current review, we summarize recent developments and propose a future framework that provides new perspectives on the regulation of cholesterol metabolism and treatment of atherosclerotic cardiovascular disease. PMID:24252657

  20. Atherosclerosis: A Link Between Lipid Intake and Protein Tyrosine Nitration

    PubMed Central

    Upmacis, Rita K.

    2009-01-01

    Atherosclerosis, a disease characterized by plaque formation in the arterial wall that can lead to heart attack and stroke, is a principal cause of death in the world. Since the 1990’s, protein nitrotyrosine formation has been known to occur in the atherosclerotic plaque. This potentially damaging reaction occurs as a result of tyrosine modification by reactive nitrogen species, such as nitrogen dioxide radical, which forms upon peroxynitrite decomposition or nitrite oxidation by hydrogen peroxide-activated peroxidase enzymes. The presence of protein-bound nitrotyrosine can be considered an indicator of a loss in the natural balance of oxidants and antioxidants, and as such, there is an emerging view that protein-bound nitrotyrosine may be a risk factor for cardiovascular disease. This review brings together evidence that the accumulation of protein nitrotyrosine during atherogenesis is more widespread than initially thought (as its presence can be detected not only in the lesion but also in the blood stream and other organs) and is closely linked to lipid intake. PMID:20157638

  1. Vascular health late after Kawasaki disease: implications for accelerated atherosclerosis.

    PubMed

    Cheung, Yiu-Fai

    2014-11-01

    Kawasaki disease (KD), an acute vasculitis that primarily affects young children, is the most common acquired paediatric cardiovascular disease in developed countries. While sequelae of arterial inflammation in the acute phase of KD are well documented, its late effects on vascular health are increasingly unveiled. Late vascular dysfunction is characterized by structural alterations and functional impairment in term of arterial stiffening and endothelial dysfunction and shown to involve both coronary and systemic arteries. Further evidence suggests that continuous low grade inflammation and ongoing active remodeling of coronary arterial lesions occur late after acute illness and may play a role in structural and functional alterations of the arteries. Potential importance of genetic modulation on vascular health late after KD is implicated by associations between mannose binding lectin and inflammatory gene polymorphisms with severity of peripheral arterial stiffening and carotid intima-media thickening. The changes in cholesterol and lipoproteins levels late after KD further appear similar to those proposed to be atherogenic. While data on adverse vascular health are less controversial in patients with persistent or regressed coronary arterial aneurysms, data appear conflicting in individuals with no coronary arterial involvements or only transient coronary ectasia. Notwithstanding, concerns have been raised with regard to predisposition of KD in childhood to accelerated atherosclerosis in adulthood. Until further evidence-based data are available, however, it remains important to assess and monitor cardiovascular risk factors and to promote cardiovascular health in children with a history of KD in the long term. PMID:25550701

  2. Atherosclerosis and flow in carotid arteries with authentic geometries.

    PubMed

    Goubergrits, L; Affeld, K; Fernandez-Britto, J; Falcon, L

    2002-01-01

    The influence of blood flow on the depositions and development of atherosclerotic lesions have been observed and described since the 19th century. Observations have shown that depositions correlate with regions of low wall shear stress. However, the exact correlations between depositions, vessel geometry and flow parameters are not yet known. The purpose of this study was the quantification of atherosclerosis risk factors in carotid bifurcation. This artery has attracted particular interest because lesions are often found in this bifurcation. Post mortem, the arteries are excised and vessel casts are produced. Afterwards, the arteries are analyzed morphometrically. The vessel casts are used for the assessment of some geometrical parameters. 31 carotid bifurcations were analyzed in this study. Eight vessel casts were digitized and rendered three-dimensional mathematical models of the arteries. These data were imported by the computational fluid dynamics program FLUENT. Further, the blood flow was reconstructed in a computer model based on the individual vessel geometry. The flow parameters, such as velocity, pressure and wall shear stress were computed. At the same time the geometrical parameters and wall alterations are known. This permits the comparison of the anatomical shape and its flow with the distribution and level of the wall alterations. PMID:12122275

  3. The European Atherosclerosis Research Study (EARS): design and objectives.

    PubMed

    1994-06-01

    The European Atherosclerosis Research Study--EARS--is a multicentre collaborative project sponsored by the European Community. Its main objective is to study, in young people, the biological expression of a paternal history of premature acute myocardial infarction (AMI) and the relative share of heredity and environment in this expression. In 14 centres in 11 European countries, the offspring of fathers who suffered from a documented AMI before the age of 55 years (cases) are compared with age- and sex-matched control individuals. Genetic variables (restriction fragment length polymorphisms of candidate genes), lifestyle variables and biochemical variables that are known or suspected to play a role in the development of coronary heart disease (CHD), are studied. The cultural and ethnic diversity within Europe allows a thorough investigation of the relative importance and the potential interactions of genetics and environment in the pathogenesis of CHD. A standardized core methodology and centralized storage of blood samples with particular types of analyses systematically carried out in one or a few specialized laboratories, from a strong basis for valid cross-cultural analyses. The results of this study will offer new clues for the modelling of individual risk for developing CHD. PMID:7960370

  4. Secondhand Smoke and Periodontal Disease: Atherosclerosis Risk in Communities Study

    PubMed Central

    Slade, Gary D.; Beck, James D.; Ágústsdóttir, Helga

    2011-01-01

    Objectives. We investigated the relationship between secondhand smoke and periodontal disease in nonsmokers. Methods. We undertook a cross-sectional analysis of the Atherosclerosis Risk in Communities study with 2739 lifetime nonsmokers aged 53–74 years, unexposed to other sources of tobacco, who received a complete periodontal examination at visit 4. Exposure was reported as average hours per week in close contact with a smoker in the preceding year. We defined severe periodontitis as 5 or more periodontal sites with probing pocket depth of 5 millimeters or more and clinical attachment levels of 3 millimeters or more in those sites. Other outcomes were extent of periodontal probing depths of 4 millimeters or more and extent of clinical attachment levels of 3 millimeters or more. Results. In a binary logistic regression model, adjusted odds of severe periodontitis for those exposed to secondhand smoke 1 to 25 hours per week increased 29% (95% confidence interval = 1.0, 1.7); for those exposed to secondhand smoke 26 hours per week, the odds were twice as high (95% confidence interval = 1.2, 3.4) as for those who were unexposed. Conclusions. Exposure to secondhand smoke and severe periodontitis among nonsmokers had a dose-dependent relationship. PMID:21551377

  5. HDL-Mimetic PLGA Nanoparticle To Target Atherosclerosis Plaque Macrophages

    PubMed Central

    Sanchez-Gaytan, Brenda L.; Fay, Francois; Lobatto, Mark E.; Tang, Jun; Ouimet, Mireille; Kim, YongTae; van der Staay, Susanne E. M.; van Rijs, Sarian M.; Priem, Bram; Zhang, Liangfang; Fisher, Edward A; Moore, Kathryn J.; Langer, Robert; Fayad, Zahi A.; Mulder, Willem J M

    2015-01-01

    High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle composed of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA–HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA–HDL nanoparticles in atherosclerotic plaques, which colocalized with plaque macrophages. This biomimetic platform integrates the targeting capacity of HDL biomimetic nanoparticles with the characteristic versatility of PLGA-based nanocarriers. PMID:25650634

  6. Pentoxifylline Decreases Serum Level of Adhesion Molecules in Atherosclerosis Patients

    PubMed Central

    Mohammadpour, Amir Hooshang; Falsoleiman, Homa; Shamsara, Jamal; Abadi, Ghazaleh Allah; Rasooli, Ramin; Ramezani, Mohammad

    2014-01-01

    Background: Inflammation is involved in development, progression, and complications of atherosclerotic disease. Clinical studies have indicated that the level of monocyte chemoattractant protein 1 (MCP-1), IL-18, and adhesion molecules correlates with the severity of atherosclerosis and can predict future cardiovascular events. Experimental studies have shown pentoxifylline (PTX) reduces these factors in animal models. The purpose of the present pilot study was to evaluate effect of PTX on a group of inflammatory biomarkers in patients with coronary artery disease (CAD). Methods: Forty patients with angiographically documented CAD, who fulfilled inclusion and exclusion criteria, were entered in the double-blind, randomized, pilot clinical study. The patients were randomly given PTX (400 mg three times daily) or placebo (3 tab/day) for 2 months. Serum concentrations of MCP-1, IL-18, intercellular adhesion Molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured before and at the end of intervention by enzyme-linked immunosorbant assay. Results: Our study showed that the serum levels of ICAM-1 and VCAM-1 was decreased in the study population after two-month treatment (P<0.05). Conclusion: Based on the results of our pilot study, administration of PTX in CAD patients significantly decreases adhesion molecules levels. PMID:24375159

  7. High-Density Lipoprotein, Lecithin: Cholesterol Acyltransferase, and Atherosclerosis

    PubMed Central

    Ossoli, Alice; Pavanello, Chiara

    2016-01-01

    Epidemiological data clearly show the existence of a strong inverse correlation between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and the incidence of coronary heart disease. This relation is explained by a number of atheroprotective properties of HDL, first of all the ability to promote macrophage cholesterol transport. HDL are highly heterogeneous and are continuously remodeled in plasma thanks to the action of a number of proteins and enzymes. Among them, lecithin:cholesterol acyltransferase (LCAT) plays a crucial role, being the only enzyme able to esterify cholesterol within lipoproteins. LCAT is synthetized by the liver and it has been thought to play a major role in reverse cholesterol transport and in atheroprotection. However, data from animal studies, as well as human studies, have shown contradictory results. Increased LCAT concentrations are associated with increased HDL-C levels but not necessarily with atheroprotection. On the other side, decreased LCAT concentration and activity are associated with decreased HDL-C levels but not with increased atherosclerosis. These contradictory results confirm that HDL-C levels per se do not represent the functionality of the HDL system. PMID:27302716

  8. High-Density Lipoprotein, Lecithin: Cholesterol Acyltransferase, and Atherosclerosis.

    PubMed

    Ossoli, Alice; Pavanello, Chiara; Calabresi, Laura

    2016-06-01

    Epidemiological data clearly show the existence of a strong inverse correlation between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and the incidence of coronary heart disease. This relation is explained by a number of atheroprotective properties of HDL, first of all the ability to promote macrophage cholesterol transport. HDL are highly heterogeneous and are continuously remodeled in plasma thanks to the action of a number of proteins and enzymes. Among them, lecithin:cholesterol acyltransferase (LCAT) plays a crucial role, being the only enzyme able to esterify cholesterol within lipoproteins. LCAT is synthetized by the liver and it has been thought to play a major role in reverse cholesterol transport and in atheroprotection. However, data from animal studies, as well as human studies, have shown contradictory results. Increased LCAT concentrations are associated with increased HDL-C levels but not necessarily with atheroprotection. On the other side, decreased LCAT concentration and activity are associated with decreased HDL-C levels but not with increased atherosclerosis. These contradictory results confirm that HDL-C levels per se do not represent the functionality of the HDL system. PMID:27302716

  9. Biomechanical factors in atherosclerosis: mechanisms and clinical implications†

    PubMed Central

    Kwak, Brenda R.; Bäck, Magnus; Bochaton-Piallat, Marie-Luce; Caligiuri, Giuseppina; Daemen, Mat J.A.P.; Davies, Peter F.; Hoefer, Imo E.; Holvoet, Paul; Jo, Hanjoong; Krams, Rob; Lehoux, Stephanie; Monaco, Claudia; Steffens, Sabine; Virmani, Renu; Weber, Christian; Wentzel, Jolanda J.; Evans, Paul C.

    2014-01-01

    Blood vessels are exposed to multiple mechanical forces that are exerted on the vessel wall (radial, circumferential and longitudinal forces) or on the endothelial surface (shear stress). The stresses and strains experienced by arteries influence the initiation of atherosclerotic lesions, which develop at regions of arteries that are exposed to complex blood flow. In addition, plaque progression and eventually plaque rupture is influenced by a complex interaction between biological and mechanical factors—mechanical forces regulate the cellular and molecular composition of plaques and, conversely, the composition of plaques determines their ability to withstand mechanical load. A deeper understanding of these interactions is essential for designing new therapeutic strategies to prevent lesion development and promote plaque stabilization. Moreover, integrating clinical imaging techniques with finite element modelling techniques allows for detailed examination of local morphological and biomechanical characteristics of atherosclerotic lesions that may be of help in prediction of future events. In this ESC Position Paper on biomechanical factors in atherosclerosis, we summarize the current ‘state of the art’ on the interface between mechanical forces and atherosclerotic plaque biology and identify potential clinical applications and key questions for future research. PMID:25230814

  10. Is Cardiovascular Reactivity Associated With Atherosclerosis Among Hypertensives?

    PubMed Central

    Gianaros, Peter J.; Bleil, Maria E.; Muldoon, Matthew F.; Jennings, J. Richard; Sutton-Tyrrell, Kim; McCaffery, Jeanne M.; Manuck, Stephen B.

    2016-01-01

    Exaggerated cardiovascular reactivity to behavioral challenges among otherwise healthy individuals has been associated with carotid atherosclerosis. We evaluated whether a similar relationship exists among hypertensives, who are at a heightened atherosclerotic risk. Untreated, hypertensive men (n=251; age range, 40 to 70 years; 197 white, 54 black) completed a standardized battery of behavioral challenges while their blood pressure responses to the battery were measured. Mean and maximum carotid intima-media thickness and the occurrence of carotid plaques were subsequently determined using B-mode ultrasonography. Although greater systolic and diastolic responses to the battery were associated with greater mean and maximum intima-media thickness in univariate analyses (P<0.01), only diastolic reactivity showed a unique association with mean and maximum carotid intima-media thickness after multivariate adjustment for age, race, socioeconomic status, smoking and alcohol use, body mass index, lipid profile, glucose and insulin concentrations, and resting blood pressure (P<0.05). Carotid plaque occurrence was associated with greater systolic reactivity (P=0.05) and was marginally associated with greater diastolic reactivity (P=0.07) in univariate analyses, but neither systolic nor diastolic reactivity was uniquely associated with the presence of carotid plaques after multivariate risk-factor adjustment. Among hypertensives, exaggerated behaviorally evoked cardiovascular reactivity appears to be uniquely associated with greater carotid intima-media thickness but not with carotid plaque occurrence. PMID:12411471

  11. Nitric oxide-oxygen radicals interactions in atherosclerosis.

    PubMed

    Rubbo, H; Batthyany, C; Radi, R

    2000-01-01

    Atherosclerosis is one of the most common diseases and the principal cause of death in western civilization. The pathogenesis of this disease can be explained on the basis of the 'oxidative-modification hypothesis,' which proposes that low-density lipoprotein (LDL) oxidation represents a key early event. Nitric oxide (*NO) regulates critical lipid membrane and lipoprotein oxidation events by a) contributing to the formation of more potent secondary oxidants from superoxide (i.e.: peroxynitrite), and b) its antioxidant properties through termination reactions with lipid radicals to possibly less reactive secondary nitrogen-containing products (LONO, LOONO). Relative rates of production and steady state concentrations of superoxide and *NO and cellular sites of production will profoundly influence the expression of differential oxidant injury-enhancing and protective effects of *NO. Full understanding of the physiological roles of *NO, coupled with detailed insight into *NO regulation of oxygen radical-dependent reactions, will yield a more rational basis for intervention strategies directed toward oxidant-dependent atherogenic processes. PMID:15693284

  12. Effect of Xin Mai Jia on atherosclerosis in rats.

    PubMed

    Li, P; Pan, G P; Jia, M; Wang, Q Q; Guo, Z G; Zhao, F R; Lei, G L; Wan, G R; Wan, G M

    2015-01-01

    We investigated the therapeutic effect of Xin Mai Jia (XMJ) on atherosclerosis (AS) in rats. Rat models of AS were established by peritoneally injecting vitamin D, feeding a high-fat diet, and inducing balloon injuries in rats. The stomachs of the rats were irrigated continuously for 10 weeks with XMJ. Blood lipid- and hemorheology-related indices of blood samples were detected. Pathological changes in the right common carotid arterial tissues were also determined. The protein expression levels of endothelial nitric oxide synthase, angio-tensin-1, and endothelin-1 were determined by western blotting. XMJ reduced cholesterol, trigylecride, and low-density lipoprotein levels as well as blood viscosity, sedimentation, and hematocrit. Furthermore, XMJ alleviated vascular endothelial injury and reduced/eliminated atherosclerotic plaques. In contrast, XMJ significantly increased the endothelium-dependent relaxing response of the AS rat models. The western blotting results showed that XMJ upregulated endothelial nitric oxide synthase but downregulated angiotensin-1 and endothelin-1. XMJ prevented the development of AS by regulating blood lipid levels, hemorheology, and vascular function. PMID:26125801

  13. Menstrual suppression: current perspectives

    PubMed Central

    Hillard, Paula Adams

    2014-01-01

    Menstrual suppression to provide relief of menstrual-related symptoms or to manage medical conditions associated with menstrual morbidity or menstrual exacerbation has been used clinically since the development of steroid hormonal therapies. Options range from the extended or continuous use of combined hormonal oral contraceptives, to the use of combined hormonal patches and rings, progestins given in a variety of formulations from intramuscular injection to oral therapies to intrauterine devices, and other agents such as gonadotropin-releasing hormone (GnRH) antagonists. The agents used for menstrual suppression have variable rates of success in inducing amenorrhea, but typically have increasing rates of amenorrhea over time. Therapy may be limited by side effects, most commonly irregular, unscheduled bleeding. These therapies can benefit women’s quality of life, and by stabilizing the hormonal milieu, potentially improve the course of underlying medical conditions such as diabetes or a seizure disorder. This review addresses situations in which menstrual suppression may be of benefit, and lists options which have been successful in inducing medical amenorrhea. PMID:25018654

  14. Vibrotactile suppression of tinnitus

    NASA Astrophysics Data System (ADS)

    Lenhardt, Martin L.

    2002-05-01

    At the Society's 142nd meeting, the efficacy of high frequency bone conducted stimulation in suppressing tinnitus was presented. The hypothesized mechanism was the reprogramming of frequency tuning of auditory neurons in the central nervous system, secondarily to peripheral hearing loss. This mechanism is unlikely in cases of tinnitus in the presence of normal audiometric sensitivity. There is the possibility that hearing loss above 10 kHz can play a role in tinnitus, an association not thoroughly explored. Somatomotor stimulation influencing the quality of tinnitus has been reported, as have interconnections of the auditory and somatosensory systems. There would appear to be an evolutionary advantage of linking the sensorimotor organization of the external ear and the auditory function of the brainstem in sound localization. Thus, stimulation of the pinna and post auricular area may be a means of suppressing tinnitus. To that end a thin aluminum ceramic bimorph was constructed to fit on the inner surface of the pinna. When driven by low (<100 Hz) and high (>10 kHz) frequencies multiplied by MHz carriers, demodulation in the skin resulted in vibrotactile stimulation. Tactile stimulation was an adjunct to the high frequencies resulting in a multimodal suppressive effect in a small pilot study.

  15. Systemic Delivery of MicroRNA-181b Inhibits Nuclear Factor-κB Activation, Vascular Inflammation, and Atherosclerosis in Apolipoprotein E–Deficient Mice

    PubMed Central

    Wara, A.K.M.; Icli, Basak; Shvartz, Eugenia; Tesmenitsky, Yevgenia; Belkin, Nathan; Li, Dazhu; Blackwell, Timothy S.; Sukhova, Galina K.; Croce, Kevin; Feinberg, Mark W.

    2014-01-01

    Rationale Activated nuclear factor (NF)-κB signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-κB may provide a novel strategy to limit chronic inflammation. Objective To examine the role of microRNA-181b (miR-181b) in endothelial NF-κB signaling and effects on atherosclerosis. Methods and Results MiR-181b expression was reduced in the aortic intima and plasma in apolipoprotein E–deficient mice fed a high-fat diet. Correspondingly, circulating miR-181b in the plasma was markedly reduced in human subjects with coronary artery disease. Systemic delivery of miR-181b resulted in a 2.3-fold overexpression of miR-181b in the aortic intima of apolipoprotein E–deficient mice and suppressed NF-κB signaling revealed by bioluminescence imaging and reduced target gene expression in the aortic arch in apolipoprotein E–deficient/NF-κB-luciferase transgenic mice. MiR-181b significantly inhibited atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4+ T cells in the vessel wall. Mechanistically, miR-181b inhibited the expression of the target gene importin-α3, an effect that reduced NF-κB nuclear translocation specifically in the vascular endothelium of lesions, whereas surprisingly leukocyte NF-κB signaling was unaffected despite a 7-fold overexpression of miR-181b. Our findings uncover that NF-κB nuclear translocation in leukocytes does not involve importin-α3, but rather importin-α5, which miR-181b does not target, highlighting that inhibition of NF-κB signaling in the endothelium is sufficient to mediate miR-181b's protective effects. Conclusions Systemic delivery of miR-181b inhibits the activation of NF-κB and atherosclerosis through cell-specific mechanisms in the vascular endothelium. These findings support the rationale that delivery of miR-181b may provide a novel therapeutic approach to treat chronic inflammatory diseases

  16. Endothelial dysfunction and progressive coronary atherosclerosis: sequential invasive studies in a patient with multiple cardiac risk factors.

    PubMed

    Chander, R; Kuhner, P A; Laws Houghton, J

    2001-08-01

    This manuscript describes sequential angiographic, endothelial and vasoreactivity characteristics of the coronary arterial circulation in a middle-aged patient with multiple cardiac risk factors who developed hemodynamically significant coronary atherosclerosis over a 6-year period. A 56-year-old woman demonstrated marked angiographic progression of coronary atherosclerosis over time beginning with minor luminal irregularities in the setting of severe endothelial dysfunction. The association of endothelial dysfunction, ineffective cardiac risk factor management and progressive atherosclerosis is discussed. PMID:11481511

  17. Race-gender differences in the association of trait anger with subclinical carotid artery atherosclerosis: the Atherosclerosis Risk in Communities Study.

    PubMed

    Williams, Janice E; Couper, David J; Din-Dzietham, Rebecca; Nieto, F Javier; Folsom, Aaron R

    2007-06-01

    This paper examines the association between trait anger and subclinical carotid artery atherosclerosis among 14,098 Black or White men and women, aged 48-67 years, in the Atherosclerosis Risk in Communities Study cohort, 1990-1992. Trait anger was assessed using the 10-item Spielberger Trait Anger Scale. Carotid atherosclerosis was determined by an averaged measure of the wall intimal-medial thickness (IMT) of the carotid bifurcation and of the internal and common carotids, measured by high-resolution B-mode ultrasound. In the full study cohort, trait anger and carotid IMT were significantly and positively associated (p = 0.04). In race-gender stratified analysis, the association was strongest and independent only in Black men, among whom a significant trait anger-carotid IMT relation was observed for both the overall trait anger measure (p = 0.004) and the anger reaction dimension (p = 0.001). In Black men, carotid IMT levels increased across categories of overall trait anger and anger reaction, resulting in clinically significant differences (67 microm (95% confidence interval: 23, 110) and 82 microm (95% confidence interval: 40, 125), respectively) from low to high anger. Sociodemographic, lifestyle, anthropometric, and biologic cardiovascular disease risk factors appear to mediate the relation in Black women, White men, and White women. In conclusion, these findings document disparate race-gender patterns in the association of trait anger with subclinical carotid artery atherosclerosis. PMID:17363362

  18. Decreased Naive and Increased Memory CD4+ T Cells Are Associated with Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Olson, Nels C.; Doyle, Margaret F.; Jenny, Nancy Swords; Huber, Sally A.; Psaty, Bruce M.; Kronmal, Richard A.; Tracy, Russell P.

    2013-01-01

    Background Adaptive immunity has been implicated in atherosclerosis in animal models and small clinical studies. Whether chronic immune activation is associated with atherosclerosis in otherwise healthy individuals remains underexplored. We hypothesized that activation of adaptive immune responses, as reflected by higher proportions of circulating CD4+ memory cells and lower proportions of naive cells, would be associated with subclinical atherosclerosis. Methods and Findings We examined cross-sectional relationships of circulating CD4+ naive and memory T cells with biomarkers of inflammation, serologies, and subclinical atherosclerosis in 912 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Circulating CD4+ naive cells were higher in women than men and decreased with age (all p-values <0.0001). European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and H. Pylori titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI))  = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β =  0.02 (0.006, 0.04); naive: β = −0.02 (−0.004, −0.03)]. Conclusions These results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4+ T cells, and with innate immunity (inflammation), in atherosclerosis. These data are also consistent with the hypothesis that immunosenescence accelerates chronic diseases by

  19. Sex Differences in Subclinical Atherosclerosis by Race/Ethnicity in the Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Kim, Catherine; Diez-Roux, Ana V.; Nettleton, Jennifer A.; Polak, Joseph F.; Post, Wendy S.; Siscovick, David S.; Watson, Karol E.; Vahratian, Anjel M.

    2011-01-01

    Sex differences in cardiovascular disease mortality are more pronounced among non-Hispanic whites than other racial/ethnic groups, but it is unknown whether this variation is present in the earlier subclinical stages of disease. The authors examined racial/ethnic variation in sex differences in coronary artery calcification (CAC) and carotid intimal media thickness at baseline in 2000–2002 among participants (n = 6,726) in the Multi-Ethnic Study of Atherosclerosis using binomial and linear regression. Models adjusted for risk factors in several stages: age, traditional cardiovascular disease risk factors, behavioral risk factors, psychosocial factors, and adult socioeconomic position. Women had a lower prevalence of any CAC and smaller amounts of CAC when present than men in all racial/ethnic groups. Sex differences in the prevalence of CAC were more pronounced in non-Hispanic whites than in African Americans and Chinese Americans after adjustment for traditional cardiovascular disease risk factors, and further adjustment for behavioral factors, psychosocial factors, and socioeconomic position did not modify these results (for race/sex, Pinteraction = 0.047). Similar patterns were observed for amount of CAC among adults with CAC. Racial/ethnic variation in sex differences for carotid intimal media thickness was less pronounced. In conclusion, coronary artery calcification is differentially patterned by sex across racial/ethnic groups. PMID:21685409