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Sample records for irbesartan suppressing atherosclerosis

  1. Selective Macrophage Ascorbate Deficiency Suppresses Early Atherosclerosis

    PubMed Central

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

    2010-01-01

    SUMMARY To test whether severe ascorbic acid deficiency in macrophages affects progression of early atherosclerosis, we used fetal liver cell transplantation to generate atherosclerosis-prone apolipoprotein E-deficient (apoE?/?) mice that selectively lacked the ascorbate transporter (SVCT2) in hematopoietic cells, including macrophages. After 13-weeks of chow diet, apoE?/? mice lacking the SVCT2 in macrophages had surprisingly less aortic atherosclerosis, decreased lesion macrophage numbers, and increased macrophage apoptosis compared to control-transplanted mice. Serum lipid levels were similar in both groups. Peritoneal macrophages lacking the SVCT2 had undetectable ascorbate, increased susceptibility to H2O2-induced mitochondrial dysfunction and apoptosis, decreased expression of genes for COX2, IL1?, IL6, and decreased lipopolysaccharide-stimulated NF-?B and anti-apoptotic gene expression. These changes were associated with decreased expression of both the receptor for advanced glycation end products (RAGE) and HIF-1?, either or both of which could have been proximal causes of decreased macrophage activation and apoptosis in ascorbate-deficient macrophages. PMID:20974251

  2. [Irbesartan in clinical practice].

    PubMed

    Malishevski?, M V

    2012-01-01

    Irbesartan is a noncompetitive angiotensin II receptor type 1 antagonist which has been successfully used for more than 10 years for the treatment of hypertensive disease. In a dose of 150-300 mg/day irbesartan produces long term effect for 24 hours. Its antihypertensive efficacy is augmented by concomitant administration of hydrochlorothiazide. Irbesartan reduces left ventricular hypertrophy and increases probability of maintenance of sinus rhythm after cardioversion of atrial fibrillation. Renoprotective effects of irbesartan has been demonstrated both at early and late stages of kidney involvement in patients with type 2 diabetes. Therapeutic efficacy and safety of irbesartan ensure high level of patients compliance. Irbesartan as monotherapy or as combination with hydrochlorothiazide demonstrate contemporary therapeutic approach to arterial hypertension as well as to diabetic nephropathy both at its early and late stages. PMID:23237398

  3. 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

  4. 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 ...

  5. 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 ...

  6. 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.

  7. Effects of Ang II Receptor Blocker Irbesartan on Adipose Tissue Function in Mice with Metabolic Disorders

    PubMed Central

    Maeda, Akinobu; Tamura, Kouichi; Wakui, Hiromichi; Ohsawa, Masato; Azushima, Kengo; Uneda, Kazushi; Kobayashi, Ryu; Tsurumi-Ikeya, Yuko; Kanaoka, Tomohiko; Dejima, Toru; Ohki, Koji; Haku, Sona; Yamashita, Akio; Umemura, Satoshi

    2014-01-01

    Recent studies indicate that the functional renin-angiotensin system (RAS) exists in the adipose tissue. The adipose tissue RAS is proposed in the pathophysiology of metabolic disorders. In the present study, we examined therapeutic effects of irbesartan, an angiotensin II (Ang II) type 1 receptor (AT1R)-specific blocker, in genetically obese diabetic KKAy mice, a model of human metabolic disorders without any dietary loading, with our focus on the analysis on possible effect of irbesartan on the adipose tissue. The treatment with irbesartan significantly lowered systolic blood pressure with a concomitant decrease in body weight in KKAy mice. In addition, irbesartan significantly decreased the adipose leptin mRNA expression and tended to decrease IL-6 mRNA expression in the adipose tissue of KKAy mice. Furthermore irbesartan preserved the adipose gene expression of AT1R-associated protein (ATRAP), an endogenous inhibitory molecule of tissue AT1R signaling, with a concomitant tendency of up-regulation of adipose tissue ATRAP/AT1R ratio. Collectively, these results suggest that the irbesartan-induced beneficial suppressive effect on the leptin-IL-6 axis in the adipose tissue in KKAy mice is partly mediated by a trend of up-regulation of the adipose ATRAP/AT1R ratio as one of pleiotropic effects of irbesartan. PMID:24834011

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

    PubMed

    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 AND 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-kB (NF-?B) 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-?B 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-?B signaling and the FAK signaling pathway, respectively, thus protecting ApoE-/- mice against atherosclerosis. PMID:26712802

  9. 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-?B (NF-?B) 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-?B 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-?B signaling and the FAK signaling pathway, respectively, thus protecting ApoE?/? mice against atherosclerosis. PMID:26712802

  10. 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 atherosclerosis. PMID:26936421

  11. Suppression of experimental atherosclerosis by the Ca++-antagonist lanthanum. Possible role of calcium in atherogenesis.

    PubMed Central

    Kramsch, D M; Aspen, A J; Apstein, C S

    1980-01-01

    Agents inhibiting calcium deposition into arteries are known to suppress atherosclerosis in animals. However, the precise role of calcium in atherogenesis is unknown. In this study, the specific Ca2+-antagonist lanthanum was used to attempt suppression of experimental atherosclerosis and to gain more insight into the possible effects of calcium on atherogenesis. Rabbits were fed an atherogenic diet with and without increasing doses of LaCl3. All cholesterol-fed rabbits showed marked increases in serum cholesterol and ca2+. Untreated atherogenic animals revealed pronounced gross and microscopic atherosclerosis and striking increases in the aortic content of cholesterol, collagen, "elastin," and calcium as well as of elastin calcium, polar amino acids, and cholesterol. With increasing LaCl3 dosage these abnormalities progressively decreased and were completely abolished at the highest dose. The ingested La3+ was absorbed only in small quantities and had no discernible effect on the calcium and connective tissue content of bone, skin, lung, heart, and skeletal muscle nor on myocardial function (left ventricle pressure and left ventricle dp/dt) or myocardial and muscle content in ATP and creatine phosphate. The data suggest that shifts in arterial Ca2+-distribution may play a decisive part in atherogenesis, and provision of arterial calcium homeostasis by La3+ a pivotal role in its prevention, despite hypercholesteremia. Other inhibitors of calcium deposition into arteries may exert their protective effect by similar mechanisms. However, a direct inhibition of atherogenesis by La3+ cannot entirely be ruled out in this study, although no direct effects of La3+ on tissue metabolism have as yet been reported. Images PMID:7364947

  12. 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

  13. 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-?, IL-6, IL-1?, 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 ? (LXR?) and peroxisome proliferator-activated receptor ?1 (PPAR?1) promoters, which are both enriched with CpG sites. This led to overexpression of LXR? and PPAR?, 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

  14. Irbesartan

    MedlinePLUS

    ... a diet that is low in fat and salt, maintaining a healthy weight, exercising at least 30 ... Do not use salt substitutes containing potassium without talking to your doctor. If your doctor prescribes a low-salt or low-sodium diet, ...

  15. 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

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

    PubMed

    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

  17. 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 Edeficient (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 Krppel-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

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

    PubMed

    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

    2015-08-01

    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 Krppel-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. Comprehensive overview: efficacy, tolerability, and cost-effectiveness of irbesartan

    PubMed Central

    Gialama, Fotini; Maniadakis, Nikos

    2013-01-01

    Background Hypertension represents a major health problem, affecting more than one billion adults worldwide. Irbesartan, an angiotensin II receptor blocker, is considered to be a highly effective treatment in the management of hypertension. The purpose of this review is to evaluate the efficacy, safety and tolerability profile , and cost-effectiveness of treatment with irbesartan in hypertension. Methods A review of the literature was conducted using the electronic PubMed and Cochrane Library databases and the Health Economic Evaluations Database of search terms relating to irbesartan efficacy, tolerability, and cost-effectiveness, and the results were utilized. Results Findings from the present analysis show that irbesartan either as monotherapy or in combination with other antihypertensive agents can achieve significant reductions in blood pressure, both systolic and diastolic, compared with alternative treatment options. Irbesartan was also found to have a renoprotective effect independent of its blood pressure-lowering in patients with type 2 diabetes and nephropathy. Furthermore, irbesartan demonstrated an excellent safety and tolerability profile , with either lower or equal adverse events compared with placebo and other alternative treatments. In terms of economic analyses, compared with other antihypertensive therapy alternatives, irbesartan was found to be a preferred option, that is less costly and more effective. Conclusion The evidence indicates that treating patients with hypertension alone or with type 2 diabetes and nephropathy using irbesartan can control hypertension, prolong life, and reduce costs in relation to existing alternatives. PMID:24124375

  2. 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; Dunr, 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

  3. 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

  4. Novel angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induced vasoconstriction in canine coronary arteries and human platelet aggregation.

    PubMed

    Li, P; Fukuhara, M; Diz, D I; Ferrario, C M; Brosnihan, K B

    2000-01-01

    This study was conducted to investigate whether the novel orally active nonpeptide angiotensin II (Ang II) AT(1) receptor antagonist irbesartan interacts with the thromboxane A(2)/prostaglandin endoperoxide H(2) (TxA(2)/PGH(2)) receptor in canine coronary arteries and human platelets. Coronary artery rings were isolated from male dog hearts (n = 18) and isometric tension of vascular rings was measured continuously at optimal basal tension in organ chambers. Autoradiographic binding of [(3)H]SQ29,548, a TxA(2) receptor antagonist, in canine coronary sections was determined. Blood for platelet aggregation studies was collected by venous puncture from healthy human volunteers (n = 6) who were free of aspirin-like agents for at least 2 weeks. Vascular reactivity and platelet aggregation in response to the TxA(2) analogs U46619 and autoradioagraphic receptor binding to the TxA(2) receptor antagonist [(3)H]SQ29,548 were studied with and without irbesartan. The TxA(2) analog U46619 produced dose-dependent vasoconstriction in coronary rings (EC(50) = 11.6 +/- 1.5 nM). Pretreatment with irbesartan inhibited U46619-induced vasoconstriction, and the dose-response curve was shifted to the right in a dose-dependent manner. The EC(50) of U46619 was increased 6- and 35-fold in the presence of 1 and 10 microM of irbesartan without a change of maximal contraction. At 1 microM, irbesartan is 2-fold more potent than the AT(1) receptor antagonist losartan in the inhibition of U46619-induced vasoconstriction in canine coronary arteries. In contrast, neither AT(1) receptor antagonists (CV11974 and valsartan), the AT(2) receptor antagonist PD123319, nor the angiotensin converting enzyme inhibitor lisinopril had any effect on U46619-induced coronary vasoconstriction. Irbesartan did not change potassium chloride-induced vasoconstriction; however, irbesartan did inhibit the vasoconstriction mediated by another TxA(2)/PGH(2) receptor agonist prostaglandin F(2alpha) (PGF(2alpha)). Neither the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester nor the cyclooxygenase inhibitor indomethacin had any effect on irbesartan's attenuation of U46619-induced vasoconstriction. Irbesartan specifically reversed U46619-preconstricted coronary artery rings with and without endothelium in a dose-dependent manner. Irbesartan at high concentrations significantly competed for [(3)H]SQ29,548 binding in canine coronary sections. U46619 stimulated dose-dependent human platelet aggregation of platelet-rich plasma. Preincubation with irbesartan significantly inhibited platelet aggregation in a concentration-dependent manner. In conclusion, the dual antagonistic actions of irbesartan by acting at both the AT(1) and TxA(2) receptors in blood vessels and platelets may overall enhance its therapeutic profile in the treatment of hypertension, atherosclerosis, and arterial thrombosis. PMID:10604953

  5. Acidic Polysaccharide Extracts from Gastrodia Rhizomes Suppress the Atherosclerosis Risk Index through Inhibition of the Serum Cholesterol Composition in Sprague Dawley Rats Fed a High-Fat Diet

    PubMed Central

    Kim, Kui-Jin; Lee, Ok-Hwan; Han, Chan-Kyu; Kim, Young-Chan; Hong, Hee-Do

    2012-01-01

    Obesity is associated with a broad spectrum of cardio-metabolic disturbances, including atherosclerosis and cardiovascular disease (CDV). A high-fat diet has been shown to cause an elevation of the plasma cholesterol levels in humans, and the control of serum cholesterol has been demonstrated to be important in the prevention of CVD and atherosclerosis. The aims of this study were to demonstrate that crude and acidic polysaccharide extracts from Gastrodia rhizomes suppress atherosclerosis through the regulation of serum lipids in Sprague Dawley (SD) rats fed a high-fat diet. We examined the concentrations of serum lipids, including total cholesterol, triglycerides, high-density lipoproteins (HDL) cholesterol, and low-density lipoproteins (LDL) cholesterol, in SD rats fed a high-fat diet and evaluated the atherogenic index. Here, we show that both crude and acidic polysaccharide extracts from Gastrodia rhizomes inhibited the total cholesterol and LDL levels. Moreover, there was a significantly suppressed atherosclerosis risk due to the acidic polysaccharide extract from Gastrodia rhizome. Taken together, our results suggested that acidic polysaccharide extracts from Gastrodia rhizomes might be beneficial for lowering the incidence of CVD and atherosclerosis by reducing the de novo synthesis of total cholesterol and the LDL levels. PMID:22408412

  6. Endothelial effects of antihypertensive treatment: focus on irbesartan

    PubMed Central

    Negro, Roberto

    2008-01-01

    The endothelium is characterized by a wide range of important homeostatic functions. It participates in the control of hemostasis, blood coagulation and fibrinolysis, platelet and leukocyte interactions with the vessel wall, regulation of vascular tone, and of blood pressure. Many crucial vasoactive endogenous compounds are produced by the endothelial cells to control the functions of vascular smooth muscle cells and of circulating blood cells. These complex systems determine a fine equilibrium which regulates the vascular tone. Impairments in endothelium-dependent vasodilation lead to the so called endothelial dysfunction. Endothelial dysfunction is then characterized by unbalanced concentrations of vasodilating and vasoconstricting factors, the most important being represented by nitric oxide (NO) and angiotensin II (AT II). High angiotensin-converting enzyme (ACE) activity leads to increased AT II generation, reduced NO levels with subsequent vasoconstriction. The net acute effect results in contraction of vascular smooth muscle cells and reduced lumen diameter. Furthermore, when increased ACE activity is chronically sustained, increase in growth, proliferation and differentiation of the vascular smooth muscle cells takes place; at the same time, a decrease in the anti-proliferative action by NO, a decrease in fibinolysis and an increase in platelets aggregation may be observed. AT II is then involved not only in the regulation of blood pressure, but also in vascular inflammation, permeability, smooth muscle cells remodelling, and oxidative stress which in turn lead to atherosclerosis and increased cardiovascular risk. Given the pivotal role exerted by AT II in contributing to alteration of endothelial function, treatment with ACE inhibitors or angiotensin receptor blockers (ARBs) may be of particular interest to restore a physiological activity of endothelial cells. In this view, the blockade of the renin-angiotensin system (RAS), has been shown to positively affect the endothelial function, beyond the antihypertensive action displayed by these compounds. In this review, attention has been specifically focused on an ARB, irbesartan, to examine its effects on endothelial function. PMID:18629353

  7. Abscisic acid ameliorates atherosclerosis by suppressing macrophage and CD4+ T cell recruitment into the aortic wall

    PubMed Central

    Guri, Amir J.; Misyak, Sarah A.; Hontecillas, Raquel; Hasty, Alyssa; Liu, Dongmin; Si, Hongwei; Bassaganya-Riera, Josep

    2009-01-01

    Abscisic acid (ABA) is a natural phytohormone which improves insulin sensitivity and reduces adipose tissue inflammation when supplemented into diets of obese mice. The objective of this study was to investigate the mechanisms by which abscisic acid (ABA) prevents or ameliorates atherosclerosis. Apolipoprotein E-deficient (ApoE ?/?) mice were fed high-fat diets with or without ABA for 84 days. Systolic blood pressure was assessed on days 0, 28, 56, and 72. Gene expression, immune cell infiltration, and histological lesions were evaluated in the aortic root wall. Human aortic endothelial cells were used to examine the effect of ABA on 3, 5-cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) production in vitro. We report that ABA-treated mice had significantly improved systolic blood pressure and decreased accumulation of F4/80+CD11b+ macrophages and CD4+ T cells in aortic root walls. At the molecular level, ABA significantly enhanced aortic endothelial nitric oxide synthase (eNOS) and tended to suppress aortic vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) expression and plasma MCP-1 concentrations. ABA also caused a dose-dependent increase in intracellular concentrations of cAMP and NO and upregulated eNOS mRNA expression in human aortic endothelial cells. This is the first report showing that ABA prevents or ameliorates atherosclerosis-induced hypertension, immune cell recruitment into the aortic root wall, and upregulates aortic eNOS expression in ApoE?/? mice. PMID:20092994

  8. Fibroblast Growth Factor 21 Prevents Atherosclerosis by Suppression of Hepatic Sterol Regulatory Element-Binding Protein-2 and Induction of Adiponectin in Mice

    PubMed Central

    Lin, Zhuofeng; Pan, Xuebo; Wu, Fan; Ye, Dewei; Zhang, Yi; Wang, Yu; Jin, Leigang; Lian, Qizhou; Huang, Yu; Ding, Hong; Triggle, Chris; Wang, Kai

    2015-01-01

    Background— Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor α and γ, the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However, the role of FGF21 in the cardiovascular system remains elusive. Methods and Results— The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E−/− mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E−/− mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apolipoprotein E−/−mice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterol synthesis and attenuation of hypercholesterolemia. Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E−/− mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterol regulatory element-binding protein-2. Conclusions— FGF21 protects against atherosclerosis via fine tuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels. PMID:25794851

  9. The value of irbesartan in the management of hypertension.

    PubMed

    Bramlage, Peter; Durand-Zaleski, Isabelle; Desai, Nisha; Pirk, Olaf; Hacker, Caroline

    2009-08-01

    Elevated blood pressure levels are highly prevalent and are a major reason for cardiovascular events and thus place a significant financial burden on healthcare systems worldwide. Guidelines recommend five first-line anti-hypertensive drug classes, but compelling indications may indicate favoring one drug class over another. Angiotensin receptor blockers (ARBs) have demonstrated a blood pressure lowering efficacy which is at least comparable with other drug classes, including ACE inhibitors (ACE-I), beta-blockers, calcium channel blockers and diuretics. They have, in addition, a lower side effect profile than other drug classes and patients on ARBs are more persistent with therapy. Compelling indications for the use of ARBs are heart failure, post-myocardial infarction, diabetic nephropathy, proteinuria/microalbuminuria, left ventricular hypertrophy, atrial fibrillation, metabolic syndrome and ACE-I induced cough. The ARB irbesartan has demonstrated a high efficacy in lowering blood pressure, which has been shown to be at least comparable with ACE-Is and superior to other ARBs such as losartan and valsartan. This translated into a better cost-effectiveness for irbesartan than for valsartan and losartan in the treatment of hypertension. In addition, irbesartan has been shown to be effective in both early and late stage diabetic nephropathy. It has further demonstrated considerable cost savings over standard therapy including beta-blockers, diuretics and non-dihydropyridine calcium channel blockers at all stages of kidney disease. Based on efficacy data from the Irbesartan Diabetic Nephropathy Trial and Reduction of Endpoints in NIDDM (non insulin dependant diabetes melitis) with the Angiotensin II Antagonist Losartan Study, it has also demonstrated cost savings over losartan in late stage renal disease. While both losartan and irbesartan are registered for the treatment of late stage diabetic nephropathy, irbesartan is also registered for early stage diabetic nephropathy in the EU. In summary, the data from randomized clinical trials on the efficacy of antihypertensive drugs provides an indication of their real value to patients. In addition observational data from clinical practice and proven end-organ protection in diabetic nephropathy provides further evidence of the true value of irbesartan compared to other ARBs in the treatment of hypertension. PMID:19601700

  10. Dealcoholized red wine containing known amounts of resveratrol suppresses atherosclerosis in hypercholesterolemic rabbits without affecting plasma lipid levels.

    PubMed

    Wang, Zhirong; Zou, Jiangang; Cao, Kejiang; Hsieh, Tze-Chen; Huang, Yuanzhu; Wu, Joseph M

    2005-10-01

    Moderate consumption of red wine is associated with a reduced risk of coronary heart disease (CHD). This phenomenon is based on data from epidemiological observations known as the French paradox, and has been attributed to CHD-protective phytochemicals, e.g. resveratrol in red wine. Since red wine also contains alcohol, it is conceivable that alcohol interacts with resveratrol to elicit the observed cardioprotective effects. To determine whether resveratrol has alcohol-independent affects, we compared cardioprotective properties of dealcoholized Chinese red wine with alcohol-containing Chinese red wine having comparable amounts of resveratrol, using a hypercholesterolemic rabbit model and resveratrol as a reference. Animals fed a high cholesterol (1.5%) diet were simultaneously given water containing resveratrol (3 mg/kg/day) or red wine (4 ml/kg/day) containing 3.98 mg/l and 3.23 mg/l resveratrol for regular and dealcoholized red wine, respectively, for a 12-week duration. Total, HDL- and LDL-cholesterol and triglyceride levels in the plasma were measured before and after the cholesterol challenge. Atherosclerotic plaques in the thoracic aorta were evaluated using histochemical methods. Vascular and endothelial functions in the femoral artery were also assessed by ultrasonographic image analysis. High cholesterol-fed animals showed a significant increase in plasma levels of total, HDL- and LDL-cholesterol, but not triglycerides, compared to those fed a regular diet. Dietary cholesterol-elicited lipid changes were similarly observed in animals concurrently fed dealcoholized red wine, red wine or resveratrol. In contrast, whereas atherosclerotic lesions were clearly evident in specimens prepared from the thoracic aorta of high cholesterol-fed animals, the size, density, and mean area of atherosclerotic plaques, and thickness of the intima layer were significantly reduced in rabbits given dealcoholized red wine, red wine, or resveratrol. These results were in agreement with data obtained by an ultrasound analysis of endothelial function, which showed a 25% reduction in flow-mediated dilation (FMD) in rabbits fed a high cholesterol diet compared to animals on control diet. This decrease was effectively prevented by the simultaneous exposure to dealcoholized red wine, red wine, or resveratrol. Our study shows that animals given dealcoholized red wine exhibited cardio-active effects comparable to those of animals orally administered resveratrol, and suggests that wine polyphenolics, rather than alcohol present in red wine, suffice in exerting cardioprotective properties. The results also provide support for the notion that resveratrol and phytochemicals in red wine can suppress atherosclerosis without affecting plasma lipid levels. PMID:16142383

  11. 77 FR 1695 - Determination That AVALIDE (Hydrochlorothiazide and Irbesartan), Oral Tablets, 25 Milligrams/300...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... indicated for treatment of hypertension in patients whose blood pressure is not adequately controlled on... multiple drugs to achieve their blood pressure goals. AVALIDE (hydrochlorothiazide and irbesartan),...

  12. 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

  13. 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.

  14. 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.

  15. Potential of the Angiotensin Receptor Blockers (ARBs) Telmisartan, Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke

    PubMed Central

    Kikuchi, Kiyoshi; Tancharoen, Salunya; Ito, Takashi; Morimoto-Yamashita, Yoko; Miura, Naoki; Kawahara, Ko-ichi; Maruyama, Ikuro; Murai, Yoshinaka; Tanaka, Eiichiro

    2013-01-01

    Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs. PMID:24065095

  16. Potential of the angiotensin receptor blockers (ARBs) telmisartan, irbesartan, and candesartan for inhibiting the HMGB1/RAGE axis in prevention and acute treatment of stroke.

    PubMed

    Kikuchi, Kiyoshi; Tancharoen, Salunya; Ito, Takashi; Morimoto-Yamashita, Yoko; Miura, Naoki; Kawahara, Ko-ichi; Maruyama, Ikuro; Murai, Yoshinaka; Tanaka, Eiichiro

    2013-01-01

    Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs. PMID:24065095

  17. Extractive-spectrophotometric determination of disopyramide and irbesartan in their pharmaceutical formulation.

    PubMed

    Abdellatef, Hisham E

    2007-04-01

    Picric acid, bromocresol green, bromothymol blue, cobalt thiocyanate and molybdenum(V) thiocyanate have been tested as spectrophotometric reagents for the determination of disopyramide and irbesartan. Reaction conditions have been optimized to obtain coloured comoplexes of higher sensitivity and longer stability. The absorbance of ion-pair complexes formed were found to increases linearity with increases in concentrations of disopyramide and irbesartan which were corroborated by correction coefficient values. The developed methods have been successfully applied for the determination of disopyramide and irbesartan in bulk drugs and pharmaceutical formulations. The common excipients and additives did not interfere in their determination. The results obtained by the proposed methods have been statistically compared by means of student t-test and by the variance ratio F-test. The validity was assessed by applying the standard addition technique. The results were compared statistically with the official or reference methods showing a good agreement with high precision and accuracy. PMID:16920393

  18. Extractive-spectrophotometric determination of disopyramide and irbesartan in their pharmaceutical formulation

    NASA Astrophysics Data System (ADS)

    Abdellatef, Hisham E.

    2007-04-01

    Picric acid, bromocresol green, bromothymol blue, cobalt thiocyanate and molybdenum(V) thiocyanate have been tested as spectrophotometric reagents for the determination of disopyramide and irbesartan. Reaction conditions have been optimized to obtain coloured comoplexes of higher sensitivity and longer stability. The absorbance of ion-pair complexes formed were found to increases linearity with increases in concentrations of disopyramide and irbesartan which were corroborated by correction coefficient values. The developed methods have been successfully applied for the determination of disopyramide and irbesartan in bulk drugs and pharmaceutical formulations. The common excipients and additives did not interfere in their determination. The results obtained by the proposed methods have been statistically compared by means of student t-test and by the variance ratio F-test. The validity was assessed by applying the standard addition technique. The results were compared statistically with the official or reference methods showing a good agreement with high precision and accuracy.

  19. 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

  20. 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

  1. 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

  2. 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

  3. Response of cardiac sympathetic nerve activity to intravenous irbesartan in heart failure

    PubMed Central

    Ramchandra, Rohit; Watson, Anna M. D.; Hood, Sally G.

    2010-01-01

    To determine the effect of irbesartan treatment on resting levels and arterial baroreflex control of cardiac sympathetic nerve activity (CSNA) in heart failure (HF), we studied conscious normal sheep and sheep with HF induced by rapid ventricular pacing for 8–10 wk (n = 7 per group). In HF, there is a large increase in CSNA that is detrimental to outcome. The causes of this increase in CSNA and the effect of angiotensin receptor blockers on CSNA in HF are unclear. CSNA, arterial blood pressure, heart rate (HR), and arterial baroreflex curves were recorded during a resting period and after 90 min of irbesartan infusion (12 mg·kg−1·h−1 iv). This dose of irbesartan abolished the pressor response to intravenous ANG II infusion but caused only a slight decrease in the pressor response to centrally administered ANG II. In HF, there was a large increase in CSNA (from 44 ± 3 to 87 ± 3 bursts/100 heartbeats). Irbesartan reduced arterial pressure in the normal and HF groups, but the usual baroreflex-mediated increases in CSNA and HR were prevented. This resulted from a significant leftward shift in the CSNA and HR baroreflex curves in both groups. Irbesartan also decreased the sensitivity of the arterial baroreflex control of CSNA. Short-term treatment with an angiotensin receptor blocker, at a dose that abolished the response to circulating, but not central, ANG II, prevented the reflex increase in CSNA in response to the drug-induced fall in arterial pressure. PMID:20147604

  4. 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 ...

  5. How Is Atherosclerosis Diagnosed?

    MedlinePLUS

    ... this page from the NHLBI on Twitter. How Is Atherosclerosis Diagnosed? Your doctor will diagnose atherosclerosis based ... PET). Rate This Content: NEXT >> Featured Video What is atherosclerosis? 05/22/2014 Describes how the build- ...

  6. Effects of low-dose spironolactone combined with irbesartan on cardiac hypertrophy induced by pressure overload in rats

    PubMed Central

    Ma, Jingtao; Zhang, Hongxue; Guo, Huicai; Xu, Yanfang

    2014-01-01

    Background: The mineralocorticoid receptor (MR) blockade in the heart is an attractive therapeutic option for the treatment of heart failure. However, the use of MR antagonist is limited by an increased incidence of hyperkalemia owing to MR blockade in the kidney. This study was designed to evaluate and compare the effectiveness of a low, non-pressure-lowering dose of spironolactone (Sp) with that of a conventional blood pressure-lowering dose combined with irbesartan on pathological cardiac remodeling as well as serum potassium level in pressure-overload rats. Methods: The pressure-overloaded myocardial remodelling was produced by partial abdominal aortic constriction (PAAC) in rats. Four weeks after PAAC, animals were respectively treated with vehicle, irbesartan (15 mg/kg) alone, low-dose Sp (1 mg/kg) or conventional-dose of Sp (20 mg/kg) in combination with irbesartan for consecutive four weeks. Results: The result demonstrated that compared to irbesartan monotherapy, the combination of irbesartan and spironolactone both in low- and conventional-dose exhibited additional cardioprotection against PAAC-induced cardiac remodelling. Low-dose spironolactone was as effective in inhibiting cardiac hypertrophy, fibrosis and in improving diastolic function as high dose. Low-dose spironolactone did not lead to a rise in potassium serum levels, but high dose did. Conclusions: This study suggests that combined low dose of spironolactone and irbesartan may be an effective and safety therapeutic strategy for cardiac hypertrophy and heart failure. PMID:25628791

  7. An update of irbesartan and renin-angiotensin system blockade in diabetic nephropathy.

    PubMed

    García-Donaire, Jose Antonio; Segura, Julian; Ruilope, Luis Miguel

    2005-08-01

    Type 2 diabetes is a chief cause of pathologies such as cardiovascular disease, nephropathy and retinopathy, and its prevalence is increasing worldwide. Development of renal disease can be slowed by tight glycaemic control and treatment of associated hypertension with angiotensin-converting enzyme inhibition, as The Diabetes Control and Complications Trial and the UK Prospective Diabetes Study have demonstrated. Recent clinical trials have supported the use of angiotensin II receptor antagonists in the treatment of diabetic nephropathy, resulting in the approval of new therapeutic indications in the US and Europe. The main goal of this review is to demonstrate how results from the Programme for Irbesartan Mortality and Morbidity Evaluation and other recent studies, based on the effects of renin-angiotensin system blockade, can be appropriate in clinical practice, thus displaying benefits of irbesartan therapy at any stage of renal disease in diabetics. PMID:16086646

  8. Impact of irbesartan, an angiotensin receptor blocker, on uric acid level and oxidative stress in high-risk hypertension patients.

    PubMed

    Chida, Ryuji; Hisauchi, Itaru; Toyoda, Shigeru; Kikuchi, Migaku; Komatsu, Takaaki; Hori, Yuichi; Nakahara, Shiro; Sakai, Yoshihiko; Inoue, Teruo; Taguchi, Isao

    2015-11-01

    Hyperuricemia is a known cardiovascular risk factor. The angiotensin II receptor blocker (ARB) losartan is known to decrease serum uric acid (UA) level. A recent in vitro study demonstrated a strong interaction between irbesartan and UA transporters that exceeded that of losartan. The purpose of the present study was to evaluate the hypouricemic effect of irbesartan in a clinical setting. A total of 40 high-risk hypertensive outpatients with coronary artery disease, cerebrovascular disease and/or diabetes complications who were taking ARBs other than irbesartan and losartan were enrolled in this study. After a 4-week control period, the patients' prescribed ARBs were exchanged for an equivalent dose of irbesartan. We assessed blood pressure, heart rate, serum UA level, parameters of lipid and glucose metabolism, cardiac and renal function and inflammatory and oxidative stress markers in blood samples taken immediately before the initiation of irbesartan treatment and again after 12 weeks of treatment. All 40 recruited patients were followed (31 men and 9 women, mean age: 68 years) without any dropouts. During the 12 weeks of irbesartan treatment, no significant changes in blood pressure, heart rate, parameters of lipid or glucose metabolism or other biomarkers of cardiac function, renal function, or inflammation were observed. However, UA level (5.91.6 to 5.51.6?mg?ml(-1), P=0.028) and the oxidative stress marker derivative reactive oxygen metabolites (dROMs) (35483 to 31065?U.CARR, P<0.001) were significantly lower at 12 weeks of treatment compared with before treatment. These results suggest that irbesartan has beneficial effects on hyperuricemia and oxidative stress. PMID:26178150

  9. Living with Atherosclerosis

    MedlinePLUS

    ... page from the NHLBI on Twitter. Living With Atherosclerosis Improved treatments have reduced the number of deaths ... Rate This Content: NEXT >> Featured Video What is atherosclerosis? 05/22/2014 Describes how the build-up ...

  10. Vaccination to Modulate Atherosclerosis

    PubMed Central

    Kimura, Takayuki; Tse, Kevin; Sette, Alessandro; Ley, Klaus

    2015-01-01

    Atherosclerosis is a chronic inflammatory disease of the artery wall. Adaptive immunity plays a key role in the pathogenesis of atherosclerosis. Recently, modulation of the immune response against atherosclerotic plaque antigen(s) has attracted attention as a potentially preventive and therapeutic approach. Here we review a series of studies on immunization with various antigens targeting treatment and prevention of atherosclerosis. Atherosclerosis-related antigens include oxidized LDL, apolipoprotein B-100, and heat shock protein 60/65. Accumulating evidence supports the idea that immunization with these antigenic proteins or peptides may reduce atherosclerosis. In this review, we discuss the current status of immunization studies and possible associated mechanisms of atheroprotection. PMID:25683179

  11. 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.

  12. Genetic Variation and Atherosclerosis

    PubMed Central

    Biros, Erik; Karan, Mirko; Golledge, Jonathan

    2008-01-01

    A family history of atherosclerosis is independently associated with an increased incidence of cardiovascular events. The genetic factors underlying the importance of inheritance in atherosclerosis are starting to be understood. Genetic variation, such as mutations or common polymorphisms has been shown to be involved in modulation of a range of risk factors, such as plasma lipoprotein levels, inflammation and vascular calcification. This review presents examples of present studies of the role of genetic polymorphism in atherosclerosis. PMID:19424482

  13. Diabetic atherosclerosis mouse models.

    PubMed

    Wu, Kenneth K; Huan, Youming

    2007-04-01

    Coronary heart disease (CHD) due to atherosclerosis is the leading cause of death in the USA, and accelerated CHD has emerged as a leading cause of morbidity and mortality in diabetic patients in the USA and worldwide. This has highlighted the importance and urgency of studying the mechanism of diabetic atherosclerosis and exploring therapeutic options. Due to its unique advantages over other animal models, the mouse is the most used model for studying the mechanism of diabetes-accelerated atherosclerosis and exploring effective therapeutic approaches. In the past decade, several diabetic atherosclerosis mouse models have been established. Currently, however, there is no ideal animal model for diabetic atherosclerosis. To determine the characteristics of the models that more closely resemble human diabetic atherosclerosis disease, this review focuses on the common diabetic atherosclerosis mouse models with respect to the following issues: (1) whether the mice retain diabetic condition; (2) whether the diabetes accelerates atherosclerosis or increases atherogenic inflammation; (3) whether these factors respond to medical interventions. The discussion is aimed at identifying different diabetic mouse models and their features, in order to heighten awareness of the appropriate models that may provide useful tools for studying the mechanism of diabetes-accelerated atherosclerosis and evaluating therapeutic options. PMID:16979174

  14. 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.

  15. WIP-ing out atherosclerosis with autophagy.

    PubMed

    Brichkina, Anna; Bulavin, Dmitry V

    2012-10-01

    Atherosclerosis commonly causes coronary and cerebrovascular diseases, which are major morbidities worldwide. Controlling these conditions remains a challenge owing to an incomplete understanding of underlying molecular mechanisms. We have recently shown that PPM1D/WIP1 phosphatase plays a crucial role in regulating atherosclerosis in mice. Deletion of Ppm1d results in the suppression of lipid droplet accumulation in macrophages, which prevents the formation of foam cells, and ultimately the development of atherosclerotic plaques. This process is controlled by the ATM-MTOR pathway and depends on the activation of selective autophagy to regulate cholesterol efflux from macrophage foam cells. Our data suggest that modulating autophagy through the PPM1D-ATM-MTOR pathway may be beneficial at both early and advanced stages of atherosclerosis. PMID:22895013

  16. 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

  17. Irbesartan/HCTZ fixed combinations in patients of different racial/ethnic groups with uncontrolled systolic blood pressure on monotherapy.

    PubMed Central

    Ofili, Elizabeth O.; Ferdinand, Keith C.; Saunders, Elijah; Neutel, Joel M.; Bakris, George L.; Cushman, William C.; Sowers, James R.; Weber, Michael A.

    2006-01-01

    The IrbesartaN/hydroChlorothiazide (HCTZ) bLood pressUre reductionS In diVErse patient populations (INCLUSIVE) trial was a multicenter, prospective, open-label, single-arm study evaluating the efficacy and safety of irbesartan/HCTZ fixed combinations in patients > or = 18 years old with uncontrolled systolic blood pressure (SBP, 140-159 mmHg; 130-159 mmHg for type-2 diabetes mellitus patients) after > or = 4 weeks of antihypertensive monotherapy. This analysis focused on different racial/ethnic subgroups. Treatment was sequential: placebo (4-5 weeks), HCTZ 12.5 mg (two weeks), irbesartan/HCTZ 150/12.5 mg (eight weeks) and irbesartan/HCTZ 300/25 mg (eight weeks). Overall, 515 Caucasians, 191 African Americans and 119 Hispanics/Latinos completing placebo treatment were enrolled. Mean SBP changes from baseline (placebo treatment end) to week 18 were -21.5 +/- 13.8 mmHg for Caucasians, -20.7 +/- 16.5 mmHg for African Americans and -22.9 +/- 13.2 mmHg for Hispanics/Latinos, respectively (p<0.001 for each). Mean diastolic BP (DBP) changes were statistically significant (p<0.001) and similar among racial/ethnic subgroups. By week 18, 70% (95% CI, 66%, 74%) of Caucasian, 66% (95% CI, 59%, 74%) of African-American and 65% (95% CI, 57%, 74%) of Hispanic/Latino patients achieved dual SBP/DBP goal. Treatments appeared to be well tolerated. In conclusion, irbesartan/HCTZ treatment provided SBP/DBP goal attainment in approximately two-thirds of Caucasian, African-American and Hispanic/Latino patients with SBP uncontrolled on antihypertensive monotherapy. PMID:16623075

  18. Atherosclerosis and Stroke

    MedlinePLUS

    ... Program Constraint-Induced Movement Therapy Emotional & Behavioral Challenges Self-Esteem after Stroke Post-Stroke Mood Disorders One-side ... vessels making them susceptible to atherosclerosis) Diabetes mellitus Obesity Physical inactivity How it starts The inner lining ...

  19. HIV and Atherosclerosis

    MedlinePLUS

    ... Pressure High Blood Pressure Tools & Resources Stroke More HIV and Atherosclerosis Updated:Jan 25,2016 Featured Video ... improve your cholesterol ratios, with or without HIV. HIV and Your Heart Home About HIV HIV and ...

  20. Infection and Atherosclerosis Development.

    PubMed

    Campbell, Lee Ann; Rosenfeld, Michael E

    2015-07-01

    Atherosclerosis is a chronic disease hallmarked by chronic inflammation, endothelial dysfunction and lipid accumulation in the vasculature. Although lipid modification and deposition are thought to be a major source of the continuous inflammatory stimulus, a large body of evidence suggests that infectious agents may contribute to atherosclerotic processes. This could occur by either direct effects through infection of vascular cells and/or through indirect effects by induction of cytokine and acute phase reactant proteins by infection at other sites. Multiple bacterial and viral pathogens have been associated with atherosclerosis by seroepidemiological studies, identification of the infectious agent in human atherosclerotic tissue, and experimental studies demonstrating an acceleration of atherosclerosis following infection in animal models of atherosclerosis. This review will focus on those infectious agents for which biological plausibility has been demonstrated in animal models and on the challenges of proving a role of infection in human atherosclerotic disease. PMID:26004263

  1. 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

  2. Nutrition and Atherosclerosis.

    PubMed

    Torres, Nimbe; Guevara-Cruz, Martha; Velzquez-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

  3. Formulation and development of a self-nanoemulsifying drug delivery system of irbesartan

    PubMed Central

    Patel, Jaydeep; Patel, Anjali; Raval, Mihir; Sheth, Navin

    2011-01-01

    Irbesartan (IRB) is an angiotensin II receptor blocker antihypertensive agent. The aim of the present investigation was to develop a self-nanoemulsifying drug delivery system (SNEDDS) to enhance the oral bioavailability of poorly water-soluble IRB. The solubility of IRB in various oils was determined to identify the oil phase of SNEDDS. Various surfactants and co-surfactants were screened for their ability to emulsify the selected oil. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region. The optimized SNEDDS formulation contained IRB (75 mg), Cremophor EL (43.33%), Carbitol (21.67%) and Capryol 90 (32%). SNEDDS was further evaluated for its percentage transmittance, emulsification time, drug content, phase separation, dilution, droplet size and zeta potential. The optimized formulation of IRB-loaded SNEDDS exhibited complete in vitro drug release in 15 min as compared with the plain drug, which had a limited dissolution rate. It was also compared with the pure drug solution by oral administration in male Wister rats. The in vivo study exhibited a 7.5-fold increase in the oral bioavailability of IRB from SNEDDS compared with the pure drug solution. These results suggest the potential use of SNEDDS to improve dissolution and oral bioavailability of poorly water-soluble IRB. PMID:22171286

  4. Wip1-dependent regulation of autophagy, obesity, and atherosclerosis.

    PubMed

    Le Guezennec, Xavier; Brichkina, Anna; Huang, Yi-Fu; Kostromina, Elena; Han, Weiping; Bulavin, Dmitry V

    2012-07-01

    Obesity and atherosclerosis-related diseases account for over one-third of deaths in the western world. Controlling these conditions remains a major challenge due to an incomplete understanding of the molecular pathways involved. Here, we show that Wip1 phosphatase, a known negative regulator of Atm-dependent signaling, plays a major role in controlling fat accumulation and atherosclerosis in mice; specifically, Wip1 deficiency prevents both conditions. In the course of atherosclerosis, deletion of Wip1 results in suppression of macrophage conversion into foam cells, thus preventing the formation of atherosclerotic plaques. This process appears to be independent of p53 but rely on a noncanonical Atm-mTOR signaling pathway and on selective autophagy in regulation of cholesterol efflux. We propose that the Wip1-dependent control of autophagy and cholesterol efflux may provide avenues for treating obesity and atherosclerosis. PMID:22768840

  5. Simultaneous analysis of irbesartan and hydrochlorothiazide: an improved HPLC method with the aid of a chemometric protocol.

    PubMed

    Vuji?, Zorica; Mulavdi?, Nedad; Smaji?, Miralem; Brbori?, Jasmina; Stankovic, Predrag

    2012-01-01

    Experimental design method was used for HPLC determination of irbesartan and hydrochlorothiazide in combined dosage forms. The traditional approach for optimization of experiments is time-consuming, involves a large number of runs and does not allow establishing the multiple interacting parameters. The main advantages of the experimental design method include the simultaneous screening of a larger number of factors affecting response and the estimation of possible interactions. On the basis of preliminary experiments, three factors-independent variables were selected as inputs (methanol content, pH of the mobile phase and temperature) and as dependent variables, five responses (resolution, symmetry of irbesartan peak, symmetry of hydrochlorothiazide peak, retention factor of irbesartan and retention factor of hydrochlorothiazide) were chosen. A full 23 factorial design, where factors were examined at two different levels ("low" and "high") was used to determine which factors had an effect on the studied response. Afterwards, experimental design was used to optimize these influent parameters in the previously selected experimental domain. The novelty of our method lies in the optimization step accomplished by Derringer's desirability function. After optimizing the experimental conditions a separation was conducted on a Supelcosil C(18) (150 mm 4.6 mm, 5 mm particle size) column with a mobile phase consisting of methanol-tetrahydrofuran-acetate buffer 47:10:43 v/v/v, pH 6.5 and a column temperature of 25 C. The developed method was successfully applied to the simultaneous separation of these drug-active compounds in their commercial pharmaceutical dosage forms. PMID:22426527

  6. Myocardial infarction accelerates atherosclerosis

    PubMed Central

    Dutta, Partha; Courties, Gabriel; Wei, Ying; Leuschner, Florian; Gorbatov, Rostic; Robbins, Clinton; Iwamoto, Yoshiko; Thompson, Brian; Carlson, Alicia L.; Heidt, Timo; Majmudar, Maulik D.; Lasitschka, Felix; Etzrodt, Martin; Waterman, Peter; Waring, Michael T.; Chicoine, Adam T.; van der Laan, Anja M.; Niessen, Hans W.M.; Piek, Jan J.; Rubin, Barry B.; Butany, Jagdish; Stone, James; Katus, Hugo A.; Murphy, Sabina A.; Morrow, David A.; Sabatine, Marc S.; Vinegoni, Claudio; Moskowitz, Michael A.; Pittet, Mikael J.; Libby, Peter; Lin, Charles P.; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias

    2012-01-01

    SUMMARY During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaque in the arterial wall and cause its rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, apoE?/? mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. When seeking the source of surplus monocytes in plaque, we found that myocardial infarction liberated hematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signaling. The progenitors then seeded the spleen yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression. PMID:22763456

  7. Myocardial infarction accelerates atherosclerosis.

    PubMed

    Dutta, Partha; Courties, Gabriel; Wei, Ying; Leuschner, Florian; Gorbatov, Rostic; Robbins, Clinton S; Iwamoto, Yoshiko; Thompson, Brian; Carlson, Alicia L; Heidt, Timo; Majmudar, Maulik D; Lasitschka, Felix; Etzrodt, Martin; Waterman, Peter; Waring, Michael T; Chicoine, Adam T; van der Laan, Anja M; Niessen, Hans W M; Piek, Jan J; Rubin, Barry B; Butany, Jagdish; Stone, James R; Katus, Hugo A; Murphy, Sabina A; Morrow, David A; Sabatine, Marc S; Vinegoni, Claudio; Moskowitz, Michael A; Pittet, Mikael J; Libby, Peter; Lin, Charles P; Swirski, Filip K; Weissleder, Ralph; Nahrendorf, Matthias

    2012-07-19

    During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression. PMID:22763456

  8. [Oxidative stress and atherosclerosis].

    PubMed

    Stark, Jlia

    2015-07-12

    Atherosclerosis is a leading cause of death in developed countries. Genetic susceptibility and environmental factors play a role in the pathogenesis. Most of these factors lead to endothelial dysfunction and other pro-atherogenic processes by causing oxidative stress. Atherosclerosis typically develops at the curved and branched regions of the arterial tree, where the laminar blood flow is disturbed. This leads to increased permeability of the endothelium to low density lipoprotein molecules, which accumulate in the intima and are oxidised by vascular cells. Oxidised low density lipoprotein takes part in many phases of atherogenesis: stimulates the binding of monocytes to the endothelium, foam cell formation, the development of plaques, plaque destabilization and thrombotic complications. Since oxidative stress plays an important role in atherogenesis, it has been suggested that antioxidant molecules might have anti-atherogenic function. Many clinical investigations have shown that antioxidants such as N-acetylcystein, vitamin E and C, folic acid, and estrogens can prevent atherosclerosis, however, randomized studies failed to confirm this effect. PMID:26149503

  9. 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 70 and hs-CRP. > Arsenic exposure and high cholesterol diet early in life suppress CEPT-1 and LXR? > Arsenic may induce atherosclerosis by modifying reverse cholesterol transport. > Prevent arsenic exposure in early life is important to decreasing atherosclerosis.

  10. Renal protection by low dose irbesartan in diabetic nephropathy is paralleled by a reduction of inflammation, not of endoplasmic reticulum stress.

    PubMed

    Hartner, Andrea; Cordasic, Nada; Klanke, Bernd; Menendez-Castro, Carlos; Veelken, Roland; Schmieder, Roland E; Hilgers, Karl F

    2014-04-01

    Diabetes can disrupt endoplasmic reticulum (ER) homeostasis which leads to ER stress. ER stress-induced renal apoptosis seems to be involved in the development of diabetic nephropathy. The present study was designed to investigate the contribution of reduced ER stress to the beneficial effects of an angiotensin receptor blocker. Insulin-dependent diabetes mellitus was induced by streptozotocin injections to hypertensive mRen2-transgenic rats. After 2weeks animals were treated with 0.7mg/kg/day irbesartan. Blood glucose, blood pressure and protein excretion were assessed. Expression of ER stress markers was measured by real-time PCR. Immunohistochemistry was performed to detect markers of ER stress, renal damage and infiltrating cells. Glomerulosclerosis and apoptosis were evaluated. Diabetic mRen2-transgenic rats developed renal injury with proteinuria, tubulointerstitial cell proliferation as well as glomerulosclerosis and podocyte injury. Moreover, an increase in inflammation, podocyte ER stress and apoptosis was detected. Irbesartan somewhat lowered blood pressure and reduced proteinuria, tubulointerstitial cell proliferation and glomerulosclerosis. Podocyte damage was ameliorated but markers of ER stress (calnexin, grp78) and apoptosis were not reduced by irbesartan. On the other hand, inflammatory cell infiltration in the tubulointerstitium and the glomerulus was significantly attenuated. We conclude that irbesartan reduced renal damage even in a very low dose. The beneficial effects of low dose irbesartan were paralleled by a reduction of blood pressure and inflammation but not by a reduction of ER stress and apoptosis. Thus, sustained endoplasmic reticulum stress in the kidney does not necessarily lead to increased inflammation and tubulointerstitial or glomerular injury. PMID:24418215

  11. Endothelial progenitor cells in atherosclerosis

    PubMed Central

    Du, Fuyong; Zhou, Jun; Gong, Ren; Huang, Xiao; Pansuria, Meghana; Virtue, Anthony; Li, Xinyuan; Wang, Hong; Yang, Xiao-Feng

    2012-01-01

    Endothelial progenitor cells (EPCs) are involved in the maintenance of endothelial homoeostasis and in the process of new vessel formation. Experimental and clinical studies have shown that atherosclerosis is associated with reduced numbers and dysfunction of EPCs; and that medications alone are able to partially reverse the impairment of EPCs in patients with atherosclerosis. Therefore, novel EPC-based therapies may provide enhancement in restoring EPCs population and improvement of vascular function. Here, for a better understanding of the molecular mechanisms underlying EPC impairment in atherosclerosis, we provide a comprehensive overview on EPC characteristics, phenotypes, and the signaling pathways underlying EPC impairment in atherosclerosis. PMID:22652782

  12. 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

  13. B Cell Subsets in Atherosclerosis

    PubMed Central

    Perry, Heather M.; Bender, Timothy P.; McNamara, Coleen A.

    2012-01-01

    Atherosclerosis, the underlying cause of heart attacks and strokes, is a chronic inflammatory disease of the artery wall. Immune cells, including lymphocytes modulate atherosclerotic lesion development through interconnected mechanisms. Elegant studies over the past decades have begun to unravel a role for B cells in atherosclerosis. Recent findings provide evidence that B cell effects on atherosclerosis may be subset-dependent. B-1a B cells have been reported to protect from atherosclerosis by secretion of natural IgM antibodies. Conventional B-2 B cells can promote atherosclerosis through less clearly defined mechanism that may involve CD4 T cells. Yet, there may be other populations of B cells within these subsets with different phenotypes altering their impact on atherosclerosis. Additionally, the role of B cell subsets in atherosclerosis may depend on their environmental niche and/or the stage of atherogenesis. This review will highlight key findings in the evolving field of B cells and atherosclerosis and touch on the potential and importance of translating these findings to human disease. PMID:23248624

  14. 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

  15. Adventitial lymphatics and atherosclerosis.

    PubMed

    Drozdz, K; Janczak, D; Dziegiel, P; Podhorska, M; Piotrowska, A; Patrzalek, D; Andrzejak, R; Szuba, A

    2012-03-01

    Lymphatic vessels are important in reverse cholesterol transport and play a crucial role in regression of atherosclerotic plaque in experimental animal models. Therefore, we attempted to analyze adventitial microcirculation including lymphatic vessels and adventitial macrophages in large human arteries in various stages of atherosclerosis. Eighty-one arterial segments of large arteries (iliac arteries and abdominal aortas) were obtained from deceased organ donors. Lymphatic vessels were identified using anti-LYVE-1 and anti-D2-40/podoplanin immunohistochemical staining. Adventitial blood vessels and macrophages were visualized using anti-CD-31 and anti-CD-68. Intimal thickness was measured under 100x magnification with an Olympus BX 41 light microscope using the visual mode analySIS 3.2 software. Lymphatic vessels were counted in each cross section of the examined arteries, and adventitial blood vessels (CD31+) were counted using the "hot spot" method. Statistical analysis was performed with Statistica 9.1 PL software (StatSoft, Cracow, Poland). Mann-Whitney, F-Cox, Chi-square, and Spearman's correlation tests were performed and the differences were considered significant at p < 0.05. Lymphatic and blood vessels in the adventitia of examined arteries were identified and quantified. Significant positive correlations were found between the number of adventitial lymphatics (LYVE-L +) and intimal thickness (r = 0.37; p < 0.05) as well as with age of the subjects (r = 0.3; p < 0.05). Thus, lymphatic vessels are present in the adventitia of large arteries in humans and the number of adventitial lymphatic vessels increases with progression of atherosclerosis as assessed by intimal thickness. PMID:22768470

  16. Therapy with the Combination of Amlodipine and Irbesartan Has Persistent Preventative Effects on Stroke Onset Associated with BDNF Preservation on Cerebral Vessels in Hypertensive Rats.

    PubMed

    Hasegawa, Yu; Nakagawa, Takashi; Uekawa, Ken; Ma, Mingjie; Lin, Bowen; Kusaka, Hiroaki; Katayama, Tetsuji; Sueta, Daisuke; Toyama, Kensuke; Koibuchi, Nobutaka; Kim-Mitsuyama, Shokei

    2016-02-01

    Although calcium channel blockers, angiotensin II receptor blockers, and combination therapy are effective for hypertensive patients, the significant differences among them against stroke onset are undetermined. In this study, we investigated the significant beneficial effects of the combination therapy using amlodipine and irbesartan against stroke onset in hypertensive rats. The animals were fed an 8% sodium diet and assigned to (1) vehicle, (2) amlodipine (2mg/kg/day), (3) irbesartan (20mg/kg/day), and (4) amlodipine + irbesartan groups. The drugs were given orally until 35days, and incidences of stroke-related signs and mortality and blood pressure (BP) were monitored. Cerebral blood flow (CBF), brain water content, weight of the brain and left ventricle, and histological evaluations were conducted for the treated groups at 42days after the start of the high-salt diet. Amlodipine and the combination therapy significantly reduced BP compared with the vehicle. Although the rates of stroke-related signs and mortality were high in the vehicle group, the rats in the treatment groups were mostly healthy until 35days. After all drugs were discontinued, stroke onset was frequently seen in the monotherapy groups until 42days, but no signs were observed in the combination therapy group. Although there were no significant differences in CBF or brain edema, the combination therapy reduced blood-brain barrier disruption, white matter injury, and reactive astrocytes compared with irbesartan, and the combination also inhibited left ventricular hypertrophy and preserved brain-derived neurotrophic factor (BDNF) expression on cerebral vessels compared to the monotherapies. These data suggest that the combination therapy had a persistent preventive effect on stroke onset in hypertensive rats, and the effects might be associated with BDNF preservation on cerebral vessels. PMID:25533877

  17. The efficacy and safety of low- and high-dose fixed combinations of irbesartan/hydrochlorothiazide in patients with uncontrolled systolic blood pressure on monotherapy: the INCLUSIVE trial.

    PubMed

    Neutel, Joel M; Saunders, Elijah; Bakris, George L; Cushman, William C; Ferdinand, Keith C; Ofili, Elizabeth O; Sowers, James R; Weber, Michael A

    2005-10-01

    This multicenter, prospective, open-label, single-arm study determined the efficacy and safety of irbesartan/hydrochlorothiazide (HCTZ) fixed combinations in patients (n=1005), aged 18 years and older, with uncontrolled systolic blood pressure (SBP) of 140-159 mm Hg (130-159 mm Hg for type 2 diabetes mellitus) after at least 4 weeks of antihypertensive monotherapy. Treatment was sequential: placebo (4-5 weeks), HCTZ 12.5 mg (2 weeks), irbesartan/HCTZ 150/12.5 mg (8 weeks), and irbesartan/HCTZ 300/25 mg (8 weeks). Enrolled patients (n=844) were aged 57.3+/-11.2 years; 52% were women, 23% were African American, and 14% were Hispanic. Thirty percent had type 2 diabetes mellitus, 46% had metabolic syndrome, and baseline blood pressure was 154.0+/-10.3/91.3+/-8.8 mm Hg. The mean change in SBP from placebo end to the primary end point, Week 18 (intent-to-treat population, n=736) was -21.5+/-14.3 mm Hg (p<0.001). The mean change in diastolic blood pressure (DBP) was -10.4+/-8.7 mm Hg (p<0.001). The mean Week 18 SBP/DBP was 132.9+/-13.8/81.1+/-9.7 mm Hg. Overall, 77% (95% confidence interval, 74%-80%) of patients achieved SBP goal (<140 mm Hg; <130 mm Hg for type 2 diabetes mellitus); 83% (95% confidence interval, 80%-86%) achieved DBP goal (<90 mm Hg; <80 mm Hg for type 2 diabetes mellitus); and 69% (95% confidence interval, 66%-72%) achieved dual SBP/DBP goal. Treatments were well tolerated. This irbesartan/HCTZ treatment regimen achieved SBP goals in more than 75% of patients uncontrolled on monotherapy. PMID:16227760

  18. 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

  19. [Chronic inflammation and atherosclerosis].

    PubMed

    von Hundelshausen, P; Weber, C

    2013-09-01

    The increasing gain of knowledge regarding the mechanistic details of the pathogenesis of chronic inflammatory diseases e. g. of rheumatic origin, chronic viral infections and atherosclerosis have revealed in conjunction with detailed insights in acute inflammation interesting similarities and differences. Cytokines such as IL-1 and tumour necrosis factor-? are proximal components of inflammatory cascades of systemic mediators activating the endothelium which leads to an endothelial dysfunction and moreover alter the balance within lymphocytic subpopulations containing distinct arsenals of secretory mediators such as interferons, interleukins and chemokines. Proinflammatory lymphocyte subtypes are TH1 und TH17 cells whereas Treg and TH2 cells are anti-inflammatory opponents. Since several years, interleukin-1- and TNF-antagonists have expanded the spectrum of drugs against rheumatic diseases and are currently studied in the setting of cardiovascular prevention with positive results on surrogate parameters. On the other hand efforts are undertaken to test the hypothesis if the pleiotropic effects of statins may have a positive influence on rheumatoid arthritis. PMID:24006166

  20. Proteomic Biomarkers of Atherosclerosis

    PubMed Central

    Vivanco, F.; Padial, L.R.; Darde, V.M.; de la Cuesta, F.; Alvarez-Llamas, G.; Diaz-Prieto, Natacha; Barderas, M.G.

    2008-01-01

    Summary Biomarkers provide a powerful approach to understanding the spectrum of cardiovascular diseases. They have application in screening, diagnostic, prognostication, prediction of recurrences and monitoring of therapy. The omics tool are becoming very useful in the development of new biomarkers in cardiovascular diseases. Among them, proteomics is especially fitted to look for new proteins in health and disease and is playing a significant role in the development of new diagnostic tools in cardiovascular diagnosis and prognosis. This review provides an overview of progress in applying proteomics to atherosclerosis. First, we describe novel proteins identified analysing atherosclerotic plaques directly. Careful analysis of proteins within the atherosclerotic vascular tissue can provide a repertoire of proteins involved in vascular remodelling and atherogenesis. Second, we discuss recent data concerning proteins secreted by atherosclerotic plaques. The definition of the atheroma plaque secretome resides in that proteins secreted by arteries can be very good candidates of novel biomarkers. Finally we describe proteins that have been differentially expressed (versus controls) by individual cells which constitute atheroma plaques (endothelial cells, vascular smooth muscle cells, macrophages and foam cells) as well as by circulating cells (monocytes, platelets) or novel biomarkers present in plasma. PMID:19578499

  1. 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

  2. Irbesartan attenuates production of high-mobility group box 1 in response to lipopolysaccharide via downregulation of interferon-? production.

    PubMed

    Kato, Yoshiro; Kamiya, Hideki; Koide, Naoki; Odkhuu, Erdenezaya; Komatsu, Takayuki; Watarai, Atsuko; Kondo, Masaki; Kato, Koichi; Nakamura, Jiro; Yokochi, Takashi

    2015-05-01

    High-mobility group box 1 (HMGB1) is suggested to participate in development of local and systemic inflammatory disorders. Irbesartan (IRB), an angiotensin II type1 receptor blocker, is widely used for treatment of hypertension, especially in patients with diabetic nephropathy. The effect of IRB on lipopolysaccharide (LPS)-induced HMGB1 and nitric oxide (NO) production was examined using RAW 264.7 macrophage-like cells. IRB inhibited LPS-induced HMGB1 production. IRB also reduced LPS-induced expression of an inducible NO synthase, and inhibited LPS-induced NO production. The expression levels of IFN-? protein and mRNA, which is a key molecule in MyD88-independent pathway of LPS signaling, were exclusively inhibited by IRB. Peroxisome proliferator-activated receptor-? and angiotensin II type 1 receptor were not involved in the inhibitory action of IRB on LPS-induced HMGB1 and NO production. Collectively, IRB was suggested to inhibit LPS-induced HMGB1 production via downregulation of IFN-? production in the MyD88-independent pathway. PMID:25817178

  3. 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 ...

  4. Epigenetics in atherosclerosis and inflammation

    PubMed Central

    Wierda, Rutger J; Geutskens, Sacha B; Jukema, J Wouter; Quax, Paul HA; van den Elsen, Peter J

    2010-01-01

    Abstract Atherosclerosis is a multifactorial disease with a severe burden on western society. Recent insights into the pathogenesis of atherosclerosis underscore the importance of chronic inflammation in both the initiation and progression of vascular remodelling. Expression of immunoregulatory molecules by vascular wall components within the atherosclerotic lesions is accordingly thought to contribute to the ongoing inflammatory process. Besides gene regulatory proteins (transcription factors), epigenetic mechanisms also play an essential and fundamental role in the transcriptional control of gene expression. These epigenetic mechanisms change the accessibility of chromatin by DNA methylation and histone modifications. Epigenetic modulators are thus critically involved in the regulation of vascular, immune and tissue-specific gene expression within the atherosclerotic lesion. Importantly, epigenetic processes are reversible and may provide an excellent therapeutic target. The concept of epigenetic regulation is gradually being recognized as an important factor in the pathogenesis of atherosclerosis. Recent research provides an essential link between inflammation and reprogramming of the epigenome. In this review we therefore discuss the basis of epigenetic regulation – and the contribution thereof in the regulation of inflammatory processes in general and during atherosclerosis in particular. Moreover we highlight potential therapeutic interventions based on epigenetic mechanisms. PMID:20132414

  5. 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 ...

  6. Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation*

    PubMed Central

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

    2015-01-01

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

  7. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms.

    PubMed

    Okuyama, Harumi; Langsjoen, Peter H; Hamazaki, Tomohito; Ogushi, Yoichi; Hama, Rokuro; Kobayashi, Tetsuyuki; Uchino, Hajime

    2015-03-01

    In contrast to the current belief that cholesterol reduction with statins decreases atherosclerosis, we present a perspective that statins may be causative in coronary artery calcification and can function as mitochondrial toxins that impair muscle function in the heart and blood vessels through the depletion of coenzyme Q10 and 'heme A', and thereby ATP generation. Statins inhibit the synthesis of vitamin K2, the cofactor for matrix Gla-protein activation, which in turn protects arteries from calcification. Statins inhibit the biosynthesis of selenium containing proteins, one of which is glutathione peroxidase serving to suppress peroxidative stress. An impairment of selenoprotein biosynthesis may be a factor in congestive heart failure, reminiscent of the dilated cardiomyopathies seen with selenium deficiency. Thus, the epidemic of heart failure and atherosclerosis that plagues the modern world may paradoxically be aggravated by the pervasive use of statin drugs. We propose that current statin treatment guidelines be critically reevaluated. PMID:25655639

  8. 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.

  9. 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 ?as(I-I), ?s(I-I) and ?(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 (?) and thermodynamic properties ?H#, ?S# and ?G# 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

  10. Obesity and atherosclerosis: mechanistic insights.

    PubMed

    Lovren, Fina; Teoh, Hwee; Verma, Subodh

    2015-02-01

    Obesity is a multifactorial chronic disease characterized by an accumulation of visceral and subcutaneous fat, which leads to a predisposition toward cardiometabolic diseases. A plethora of mechanisms, including abnormalities in lipid metabolism, insulin resistance, inflammation, endothelial dysfunction, adipokine imbalance, and inflammasome activation have been suggested to underlie the relationship between obesity and atherosclerosis. More recent data point toward an emerging role of impaired autophagy and altered gut microbiome homeostasis as potentially contributing factors. This review provides an overview of this area. PMID:25661552

  11. 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

  12. Atherosclerosis in Juvenile Idiopathic Arthritis

    PubMed Central

    Jednacz, Ewa; Rutkowska-Sak, Lidia

    2012-01-01

    Atherosclerosis is a chronic inflammatory disease of the arteries. Clinical consequences of the atherosclerotic process occur in the adult population, however atherosclerotic process begins in childhood. The classic risk factors for atherosclerosis include obesity, dyslipidaemia, age, gender or family history. In recent years, attention has been drawn to the similarity between atherosclerotic inflammatory processes and inflammatory changes in the course of systemic connective tissue disease, in particular systemic lupus etythematosus (SLE) or rheumatoid arthritis (RA). There is also observed the similarity of the pathogenetic background of development of atherosclerosis and juvenile idiopathic arthritis (JIA). Elevated levels of pro-inflammatory cytokines are observed in the course of juvenile idiopathic arthritis. Also homocysteine concentrations, which may play a significant role in the development of atherosclerotic lesions, are observed higher in patients with JIA. Some studies revealed higher carotid intima-media thickness (IMT) index values in children with JIA. In view of the fact that atherosclerotic process begins as early as in childhood, the introduction of appropriate preventive measures in children is a matter of utmost importance. PMID:22933832

  13. 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

  14. Regulatory T cells in atherosclerosis: critical immune regulatory function and therapeutic potential.

    PubMed

    Spitz, Charlotte; Winkels, Holger; Brger, Christina; Weber, Christian; Lutgens, Esther; Hansson, Gran 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-?, 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

  15. Ultrasound Imaging for Risk Assessment in Atherosclerosis

    PubMed Central

    Steinl, David C.; Kaufmann, Beat A.

    2015-01-01

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

  16. 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

  17. Multi-Ethnic Study of Atherosclerosis (MESA)

    ClinicalTrials.gov

    2015-06-02

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

  18. 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

  19. Cathepsin G activity lowers plasma LDL and reduces atherosclerosis

    PubMed Central

    Wang, Jing; Sjberg, Sara; Tang, Ting-Ting; rni, 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

  20. ?-Elemene reduces the progression of atherosclerosis in rabbits.

    PubMed

    Zhong, Ying; Liu, Jun; Huo, Wei-Min; Duan, Wen-Li; Wang, Xue; Shang, Jing

    2015-06-01

    The present study aimed at investigating the possible effects of ?-elemene on the progression of atherosclerosis in a rabbit model. The rabbit atherosclerosis model was established by the combination of balloon angioplasty-induced endothelial injury and an atherogenic diet fed to the rabbits. New Zealand White rabbits were randomly divided into four groups (8/group): the normal control group (fed with normal chow diet), and three experimental groups, placebo group, atorvastatin group, and ?-elemene group (received the atherogenic diet). After two weeks on the diet, the three experimental groups underwent balloon injury at right common carotid artery and were treated with drugs or placebo for five weeks. Serum lipids were measured. Carotid artery lesions were isolated for histological and immunohistochemical analysis. In vitro, RAW264.7 macrophages were pretreated with ?-elemene and ox-LDL for 24 h and the viability of macrophages was assayed using the MTT method. TNF-? and IL-6 were also determined. Compared with the control group, the thickness of the atherosclerosis lesion in the placebo group was significantly increased; The thickness the drug treatment groups were significantly decreased, compared with that of the placebo group. The infiltration of macrophage was markedly reduced in the ?-elemene group compared with that of the placebo group. ?-elemene treatment also reduced the levels of TC, TG, and LDL-C, compared with the placebo group. ?-elemene decreased the TNF-? and IL-6 levels in vitro. In conclusion, our results demonstrated that ?-elemene retarded the progression of atherosclerosis in vivo and in vitro, which may be related to the capacity of ?-elemene to reduce the infiltration of macrophages and suppress inflammatory factors. PMID:26073337

  1. 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 ...

  2. 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

  3. Rapid Progression of Coronary Atherosclerosis: A Review.

    PubMed

    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

  4. Therapeutic approaches to drug targets in atherosclerosis

    PubMed Central

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

    2013-01-01

    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, PPAR?, 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

  5. 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.

  6. 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

  7. Role of LCAT in Atherosclerosis.

    PubMed

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

    2016-02-01

    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

  8. 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.

  9. 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

  10. 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

  11. BIOLOGICAL IMAGING OF ATHEROSCLEROSIS: MOVING BEYOND ANATOMY

    PubMed Central

    Verjans, Johan W.; Jaffer, Farouc A.

    2013-01-01

    Biological or molecular imaging is now providing exciting new strategies to study atherosclerosis in both animals and humans. These technologies hold the promise to provide disease-specific, molecular information within the context of a systemic or organ-specific disease beyond traditional anatomical-based imaging. By integration of biological, chemical and anatomical imaging knowledge into diagnostic strategies, a more comprehensive and predictive picture of atherosclerosis is likely to emerge. As such, biological imaging is well-positioned to study different stages of atherosclerosis and its treatment, including the sequence of atheroma initiation, progression, and plaque rupture. In this review we describe the evolving concepts in atherosclerosis imaging with a focus on coronary artery disease, and we provide an overview of recent exciting translational developments in biological imaging. The illuminated examples and discussions will highlight how biological imaging is providing new clinical approaches to identify high-risk plaques, and to streamline the development process of new atherosclerosis therapies. PMID:23733542

  12. Atherosclerosis

    MedlinePLUS

    ... hardens and narrows your arteries. This limits the flow of oxygen-rich blood to your organs and other parts ... your neck (the carotid arteries). These arteries supply oxygen-rich blood to your brain. If blood flow to your brain is reduced or blocked, you ...

  13. Atherosclerosis

    MedlinePLUS

    ... find sterols and stanols in some dietary supplements. Omega-3 fatty acids. If you have heart disease or high cholesterol, consider taking an omega-3 supplement. There are many types of omega-3 ...

  14. HDAC9 represses cholesterol efflux and generation of alternatively activated macrophages in atherosclerosis development

    PubMed Central

    Cao, Qiang; Rong, Shunxing; Repa, Joyce J; Clair, Richard St.; Parks, John S.; Mishra, Nilamadhab

    2014-01-01

    Objective Recent genome-wide association studies revealed that a genetic variant in the loci corresponding to histone deacetylase 9 (HDAC9) is associated with large vessel stroke. HDAC9 expression was upregulated in human atherosclerotic plaques in different arteries. The molecular mechanisms how HDAC9 might increase atherosclerosis is not clear. Approach and Results In this study, we show that systemic and bone marrow cell deletion of HDAC9 decreased atherosclerosis in LDLr?/? mice with minimal effect on plasma lipid concentrations. HDAC9 deletion resulted upregulation of lipid homeostatic genes, downregulation of inflammatory genes, and polarization towards an M2 phenotype via increased accumulation of total acetylated H3 and H3K9 at the promoters of ABCA1, ABCG1, and PPAR-? in macrophages. Conclusions We conclude that macrophage HDAC9 upregulation is atherogenic via suppression of cholesterol efflux and generation of alternatively activated macrophages in atherosclerosis. PMID:25035344

  15. 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

  16. Noninvasive Assessment of Preclinical Atherosclerosis

    PubMed Central

    Lane, Helen A; Smith, Jamie C; Davies, J Stephen

    2006-01-01

    Initially considered as a semipermeable barrier separating lumen from vessel wall, the endothelium is now recognised as a complex endocrine organ responsible for a variety of physiological processes vital for vascular homeostasis. These include the regulation of vascular tone, luminal diameter, and blood flow; hemostasis and thrombolysis; platelet and leucocyte vessel-wall interactions; the regulation of vascular permeability; and tissue growth and remodelling. The endothelium modulates arterial stiffness, which precedes overt atherosclerosis and is an independent predictor of cardiovascular events. Unsurprisingly, dysfunction of the endothelium may be considered as an early and potentially reversible step in the process of atherogenesis and numerous methods have been developed to assess endothelial status and large artery stiffness. Methodology includes flow-mediated dilatation of the brachial artery, assessment of coronary flow reserve, carotid intimamedia thickness, pulse wave analysis, pulse wave velocity, and plethysmography. This review outlines the various modalities, indications, and limitations of available methods to assess arterial dysfunction and vascular risk. PMID:17319466

  17. Aging, Atherosclerosis, and IGF-1

    PubMed Central

    Higashi, Yusuke; Sukhanov, Sergiy; Anwar, Asif; Shai, Shaw-Yung

    2012-01-01

    Insulin-like growth factor 1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that circulates at high levels in the plasma and is expressed in most cell types. IGF-1 has major effects on development, cell growth and differentiation, and tissue repair. Recent evidence indicates that IGF-1 reduces atherosclerosis burden and improves features of atherosclerotic plaque stability in animal models. Potential mechanisms for this atheroprotective effect include IGF-1–induced reduction in oxidative stress, cell apoptosis, proinflammatory signaling, and endothelial dysfunction. Aging is associated with increased vascular oxidative stress and vascular disease, suggesting that IGF-1 may exert salutary effects on vascular aging processes. In this review, we will provide a comprehensive update on IGF-1's ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging. PMID:22491965

  18. Atherosclerosis in Systemic Lupus Erythematosus

    PubMed Central

    Stojan, George; Petri, Michelle

    2015-01-01

    Accelerated atherosclerosis and its long-term sequelae are a major cause of late mortality among patients with systemic lupus erythematosus (SLE). Traditional Framingham risk factors such as hypertension, hypercholesterolemia, diabetes, and smoking do not account in entirety for this risk. SLE specific factors like disease activity and duration, use of corticosteroids, presence of antiphospholipid antibodies, and others are important risk factors. SLE is considered a coronary heart disease; equivalent and aggressive management of all traditional risk factors is recommended. Despite their role in primary and secondary prevention in the general population, statins seem to have no effect on cardiovascular outcomes in adult or pediatric SLE populations. The use of hydroxychloroquine has a cardioprotective effect, and mycophenolate mofetil may reduce cardiovascular events based on basic science data and data from the transplant population. The role of vitamin D supplementation and treatment of hyperhomocysteinemia remain controversial, but due to the safety of therapy and the potential benefit, they remain as optional therapies. PMID:23792700

  19. 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 atherosclerotic cardiovascular diseases. PMID:25462164

  20. 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

  1. 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

  2. Immune activation, immunosenescence, and osteoprotegerin as markers of endothelial dysfunction in subclinical HIV-associated atherosclerosis.

    PubMed

    D'Abramo, Alessandra; Zingaropoli, Maria Antonella; Oliva, Alessandra; D'Agostino, Claudia; Al Moghazi, Samir; De Luca, Giulia; Iannetta, Marco; Mastroianni, Claudio Maria; Vullo, Vincenzo

    2014-01-01

    HIV-infected patients have a significantly greater risk of cardiovascular disease. Several markers including osteoprotegerin have been shown to be involved in the development and progression of atherosclerosis. We investigated the relationship between T-cell phenotype, osteoprotegerin, and atherosclerosis evaluated by carotid intima-media thickness (c-IMT) in 94 HIV+ patients on suppressive antiretroviral therapy with Framingham score <10%. As for the control group, 24 HIV-negative subjects were enrolled. c-IMT was assessed by ultrasound. CD4+/CD8+ T-cell activation (CD38+ HLADR+) and senescence (CD57+ CD28-) were measured by flow cytometry. IL-6 and OPG levels were measured by ELISA kit. c-IMT was higher in HIV+ than in controls. Among HIV+ patients, 44.7% had pathological c-IMT (?0.9?mm). CD8+ T-cell activation and senescence and OPG plasma levels were higher in HIV+ patients than in controls. Subjects with pathological c-IMT exhibited higher CD8+ immune activation and immunosenescence and OPG levels than subjects with normal c-IMT. Multivariate analysis showed that age, CD8+ CD38+ HLADR+, and CD8+ CD28- CD57+ were independently associated with pathological c-IMT. Several factors have been implicated in the pathogenesis of atherosclerosis in HIV patients. Immune activation and immunosenescence of CD8+ T cell together with OPG plasma levels might be associated with the development and progression of early atherosclerosis, even in the case of viral suppression. PMID:25374442

  3. Immune Activation, Immunosenescence, and Osteoprotegerin as Markers of Endothelial Dysfunction in Subclinical HIV-Associated Atherosclerosis

    PubMed Central

    D'Abramo, Alessandra; Zingaropoli, Maria Antonella; Oliva, Alessandra; D'Agostino, Claudia; Al Moghazi, Samir; De Luca, Giulia; Iannetta, Marco; Mastroianni, Claudio Maria; Vullo, Vincenzo

    2014-01-01

    HIV-infected patients have a significantly greater risk of cardiovascular disease. Several markers including osteoprotegerin have been shown to be involved in the development and progression of atherosclerosis. We investigated the relationship between T-cell phenotype, osteoprotegerin, and atherosclerosis evaluated by carotid intima-media thickness (c-IMT) in 94 HIV+ patients on suppressive antiretroviral therapy with Framingham score <10%. As for the control group, 24 HIV-negative subjects were enrolled. c-IMT was assessed by ultrasound. CD4+/CD8+ T-cell activation (CD38+ HLADR+) and senescence (CD57+ CD28?) were measured by flow cytometry. IL-6 and OPG levels were measured by ELISA kit. c-IMT was higher in HIV+ than in controls. Among HIV+ patients, 44.7% had pathological c-IMT (?0.9?mm). CD8+ T-cell activation and senescence and OPG plasma levels were higher in HIV+ patients than in controls. Subjects with pathological c-IMT exhibited higher CD8+ immune activation and immunosenescence and OPG levels than subjects with normal c-IMT. Multivariate analysis showed that age, CD8+ CD38+ HLADR+, and CD8+ CD28? CD57+ were independently associated with pathological c-IMT. Several factors have been implicated in the pathogenesis of atherosclerosis in HIV patients. Immune activation and immunosenescence of CD8+ T cell together with OPG plasma levels might be associated with the development and progression of early atherosclerosis, even in the case of viral suppression. PMID:25374442

  4. 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.

  5. Innate and Adaptive Immunity in Atherosclerosis

    PubMed Central

    Packard, Ren 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

  6. 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

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

    PubMed Central

    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.; Torrecilla, Esther; Vázquez, Gumersindo Fernández; Rubio, Miguel A.; Cabrerizo, Lucio; Barabash, Ana; Pernaute, Andrés Sánchez; Torres, Antonio J.; 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

  8. Periodontal innate immune mechanisms relevant to atherosclerosis.

    PubMed

    Amar, S; Engelke, M

    2015-06-01

    Atherosclerosis is a common cardiovascular disease in the USA where it is a leading cause of illness and death. Atherosclerosis is the most common cause for heart attack and stroke. Most commonly, people develop atherosclerosis as a result of diabetes, genetic risk factors, high blood pressure, a high-fat diet, obesity, high blood cholesterol levels, and smoking. However, a sizable number of patients suffering from atherosclerosis do not harbor the classical risk factors. Ongoing infections have been suggested to play a role in this process. Periodontal disease is perhaps the most common chronic infection in adults with a wide range of clinical variability and severity. Research in the past decade has shed substantial light on both the initiating infectious agents and host immunological responses in periodontal disease. Up to 46% of the general population harbors the microorganism(s) associated with periodontal disease, although many are able to limit the progression of periodontal disease or even clear the organism(s) if infected. In the last decade, several epidemiological studies have found an association between periodontal infection and atherosclerosis. This review focuses on exploring the molecular consequences of infection by pathogens that exacerbate atherosclerosis, with the focus on infections by the periodontal bacterium Porphyromonas gingivalis as a running example. PMID:25388989

  9. 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

  10. Functions of cyclophilin A in atherosclerosis

    PubMed Central

    Tian-tian, Zhang; Jun-feng, Zhang; Heng, Ge

    2013-01-01

    Cyclophilin A (CypA) is a ubiquitously distributed protein present both in intracellular and extracellular spaces. In atherosclerosis, various cells, including endothelial cells, monocytes, vascular smooth muscle cells and platelets, secrete CypA in response to excessive levels of reactive oxygen species. Atherosclerosis, a complicated disease, is the result of the interplay of different risk factors. Researchers have found that CypA links many risk factors, including hyperlipidemia, hypertension and diabetes, to atherosclerosis that develop into a vicious cycle. Furthermore, most studies have shown that secreted CypA participates in the developmental process of atherosclerosis via many important intracellular mechanisms. CypA can cause injury to and apoptosis of endothelial cells, leading to dysfunction of the endothelium. CypA may also induce the activation and migration of leukocytes, producing proinflammatory cytokines that promote inflammation in blood vessels. In addition, CypA can promote the proliferation of monocytes/macrophages and vascular smooth muscle cells, leading to the formation of foam cells and the remodelling of the vascular wall. Studies investigating the roles of CypA in atherosclerosis may provide new direction for preventive and interventional treatment strategies in atherosclerosis. PMID:23940449

  11. 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

  12. Superoxide and Peroxynitrite in Atherosclerosis

    NASA Astrophysics Data System (ADS)

    White, C. Roger; Brock, Tommy A.; Chang, Ling-Yi; Crapo, James; Briscoe, Page; Ku, David; Bradley, William A.; Gianturco, Sandra H.; Gore, Jeri; Freeman, Bruce A.; Tarpey, Margaret M.

    1994-02-01

    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 (O^-_2), 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 O^-_2. 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 ? 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 O^-_2 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.

  13. Optimal therapeutic strategy for treating patients with hypertension and atherosclerosis: focus on olmesartan medoxomil

    PubMed Central

    Mason, R Preston

    2011-01-01

    Cardiovascular (CV) disease is a major factor in mortality rates around the world and contributes to more than one-third of deaths in the US. The underlying cause of CV disease is atherosclerosis, a chronic inflammatory process that is clinically manifested as coronary artery disease, carotid artery disease, or peripheral artery disease. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Consequently, developing a treatment regimen that can slow or even reverse the atherosclerotic process is imperative. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with CV risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. Since the reninangiotensinaldosterone system (RAAS) plays a key role in vascular inflammatory responses, hypertension treatment with RAAS-blocking agents (angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin II receptor blockers [ARBs]) may slow inflammatory processes and disease progression. Reduced nitric oxide (NO) bioavailability has an important role in the process of endothelial dysfunction and hypertension. Therefore, agents that increase NO and decrease oxidative stress, such as ARBs and ACEIs, may interfere with atherosclerosis. Studies show that angiotensin II type 1 receptor antagonism with an ARB improves endothelial function and reduces atherogenesis. In patients with hypertension, the ARB olmesartan medoxomil provides effective blood pressure lowering, with inflammatory marker studies demonstrating significant RAAS suppression. Several prospective, randomized studies show vascular benefits with olmesartan medoxomil: reduced progression of coronary atherosclerosis in patients with stable angina pectoris (OLIVUS); decreased vascular inflammatory markers in patients with hypertension and micro- (pre-clinical) inflammation (EUTOPIA); improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis (MORE); and resistance vessel remodeling in patients with stage 1 hypertension (VIOS). Although CV outcomes were not assessed in these studies, the observed benefits in surrogate endpoints of disease suggest that RAAS suppression with olmesartan medoxomil may potentially have beneficial effects on CV outcomes in these patient populations. PMID:21796255

  14. T regulatory cells: a promising new target in atherosclerosis.

    PubMed

    Tselios, Konstantinos; Sarantopoulos, Alexandros; Gkougkourelas, Ioannis; Boura, Panagiota

    2014-01-01

    T regulatory cells (Tregs) comprise the cardinal mechanism of peripheral immune tolerance by modulating the function of virtually each immune cell. Given that atherosclerosis is a chronic inflammation of the arterial wall, certain components of the immune system have been proven to have a central role in its pathogenesis. Consequently, various clinical and experimental studies have been conducted to elucidate the role of Tregs in suppressing this immune-mediated inflammation. In this review, current experimental and clinical knowledge on the role of Tregs in the atherogenic process is presented after a short introduction to their generation and function. Based on these data, Treg-targeted therapeutic approaches are discussed in regard to their potential for clinical application. PMID:25404046

  15. 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

  16. 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

  17. Functionally Defective High-Density Lipoprotein and Paraoxonase: A Couple for Endothelial Dysfunction in Atherosclerosis

    PubMed Central

    Eren, Esin; Yilmaz, Necat; Aydin, Ozgur

    2013-01-01

    The endothelium is the primary target for biochemical or mechanical injuries caused by the putative risk factors of atherosclerosis. Endothelial dysfunction represents the ultimate link between atherosclerotic risk factors that promote atherosclerosis. HDL-C is thought to exert at least some parts of its antiatherogenic facilities via stimulating endothelial NO production, nearby inhibiting oxidative stress and inflammation. HDL-C is capable of opposing LDL's inductive effects and avoiding the ox-LDL's inhibition of eNOS. Paraoxonase 1 (PON1) is an HDL-associated enzyme esterase which appears to contribute to the antioxidant and antiatherosclerotic capabilities of HDL-C. Healthy HDL, namely the particle that contains the active Paraoxonase 1, has the power to suppress the formation of oxidized lipids. Dysfunctional HDL, on the contrary, has reduced Paraoxonase 1 enzyme activity and not only fails in its mission but also potentially leads to greater formation of oxidized lipids/lipoproteins to cause endothelial dysfunction. The association of HDL-C PON1 and endothelial dysfunction depends largely on the molecules with exact damaging effect on NO synthase coupling. Loss of nitric oxide bioavailability has a pivotal role in endothelial dysfunction preceding the appearance of atherosclerosis. Analyses of HDL-C and Paraoxonase1 would be more important in the diagnosis and treatment of atherosclerosis in the very near future. PMID:24222847

  18. Nanoparticles Containing a Liver X Receptor Agonist Inhibit Inflammation and Atherosclerosis

    PubMed Central

    Zhang, Xue-Qing; Even-Or, Orli; Xu, Xiaoyang; van Rosmalen, Mariska; Lim, Lucas; Gadde, Suresh

    2015-01-01

    Liver X receptor (LXR) signaling pathways regulate lipid metabolism and inflammation, which has generated widespread interest in developing synthetic LXR agonists as potential therapeutics for the management of atherosclerosis. In this study, we demonstrate that nanoparticles (NPs) containing the synthetic LXR agonist GW3965 (NP-LXR) exert anti-inflammatory effects and inhibit the development of atherosclerosis without causing hepatic steatosis. These NPs were engineered through self-assembly of a biodegradable diblock poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) copolymer. NP-LXR was significantly more effective than free GW3965 at inducing LXR target gene expression and suppressing inflammatory factors in macrophages in vitro and in vivo. Addtionally, the NPs elicited negligible lipogenic gene stimulation in the liver. Using the Ldlr−/− mouse model of atherosclerosis, we saw abundant co-localization of fluorescently labeled NPs within plaque macrophages following systemic administration. Notably, six intravenous injections of NP-LXR over two weeks markedly reduced the CD68-positive cell (macrophage) content of plaques (by 50%) without increasing total cholesterol or triglycerides in the liver and plasma. Together, these findings identify GW3965-encapsulated PLGA-b-PEG NPs as a promising nanotherapeutic approach to combat atherosclerosis, providing the benefits of LXR agonists without their adverse effects on hepatic and plasma lipid metabolism. PMID:25156796

  19. 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

  20. 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

  1. Ribosomal Protein L13a Deficiency in Macrophages Promotes Atherosclerosis by Limiting Translation Control-Dependent Retardation of Inflammation

    PubMed Central

    Basu, Abhijit; Poddar, Darshana; Robinet, Peggy; Smith, Jonathan D.; Febbraio, Maria; Baldwin, William M.; Mazumder, Barsanjit

    2014-01-01

    Objective Unresolved inflammatory response of macrophages plays a pivotal role in the pathogenesis of atherosclerosis. Previously we showed that ribosomal protein L13a-dependent translational silencing suppresses the synthesis of a cohort of inflammatory proteins in monocytes and macrophages. We also found that genetic abrogation of L13a expression in macrophages significantly compromised the resolution of inflammation in a mouse model of LPS-induced endotoxemia. However, its function in the pathogenesis of atherosclerosis is not known. Here, we examine whether L13a in macrophage has a protective role against high fat diet-induced atherosclerosis. Approach and Results We bred the macrophage-specific L13a knockout mice L13a Flox+/+ Cre+/+ onto apoE?/? background and generated the experimental double knockout (KO) mice L13a Flox+/+ Cre+/+ apoE?/?. L13a Flox+/+ Cre?/? mice on apoE?/? background were used as controls. Control and KO mice were subjected to high-fat diet for 10 weeks. Evaluation of aortic sinus sections and entire aorta by en face showed significantly higher atherosclerosis in the KO mice. Severity of atherosclerosis in KO mice was accompanied by thinning of the smooth muscle cell (SMC) layer in the media, larger macrophage area in the intimal plaque region and higher plasma levels of inflammatory cytokines. In addition, macrophages isolated from KO mice had higher polyribosomal abundance of several target mRNAs, thus showing defect in translation control. Conclusion Our data demonstrate that loss of L13a in macrophages increases susceptibility to atherosclerosis in apoE?/? mice, revealing an important role of L13a-dependent translational control as an endogenous protection mechanism against atherosclerosis. PMID:24436370

  2. Anti-inflammatory therapies for atherosclerosis.

    PubMed

    Bck, Magnus; Hansson, Gran K

    2015-04-01

    The view of atherosclerosis as an inflammatory disease has emerged from observations of immune activation and inflammatory signalling in human atherosclerotic lesions, from the definition of inflammatory biomarkers as independent risk factors for cardiovascular events, and from evidence of low-density lipoprotein-induced immune activation. Studies in animal models of hyperlipidaemia have also supported the beneficial effects of countering inflammation to delay atherosclerosis progression. Specific inflammatory pathways with relevance to human diseases have been identified, and inhibitors of these pathways are either already in use for the treatment of other diseases, or are under development and evaluation. These include 'classic' drugs (such as allopurinol, colchicine, and methotrexate), biologic therapies (for example tumour necrosis factor inhibitors and IL-1 neutralization), as well as targeting of lipid mediators (such as phospholipase inhibitors and antileukotrienes) or intracellular pathways (inhibition of NADPH oxidase, p38 mitogen-activated protein kinase, or phosphodiesterase). The evidence supporting the use of anti-inflammatory therapies for atherosclerosis is mainly based on either observational or small interventional studies evaluating surrogate markers of disease activity. Nevertheless, these data are crucial to understand the role of inflammation in atherosclerosis, and to design randomized controlled studies to evaluate the effect of specific anti-inflammatory strategies on cardiovascular outcomes. PMID:25666404

  3. 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

  4. 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...

  5. 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

  6. Carotid Atherosclerosis in Ischemic Cerebrovascular Patients

    PubMed Central

    Zhang, Ai Juan; Zhang, Ai Yuan; Zhong, Chi

    2009-01-01

    Background Cerebral emboli resulting from atherosclerosis at the carotid bifurcation is a major cause of ischemic stroke. A convenient and prompt evaluation is necessary for secondary prevention and treatment. Methods In this study, one hundred and thirty eight patients with cerebral ischemic events were enrolled; 100 patients with nonischemic cerebral diseases were enrolled as controls. Noninvasive ultrasound was used to measure the atherosclerotic plaques and intima-media thickness (IMT) of carotid and femoral artery. Results Our results showed that patients in study group had higher incidence and severity of carotid and femoral plaques, and higher mean intima-media thickness (IMT) at both the carotid and femoral sites compared with that of controls (p < 0.01). Carotid atherosclerosis were highly prone to have instability plaques in study group(p < 0.001). Conclusions This cross-sectional study showed that, the prevalence of carotid atherosclerosis and the unstable plaques were higher in cerebral ischemic patients. Keywords Carotid artery; Atherosclerosis; Intima-media thickness; Cerebral ischemic stroke PMID:22505964

  7. Innervation of the arterial wall and its modification in atherosclerosis.

    PubMed

    Chistiakov, Dmitry A; Ashwell, Kenneth W; Orekhov, Alexander N; Bobryshev, Yuri V

    2015-12-01

    The autonomic nervous system (ANS) plays an essential role in the regulation of vascular tone. Sympathetic neurotransmitters epinephrine and norepinephrine are released from the terminals of perivascular nerves and suppress endothelial production of nitric oxide (NO), an important vasodilator. Sympathetic nerves also release neuropeptide Y, a co-transmitter that stimulates vasoconstriction and proliferation of vascular smooth muscle cells. Parasympathetic nerves release acetylcholine, which leads to vascular contraction when NO production is inhibited. The ANS produces a variety of other vasoactive substances including ATP, calcitonin gene-related peptide, dopamine, and serotonin. On the other hand, the vascular system can reciprocally influence ANS activity through the release of NO, reactive oxygen species (ROS), angiotensin II, and other mechanisms. In pathological conditions such as atherosclerosis, hyperactivation of sympathetic neural activity has pro-atherogenic effects on the vascular function by increasing vasoconstriction, accumulation of modified lipoproteins in the vascular wall, induction of endothelial dysfunction, and stimulation of oxidative stress and vascular remodeling. Indeed, suppression of the sympathetic ANS should be beneficial for the treatment of cardiovascular diseases. PMID:26164815

  8. New insights into immunological aspects of atherosclerosis.

    PubMed

    Jawie?, Jacek

    2008-03-01

    Although atherosclerosis was previously thought to be mainly a degenerative disease, it is now well ascertained that its pathogenesis is inflammatory. This review describes the history of a new atherogenetic concept, including the pivotal role of apoE-knockout mice in understanding the inflammatory background of atherosclerosis. There has been lack of unequivocal evidence of an important inflammatory component in atherogenesis. This evidence was delivered by a new technique--gene targeting, for the invention of which Mario R. Capecchi, Martin J. Evans and Oliver Smithies received in 2007 the Nobel Prize in Physiology or Medicine. The pivotal stage of atherogenesis is the antigen presentation by macrophages to T lymphocytes. This antigen could be a fragment of oxidized low-density lipoproteins "digested" by macrophage, heat shock protein 60, beta2-glycoprotein I or fragments of bacterial antigens. For interaction between the immunological cells a presence of CD40 receptor on macrophages and its ligand CD40L on the surface of T lymphocytes are necessary. During the interaction between these cells an immunological type T helper 1 (Th1--cellular) or T helper 2 (Th2--humoral) response arises. Th1 response and its mediators: interferon gamma, tumor necrosis factor alpha, interleukin-1, interleukin-12 and interleukin-18 enhance atherogenesis, whereas Th2 response and its mediators: interleukin-4, interleukin-5, interleukin-10 and interleukin-13 inhibit the development of atherosclerosis. Atherosclerosis is therefore a chronic inflammatory disease, in most cases initiated by hypercholesterolemia. Nowadays, hypercholesterolemia and inflammation are considered as "partners in crime". The concept of atherosclerosis as inflammatory disease is fairly new, however, it is already considered as an undisputable achievement of science which have particular therapeutic consequences. PMID:18476459

  9. Inflammatory reactions in the pathogenesis of atherosclerosis.

    PubMed

    Fan, Jianglin; Watanabe, Teruo

    2003-01-01

    Atherosclerosis and its complications constitute the most common causes of death in Western societies and Japan. Although several theories or hypotheses about atherogenesis have been proposed during the past decades, none can completely explain the whole process of the pathogenesis of atherosclerosis because this disease is associated with multiple risk factors. In spite of this, the concept that atherosclerosis is a specific form of chronic inflammatory process resulting from interactions between plasma lipoproteins, cellular components ( monocyte/macrophages, T lymphocytes, endothelial cells and smooth muscle cells ) and the extracellular matrix of the arterial wall, is now well accepted. Histologically, atherosclerotic lesions from the early-stage ( fatty streak ) to more complicated lesions possess all the features of chronic inflammation. It has been demonstrated that atherogenic lipoproteins such as oxidized low density lipoprotein ( LDL ), remnant lipoprotein (beta-VLDL) and lipoprotein [ Lp ] ( a ) play a critical role in the pro-inflammatory reaction, whereas high density lipoprotein ( HDL ), anti-atherogenic lipoproteins, exert anti-inflammatory functions. In cholesterol-fed animals, the earliest events in the arterial wall during atherogenesis are the adhesion of monocytes and lymphocytes to endothelial cells followed by the migration of these cells into the intima. It has been shown that these early events in atherosclerosis are triggered by the presence of high levels of atherogenic lipoproteins in the plasma and are mediated by inflammatory factors such as adhesion molecules and cytokines in the arterial wall. The development of genetically modified laboratory animals ( transgenic and knock-out mice and transgenic rabbits ) has provided a powerful approach for dissecting individual candidate genes and studying their cause-and-effect relationships in lesion formation and progression. The purpose of this article is to review the recent progress regarding the inflammatory processes during the development of atherosclerosis based on both human and experimental studies. In particular, we will address the mechanisms of atherogenic lipoproteins in terms of inflammatory reactions associated with hypercholesterolemia. Understanding the molecular mechanisms responsible for inflammatory reactions during atherogenesis may help us to develop novel therapeutic strategies to control, treat and prevent atherosclerosis in the future. PMID:12740479

  10. Connecting the Lines between Hypogonadism and Atherosclerosis

    PubMed Central

    Fahed, Akl C.; Gholmieh, Joanna M.; Azar, Sami T.

    2012-01-01

    Epidemiological studies show that atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality worldwide and point to gender differences with ageing males being at highest risk. Atherosclerosis is a complex process that has several risk factors and mediators. Hypogonadism is a commonly undiagnosed disease that has been associated with many of the events, and risk factors leading to atherosclerosis. The mechanistic relations between testosterone levels, atherosclerotic events, and risk factors are poorly understood in many instances, but the links are clear. In this paper, we summarize the research journey that explains the link between hypogonadism, each of the atherosclerotic events, and risk factors. We look into the different areas from which lessons could be learned, including epidemiological studies, animal and laboratory experiments, studies on androgen deprivation therapy patients, and studies on testosterone-treated patients. We finish by providing recommendations for the clinician and needs for future research. PMID:22518131

  11. Lipidomics: A Tool for Studies of Atherosclerosis

    PubMed Central

    Ekroos, Kim; Jnis, Minna; Tarasov, Kirill; Hurme, Reini

    2010-01-01

    Lipids, abundant constituents of both the vascular plaque and lipoproteins, play a pivotal role in atherosclerosis. Mass spectrometry-based analysis of lipids, called lipidomics, presents a number of opportunities not only for understanding the cellular processes in health and disease but also in enabling personalized medicine. Lipidomics in its most advanced form is able to quantify hundreds of different molecular lipid species with various structural and functional roles. Unraveling this complexity will improve our understanding of diseases such as atherosclerosis at a level of detail not attainable with classical analytical methods. Improved patient selection, biomarkers for gauging treatment efficacy and safety, and translational models will be facilitated by the lipidomic deliverables. Importantly, lipid-based biomarkers and targets should lead the way as we progress toward more specialized therapeutics. PMID:20425241

  12. Lipoprotein lipase: from gene to atherosclerosis.

    PubMed

    Li, Yuan; He, Ping-Ping; Zhang, Da-Wei; Zheng, Xi-Long; Cayabyab, Fracisco S; Yin, Wei-Dong; Tang, Chao-Ke

    2014-12-01

    Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism and responsible for catalyzing lipolysis of triglycerides in lipoproteins. LPL is produced mainly in adipose tissue, skeletal and heart muscle, as well as in macrophage and other tissues. After synthesized, it is secreted and translocated to the vascular lumen. LPL expression and activity are regulated by a variety of factors, such as transcription factors, interactive proteins and nutritional state through complicated mechanisms. LPL with different distributions may exert distinct functions and have diverse roles in human health and disease with close association with atherosclerosis. It may pose a pro-atherogenic or an anti-atherogenic effect depending on its locations. In this review, we will discuss its gene, protein, synthesis, transportation and biological functions, and then focus on its regulation and relationship with atherosclerosis and potential underlying mechanisms. The goal of this review is to provide basic information and novel insight for further studies and therapeutic targets. PMID:25463094

  13. Molecular intravascular imaging approaches for atherosclerosis

    PubMed Central

    Press, Marcella Calfon; Jaffer, Farouc A.

    2014-01-01

    Coronary artery disease (CAD) is an inflammatory process that results in buildup of atherosclerosis, typically lipid-rich plaque in the arterial wall. Progressive narrowing of the vessel wall and subsequent plaque rupture can lead to myocardial infarction and death. Recent advances in intravascular fluorescence imaging techniques have provided exciting coronary artery-targeted platforms to further characterize the molecular changes that occur within the vascular wall as a result of atherosclerosis and following coronary stent-induced vascular injury. This review will summarize exciting recent developments in catheter-based imaging of coronary arterial-sized vessels; focusing on two-dimensional near-infrared fluorescence imaging (NIRF) molecular imaging technology as an approach to specifically identify inflammation and fibrin directly within coronary artery-sized vessels. Intravascular NIRF is anticipated to provide new insights into the in vivo biology underlying high-risk plaques, as well as high-risks stents prone to stent restenosis or stent thrombosis. PMID:25221639

  14. Phenotypic polarization of macrophages in atherosclerosis

    PubMed Central

    Leitinger, Norbert; Schulman, Ira G.

    2013-01-01

    Macrophages orchestrate the inflammatory response in inflamed tissues and recent work indicates that these cells can alter their phenotypes and functions accordingly in response to changes in the microenvironment. Initial work in models of cardiovascular disease used immunological markers to characterize macrophage phenotypes present in atherosclerotic plaque and these studies have lately been extended through the use of markers that are more specific for atherosclerosis and metabolic disease. Together these studies have led to a novel view of the function of macrophages in the development of atherosclerosis that suggests a dynamic plasticity. Understanding this plasticity and the ensuing macrophage heterogeneity could lead to novel strategies of pharmacological intervention to combat chronic inflammation in metabolic diseases. Most importantly, revealing the functional characteristics of individual macrophage phenotypes will lead to a better understanding of their contribution to lesion development and plaque stability. PMID:23640492

  15. Endothelial MicroRNAs and Atherosclerosis

    PubMed Central

    Sun, Xinghui; Belkin, Nathan; Feinberg, Mark W.

    2013-01-01

    The vascular endothelium, a thin layer of endothelial cells (ECs) that line the inner surface of blood vessels, is a critical interface between blood and all tissues. EC activation, dysfunction, and vascular inflammation occur when the endothelium is exposed to various insults such as proinflammatory cytokines, oxidative stress, hypertension, hyperglycemia, aging, and shear stress. These insults lead to the pathogenesis of a range of disease states, including atherosclerosis. Several signaling pathways, especially nuclear factor ?B mediated signaling, play crucial roles in these pathophysiological processes. Recently, microRNAs (miRNAs) have emerged as important regulators of EC function by fine-tuning gene expression. In this review, we discuss how miRNAs regulate EC function and vascular inflammation in response to a variety of pathophysiologic stimuli. An understanding of the role of miRNAs in EC activation and dysfunction may provide novel targets and therapeutic opportunities for controlling atherosclerosis and other chronic inflammatory disease states. PMID:24158362

  16. Flow-dependent cellular mechanotransduction in atherosclerosis

    PubMed Central

    Conway, Daniel E.; Schwartz, Martin A.

    2013-01-01

    Summary Atherosclerosis depends on risk factors such as hyperlipidemia, smoking, hypertension and diabetes. Although these risk factors are relatively constant throughout the arterial circulation, atherosclerotic plaques occur at specific sites where flow patterns are disturbed, with lower overall magnitude and complex changes in speed and direction. Research over the past few decades has provided new insights into the cellular mechanisms of force transduction and how mechanical effects act in concert with conventional risk factors to mediate plaque formation and progression. This Commentary summarizes our current understanding of how mechanotransduction pathways synergize with conventional risk factors in atherosclerosis. We attempt to integrate cellular studies with animal and clinical data, and highlight major questions that need to be answered to develop more effective therapies. PMID:24190880

  17. Conjugated linoleic acid and atherosclerosis in rabbits.

    PubMed

    Lee, K N; Kritchevsky, D; Pariza, M W

    1994-07-01

    Conjugated linoleic acid (CLA) consists of a series of positional and geometric dienoic isomers of linoleic acid that occur naturally in foods. CLA exhibits antioxidant activity in vitro and in vivo. To assess the effect of CLA on atherosclerosis, 12 rabbits were fed a semi-synthetic diet containing 14% fat and 0.1% cholesterol for 22 weeks. For 6 of these rabbits, the diet was augmented with CLA (0.5 g CLA/rabbit per day). Blood samples were taken monthly for lipid analysis. By 12 weeks total and LDL cholesterol and triglycerides were markedly lower in the CLA-fed group. Interestingly, the LDL cholesterol to HDL cholesterol ratio and total cholesterol to HDL cholesterol ratio were significantly reduced in CLA-fed rabbits. Examination of the aortas of CLA-fed rabbits showed less atherosclerosis. PMID:7980704

  18. 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

  19. 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

  20. 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.

  1. 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

  2. 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

  3. MicroRNA Regulation of Atherosclerosis.

    PubMed

    Feinberg, Mark W; Moore, Kathryn J

    2016-02-19

    Atherosclerosis and its attendant clinical complications, such as myocardial infarction, stroke, and peripheral artery disease, are the leading cause of morbidity and mortality in Western societies. In response to biochemical and biomechanical stimuli, atherosclerotic lesion formation occurs from the participation of a range of cell types, inflammatory mediators, and shear stress. Over the past decade, microRNAs (miRNAs) have emerged as evolutionarily conserved, noncoding small RNAs that serve as important regulators and fine-tuners of a range of pathophysiological cellular effects and molecular signaling pathways involved in atherosclerosis. Accumulating studies reveal the importance of miRNAs in regulating key signaling and lipid homeostasis pathways that alter the balance of atherosclerotic plaque progression and regression. In this review, we highlight current paradigms of miRNA-mediated effects in atherosclerosis progression and regression. We provide an update on the potential use of miRNAs diagnostically for detecting increasing severity of coronary disease and clinical events. Finally, we provide a perspective on therapeutic opportunities and challenges for miRNA delivery in the field. PMID:26892968

  4. Atherosclerosis in epilepsy: its causes and implications.

    PubMed

    Hamed, Sherifa A

    2014-12-01

    Evidence from epidemiological, longitudinal, prospective, double-blinded clinical trials as well as case reports documents age-accelerated atherosclerosis with increased carotid artery intima media thickness (CA-IMT) in patients with epilepsy. These findings raise concern regarding their implications for age-accelerated cognitive and behavioral changes in midlife and risk of later age-related cognitive disorders including neurodegenerative processes such as Alzheimer's disease (AD). Chronic epilepsy, cerebral atherosclerosis, and age-related cognitive disorders including AD share many clinical manifestations (e.g. characteristic cognitive deficits), risk factors, and structural and pathological brain abnormalities. These shared risk factors include increased CA-IMT, hyperhomocysteinemia (HHcy), lipid abnormalities, weight gain and obesity, insulin resistance (IR), and high levels of inflammatory and oxidative stresses. The resulting brain structural and pathological abnormalities include decreased volume of the hippocampus, increased cortical thinning of the frontal lobe, ventricular expansion and increased white matter ischemic disease, total brain atrophy, and ?-amyloid protein deposition in the brain. The knowledge that age-accelerated atherosclerosis may contribute to age-accelerated cognitive and behavioral abnormalities and structural brain pathologies in patients with chronic epilepsy represents an important research path to pursue future clinical and management considerations. PMID:25164495

  5. Mesenchymal Stem Cells Reduce Murine Atherosclerosis Development.

    PubMed

    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

  6. Lifestyle effects on hematopoiesis and atherosclerosis.

    PubMed

    Nahrendorf, Matthias; Swirski, Filip K

    2015-02-27

    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 neuroimmune and immunometabolic 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

  7. 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

  8. The role of the vascular dendritic cell network in atherosclerosis

    PubMed Central

    Alberts-Grill, Noah; Denning, Timothy L.; Rezvan, Amir

    2013-01-01

    A complex role has been described for dendritic cells (DCs) in the potentiation and control of vascular inflammation and atherosclerosis. Resident vascular DCs are found in the intima of atherosclerosis-prone vascular regions exposed to disturbed blood flow patterns. Several phenotypically and functionally distinct vascular DC subsets have been described. The functional heterogeneity of these cells and their contributions to vascular homeostasis, inflammation, and atherosclerosis are only recently beginning to emerge. Here, we review the available literature, characterizing the origin and function of known vascular DC subsets and their important role contributing to the balance of immune activation and immune tolerance governing vascular homeostasis under healthy conditions. We then discuss how homeostatic DC functions are disrupted during atherogenesis, leading to atherosclerosis. The effectiveness of DC-based “atherosclerosis vaccine” therapies in the treatment of atherosclerosis is also reviewed. We further provide suggestions for distinguishing DCs from macrophages and discuss important future directions for the field. PMID:23552284

  9. 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

  10. Nitro-fatty acids reduce atherosclerosis in apoE?/? mice

    PubMed Central

    Rudolph, Tanja K.; Rudolph, Volker; Edreira, Martin M.; Cole, Marsha P.; Bonacci, Gustavo; Schopfer, Francisco J.; Woodcock, Steven R.; Franek, Andreas; Pekarova, Michaela; Khoo, Nicholas KH; Hasty, Alyssa H.; Baldus, Stephan; Freeman, Bruce A.

    2010-01-01

    Objective Inflammatory processes and foam cell formation are key determinants in the initiation and progression of atherosclerosis. Electrophilic nitro-fatty acids, byproducts of nitric oxide- and nitrite-dependent redox reactions of unsaturated fatty acids, exhibit anti-inflammatory signaling actions in inflammatory and vascular cell model systems. The in vivo action of nitro-fatty acids in chronic inflammatory processes such as atherosclerosis remains to be elucidated. Methods and Results Herein, we demonstrate that subcutaneously administered 9- and 10-nitro-octadecenoic acid (nitro-oleic acid) potently reduced atherosclerotic lesion formation in apolipoprotein E deficient mice. Nitro-fatty acids did not modulate serum lipoprotein profiles. Immunostaining and gene expression analyses revealed that nitro-oleic acid attenuated lesion formation by suppressing tissue oxidant generation, inhibiting adhesion molecule expression and decreasing vessel wall infiltration of inflammatory cells. In addition, nitro-oleic acid reduced foam cell formation by attenuating oxidized LDL-induced phosphorylation of signal transducer and activator of transcription-1 (STAT-1), a transcription factor linked to foam cell formation in atherosclerotic plaques. Atherosclerotic lesions of nitro-oleic acid-treated animals also showed an increased content of collagen and ?-smooth muscle actin, suggesting conferral of higher plaque stability. Conclusions These results reveal the anti-atherogenic actions of electrophilic nitro-fatty acids in a murine model of atherosclerosis. PMID:20167658

  11. 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

  12. 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

  13. The Bcl6SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis

    PubMed Central

    Barish, Grant D.; Yu, Ruth T.; Karunasiri, Malith S.; Becerra, Diana; Kim, Jason; Tseng, Tiffany W.; Tai, Li-Jung; LeBlanc, Matthias; Diehl, Cody; Cerchietti, Leandro; Miller, Yury I.; Witztum, Joseph L.; Melnick, Ari M.; Dent, Alexander L.; Tangirala, Rajendra K.; Evans, Ronald M.

    2012-01-01

    SUMMARY Chronic inflammation is a hallmark of atherosclerosis, but its transcriptional underpinnings are poorly understood. We show that the transcriptional repressor Bcl6 is an anti-inflammatory regulator whose loss in bone marrow of Ldlr?/? mice results in severe atherosclerosis and xanthomatous tendonitis, a virtually pathognomonic complication in patients with familial hypercholesterolemia. Disruption of the interaction between Bcl6 and SMRT or NCoR with a peptide inhibitor in vitro recapitulated atherogenic gene changes in mice transplanted with Bcl6-deficient bone marrow, pointing to these cofactors as key mediators of Bcl6 inflammatory suppression. Using ChIP-seq, we reveal the SMRT and NCoR co-repressor cistromes, each consisting of over 30,000 binding sites with a nearly 50% overlap. While the complete cistromes identify a diversity of signaling pathways, the Bcl6-bound sub-cistromes for each co-repressor are highly enriched for NF-?B-driven inflammatory and tissue remodeling genes. These results reveal that Bcl6-SMRT/NCoR complexes constrain immune responses and contribute to the prevention of atherosclerosis. PMID:22465074

  14. Function of CD147 in atherosclerosis and atherothrombosis.

    PubMed

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

    2015-02-01

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

  15. 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

  16. Correlating corneal arcus with atherosclerosis in familial hypercholesterolemia

    PubMed Central

    Zech, Loren A; Hoeg, Jeffery M

    2008-01-01

    Background A relationship between corneal arcus and atherosclerosis has long been suspected but is controversial. The homozygous familial hypercholesterolemia patients in this study present a unique opportunity to assess this issue. They have both advanced atherosclerosis and corneal arcus. Methods This is a cross-sectional study of 17 patients homozygous for familial hypercholesterolemia presenting to the Clinical Center of the National Institutes of Health. Plasma lipoproteins, circumferential extent of arcus, thoracic aorta and coronary calcific atherosclerosis score, and Achilles tendon width were measured at the National Institutes of Health. Results Patients with corneal arcus had higher scores for calcific atherosclerosis (mean 2865 compared to 412), cholesterol-year score (mean 11830 mg-yr/dl compared to 5707 mg-yr/dl), and Achilles tendon width (mean 2.54 cm compared to 1.41 cm) than those without. Corneal arcus and Achilles tendon width were strongly correlated and predictive of each other. Although corneal arcus was correlated with calcific atherosclerosis (r = 0.67; p = 0.004), it was not as highly correlated as was the Achilles tendon width (r = 0.855; p < 0.001). Conclusion Corneal arcus reflects widespread tissue lipid deposition and is correlated with both calcific atherosclerosis and xanthomatosis in these patients. Patients with more severe arcus tend to have more severe calcific atherosclerosis. Corneal arcus is not as good an indicator of calcific atherosclerosis as Achilles tendon thickness, but its presence suggests increased atherosclerosis in these hypercholesterolemic patients. PMID:18331643

  17. Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration

    PubMed Central

    Wang, Y; Parlevliet, E T; Geerling, J J; Tuin, S J L; Zhang, H; Bieghs, V; Jawad, A H M; Shiri-Sverdlov, R; Bot, I; Jager, S C A; Havekes, L M; Romijn, J A; Willems van Dijk, K; Rensen, P C N

    2014-01-01

    Background and Purpose The aetiology of inflammation in the liver and vessel wall, leading to non-alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored. Here, we tested the hypothesis that exendin-4 reduces inflammation in both the liver and vessel wall, and investigated the common underlying mechanism. Experimental Approach Female APOE*3-Leiden.CETP mice, a model with human-like lipoprotein metabolism, were fed a cholesterol-containing Western-type diet for 5 weeks to induce atherosclerosis and subsequently treated for 4 weeks with exendin-4. Key Results Exendin-4 modestly improved dyslipidaemia, but markedly decreased atherosclerotic lesion severity and area (?33%), accompanied by a reduction in monocyte adhesion to the vessel wall (?42%) and macrophage content in the plaque (?44%). Furthermore, exendin-4 reduced hepatic lipid content and inflammation as well as hepatic CD68+ (?18%) and F4/80+ (?25%) macrophage content. This was accompanied by less monocyte recruitment from the circulation as the Mac-1+ macrophage content was decreased (?36%). Finally, exendin-4 reduced hepatic chemokine expression in vivo and suppressed oxidized low-density lipoprotein accumulation in peritoneal macrophages in vitro, effects dependent on the GLP-1 receptor. Conclusions and Implications Exendin-4 reduces inflammation in both the liver and vessel wall by reducing macrophage recruitment and activation. These data suggest that exendin-4 could be a valuable strategy to treat NASH and atherosclerosis simultaneously. PMID:24490861

  18. 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.

  19. 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 baseline parameters. Conclusion Use of the ARB irbesartan as an add-on to other antihypertensive therapy did not significantly affect intradialytic hemodynamics, neither in short nor long-term, and no significant increase in hypotensive episodes was seen. Trial registration Clinicaltrials.gov NCT00791830 PMID:26030651

  20. 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-?B 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

  1. 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

  2. Statins and atherosclerosis: the role of epigenetics.

    PubMed

    Storino Farina, Marcelo; Rojano Rada, Jairo; Molina Garrido, Antony; Martnez, 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

  3. Imaging and nanomedicine in inflammatory atherosclerosis.

    PubMed

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

    2014-06-01

    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

  4. 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

  5. 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.

  6. 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

  7. 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 ...

  8. 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

  9. 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

  10. Effect of cuprofilin on experimental atherosclerosis.

    PubMed

    Vlad, M; Bordas, E; Caseanu, E; Uza, G; Creteanu, E; Polinicenco, C

    1995-04-01

    The effect of Cuprofilin, a newly synthesized C.(II)-chlorophyll complex, was assessed in rats with experimental atherosclerosis. The study was focused on changes in serum cholesterol, lipids, and triglycerides concentration as well as on serum and abdominal aorta Cu and Zn values. It has been ascertained that after 90 d in animals fed a rich lipid diet there was a statistically significant increase in serum cholesterol, triglycerides, and lipid concentration (p < 0.01). A significant augmentation of serum Cu values (p < 0.01) accompanied by a marked lowering of the same element in abdominal aorta (p < 0.01) was also found, as compared to the results registered in the control group. However, Cuprofilin, administered for 90 d in the group of animals with experimental atherosclerosis, significantly decreased the serum cholesterol, triglycerides, and serum lipid values (p < 0.01), increased copper content in aortic tissue (p < 0.01) and lowered serum copper concentration (p < 0.01) as compared to the untreated group. Moreover, in the aorta of administered animals the lipid infiltration has been demonstrated to be significantly diminished vs the untreated group. PMID:7626376

  11. 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.

  12. Carotid Intima-Media Thickness for Atherosclerosis.

    PubMed

    Nezu, Tomohisa; Hosomi, Naohisa; Aoki, Shiro; Matsumoto, Masayasu

    2016-01-01

    The carotid intima-media thickness (IMT) is a widely used surrogate marker for atherosclerosis worldwide. The carotid IMT can be simply, noninvasively, and reproducibly measured through B-mode carotid ultrasound. The carotid IMT is also a strong predictor of future cerebral and cardiovascular events. In addition, regressions of increased carotid IMT by lipid-lowering and antihypertensive drugs have been reported. Despite the strong association between increased carotid IMT and cardiovascular disease, it remains unclear whether routine carotid IMT measurement is useful for the detection of subclinical atherosclerosis in clinical practice. Researches should consider other methodological aspects, such as the definition of carotid plaques, the choice of measurement sites on the common or internal carotid artery, and the assessment of maximum or minimum IMT. The detailed guidelines for measuring carotid IMT vary by county. Thus, the usefulness of the carotid IMT may be assessed in different countries taking racial differences into account. Other important parameters revealed by carotid ultrasound, such as artery stenosis and the characteristics and size of plaques, should also be considered. Physicians should comprehensively interpret the results of carotid ultrasonography. Therefore, carotid ultrasonography is an essential tool for assessing cardiovascular risk in clinical settings. PMID:26460381

  13. Periodontitis as a Risk Factor of Atherosclerosis

    PubMed Central

    Bartova, Jirina; Sommerova, Pavla; Lyuya-Mi, Yelena; Mysak, Jaroslav; Janatova, Tatjana; Podzimek, Stepan

    2014-01-01

    Over the last two decades, the amount of evidence corroborating an association between dental plaque bacteria and coronary diseases that develop as a result of atherosclerosis has increased. These findings have brought a new aspect to the etiology of the disease. There are several mechanisms by which dental plaque bacteria may initiate or worsen atherosclerotic processes: activation of innate immunity, bacteremia related to dental treatment, and direct involvement of mediators activated by dental plaque and involvement of cytokines and heat shock proteins from dental plaque bacteria. There are common predisposing factors which influence both periodontitis and atherosclerosis. Both diseases can be initiated in early childhood, although the first symptoms may not appear until adulthood. The formation of lipid stripes has been reported in 10-year-old children and the increased prevalence of obesity in children and adolescents is a risk factor contributing to lipid stripes development. Endothelium damage caused by the formation of lipid stripes in early childhood may lead to bacteria penetrating into blood circulation after oral cavity procedures for children as well as for patients with aggressive and chronic periodontitis. PMID:24741613

  14. 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

  15. NPC1, intracellular cholesterol trafficking and atherosclerosis.

    PubMed

    Yu, Xiao-Hua; Jiang, Na; Yao, Ping-Bo; Zheng, Xi-Long; Cayabyab, Francisco S; Tang, Chao-Ke

    2014-02-15

    Post-lysosomal cholesterol trafficking is an important, but poorly understood process that is essential to maintain lipid homeostasis. Niemann-Pick type C1 (NPC1), an integral membrane protein on the limiting membrane of late endosome/lysosome (LE/LY), is known to accept cholesterol from NPC2 and then mediate cholesterol transport from LE/LY to endoplasmic reticulum (ER) and plasma membrane in a vesicle- or oxysterol-binding protein (OSBP)-related protein 5 (ORP5)-dependent manner. Mutations in the NPC1 gene can be found in the majority of NPC patients, who accumulate massive amounts of cholesterol and other lipids in the LE/LY due to a defect in intracellular lipid trafficking. Liver X receptor (LXR) is the major positive regulator of NPC1 expression. Atherosclerosis is the pathological basis of coronary heart disease, one of the major causes of death worldwide. NPC1 has been shown to play a critical role in the atherosclerotic progression. In this review, we have summarized the role of NPC1 in regulating intracellular cholesterol trafficking and atherosclerosis. PMID:24296264

  16. Cardiac CT: atherosclerosis to acute coronary syndrome

    PubMed Central

    Munnur, Ravi Kiran; Cameron, James D.; Ko, Brian S.; Meredith, Ian T.

    2014-01-01

    Coronary computed tomographic angiography (CCTA) is a robust non-invasive method to assess coronary artery disease (CAD). Qualitative and quantitative assessment of atherosclerotic coronary stenosis with CCTA has been favourably compared with invasive coronary angiography (ICA) and intravascular ultrasound (IVUS). Importantly, it allows the study of preclinical stages of atherosclerotic disease, may help improve risk stratification and monitor the progressive course of the disease. The diagnostic accuracy of CCTA in the assessment of coronary artery bypass grafts (CABG) is excellent and the constantly improving technology is making the evaluation of stents feasible. Novel techniques are being developed to assess the functional significance of coronary stenosis. The excellent negative predictive value of CCTA in ruling out disease enables early and safe discharge of patients with suspected acute coronary syndromes (ACS) in the Emergency Department (ED). In addition, CCTA is useful in predicting clinical outcomes based on the extent of coronary atherosclerosis and also based on individual plaque characteristics such as low attenuation plaque (LAP), positive remodelling and spotty calcification. In this article, we review the role of CCTA in the detection of coronary atherosclerosis in native vessels, stented vessels, calcified arteries and grafts; the assessment of plaque progression, evaluation of chest pain in the ED, assessment of functional significance of stenosis and the prognostic significance of CCTA. PMID:25610801

  17. On to the road to degradation: atherosclerosis and the proteasome

    PubMed Central

    Herrmann, Joerg; Lerman, Lilach O.; Lerman, Amir

    2010-01-01

    Protein metabolism is a central element of every living cell. The ubiquitin-proteasome system (UPS) is an integral part of the protein metabolism machinery mediating post-transcriptional processing and degradation of the majority of intracellular proteins. Over the past few years, remarkable progress has been made in our understanding of the role of the UPS in vascular biology and pathobiology, particularly atherosclerosis. This review reflects on the recent developments from the effects on endothelial cells and the initial stage of atherosclerosis to the effects on vascular smooth muscle and the progression stage of atherosclerosis and finally to the effects on cell viability and the complication stage of atherosclerosis. It will conclude with the integration of the available information in a synoptic view of the involvement of the UPS in atherosclerosis. PMID:19815565

  18. Accelerated atherosclerosis in SLE: mechanisms and prevention approaches.

    PubMed

    Wilhelm, Ashley J; Major, Amy S

    2012-10-01

    Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by increased serum autoantibody levels and tissue damage. With improved diagnosis and more effective treatment of the resultant kidney disease, accelerated atherosclerosis has become a major cause of morbidity in patients suffering from SLE. Although the exact mechanisms for SLE-accelerated atherosclerosis are unknown, multiple factors have been established as potential players in this process. Among these potential players are dysregulation of T and B cell populations and increased circulating levels of inflammatory cytokines. In addition, SLE patients exhibit a proatherogenic lipid profile characterized by low HDL and high LDL and triglycerides. Recent therapeutic approaches have focused on targeting B cells, the producers of autoantibodies, but most studies do not consider the effects of these treatments on atherosclerosis. Evidence suggests that T cells play a major role in SLE-accelerated atherosclerosis. Therefore, therapies targeted at T cells may also prove invaluable in treating SLE and atherosclerosis. PMID:24672580

  19. Deficiency of the NR4A Orphan Nuclear Receptor NOR1 in Hematopoietic Stem Cells Accelerates Atherosclerosis

    PubMed Central

    Qing, Hua; Liu, Yi; Zhao, Yue; Aono, Jun; Jones, Karrie L.; Heywood, Elizabeth B.; Howatt, Deborah; Binkley, Cassi M.; Daugherty, Alan; Liang, Ying; Bruemmer, Dennis

    2014-01-01

    Objective The NR4A orphan nuclear receptor NOR1 functions as a constitutively active transcription factor regulating cellular inflammation and proliferation. In the present study, we employed bone marrow transplantation to determine the selective contribution of NOR1 expression in hematopoietic stem cells to the development of atherosclerosis. Methods and Results Reconstitution of lethally irradiated apoE?/? mice with NOR1-deficient hematopoietic stem cells accelerated atherosclerosis formation and macrophage recruitment following feeding a diet enriched in saturated fat. NOR1 deficiency in hematopoietic stem cells induced splenomegaly and monocytosis, specifically the abundance of inflammatory Ly6C+ monocytes. Bone marrow transplantation studies further confirmed that NOR1 suppresses the proliferation of macrophage and dendritic progenitor (MDP) cells. Expression analysis identified RUNX1, a critical regulator of hematopoietic stem cell expansion, as a target gene suppressed by NOR1 in MDP cells. Finally, in addition to inducing Ly6C+ monocytosis, NOR1 deletion increased the replicative rate of lesional macrophages and induced local foam cell formation within the atherosclerotic plaque. Conclusion Collectively, our studies demonstrate that NOR1 deletion in hematopoietic stem cells accelerates atherosclerosis formation by promoting myelopoiesis in the stem cell compartment and by inducing local pro-atherogenic activities in the macrophage, including lesional macrophage proliferation and foam cell formation. PMID:24806827

  20. Deficiency of the NR4A orphan nuclear receptor NOR1 in hematopoietic stem cells accelerates atherosclerosis.

    PubMed

    Qing, Hua; Liu, Yi; Zhao, Yue; Aono, Jun; Jones, Karrie L; Heywood, Elizabeth B; Howatt, Deborah; Binkley, Cassi M; Daugherty, Alan; Liang, Ying; Bruemmer, Dennis

    2014-09-01

    The NR4A orphan nuclear receptor NOR1 functions as a constitutively active transcription factor regulating cellular inflammation and proliferation. In this study, we used bone marrow transplantation to determine the selective contribution of NOR1 expression in hematopoietic stem cells to the development of atherosclerosis. Reconstitution of lethally irradiated apoE(-/-) mice with NOR1-deficient hematopoietic stem cells accelerated atherosclerosis formation and macrophage recruitment following feeding a diet enriched in saturated fat. NOR1 deficiency in hematopoietic stem cells induced splenomegaly and monocytosis, specifically the abundance of inflammatory Ly6C(+) monocytes. Bone marrow transplantation studies further confirmed that NOR1 suppresses the proliferation of macrophage and dendritic progenitor (MDP) cells. Expression analysis identified RUNX1, a critical regulator of hematopoietic stem cell expansion, as a target gene suppressed by NOR1 in MDP cells. Finally, in addition to inducing Ly6C(+) monocytosis, NOR1 deletion increased the replicative rate of lesional macrophages and induced local foam cell formation within the atherosclerotic plaque. Collectively, our studies demonstrate that NOR1 deletion in hematopoietic stem cells accelerates atherosclerosis formation by promoting myelopoiesis in the stem cell compartment and by inducing local proatherogenic activities in the macrophage, including lesional macrophage proliferation and foam cell formation. PMID:24806827

  1. 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

  2. The pathogenesis of atherosclerosis: atherogenesis and inflammation.

    PubMed

    Munro, J M; Cotran, R S

    1988-03-01

    Current concepts of the pathogenesis of atherosclerosis have been reviewed, emphasizing some of the similarities of the mechanisms and events involved to those in inflammation. Figure 2 is a schematic summary of these events. Hyperlipidemia, or some component of hyperlipidemic serum, as well as other risk factors, are thought to cause endothelial injury, resulting in adhesion of platelets and/or monocytes and release of PDGF (and other growth factors), which leads to smooth muscle migration and proliferation. It is clear that endothelial injury need not be denuding, and in fact may consist of altered endothelial function (dysfunction); adhesion of monocytes, increased permeability of endothelium, and disturbances in growth control can occur without morphologically obvious endothelial injury. Hyperlipidemia, hypertension, smoking, immune injury, and other risk factors may contribute to this endothelial dysfunction in different ways and sometimes in combination. Smooth muscle cells produce large amounts of collagen, elastin, and proteoglycans and these form part of the atheromatous plaque. Hyperlipidemia contributes in a number of ways (as discussed earlier), and indeed, in the severely hypercholesterolemic patient, such as one with familial hypercholesterolemia, is alone sufficient to cause atherosclerosis in the absence of other risk factors. Foam cells of atheromatous plaques are derived both from macrophages and from smooth muscle cells; from macrophages via the beta-VLDL receptor and also possibly by way of LDL modification, recognized by the acetyl-LDL receptor (such as oxidized LDL); and from smooth muscle cells by less certain mechanisms. Extracellular lipid is derived from insudation from the lumen, particularly in the presence of hypercholesterolemia, and also from degenerating foam cells. Cholesterol accumulation in the plaque should be viewed as reflecting imbalance between influx and efflux, and it is possible that high-density lipoprotein is the molecule which helps clear the cholesterol from these accumulations (134). The diagram (right) also depicts the possibility that smooth muscle proliferation may occur without endothelial injury at all. There are several postulated mechanisms for such an occurrence: loss of growth control, direct smooth muscle injury (such as by LDL), and autonomous proliferation by the mechanisms suggested by Benditt. The theoretical scheme presented is based largely on in vitro work, only partly substantiated by experimental and human studies, and does not explain the precise mechanisms by which all risk factors increase the susceptibility to atherosclerosis.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3279259

  3. Suppression of adrenal ?arrestin1-dependent aldosterone production by ARBs: head-to-head comparison.

    PubMed

    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 ?arrestin1 (?arr1), both of which can couple to its type 1 receptors (AT?Rs), 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 AT?R antagonist drugs (angiotensin receptor blockers, ARBs, or sartans) at preventing activation of these two signaling mediators (G proteins and ?arrs) 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 AT?R. However, candesartan and valsartan were the most potent at blocking AngII-induced ?arr 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 AT?R, with very low potency towards ?arr inhibition. As a result, they were very weak suppressors of ?arr1-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

  4. 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

  5. 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

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

    PubMed

    Dorighello, Gabriel G; Paim, Bruno A; Kiihl, Samara F; Ferreira, Mnica 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

  7. 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

  8. 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

  9. 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.

  10. Atherosclerosis risk factors in pigeon squabs

    SciTech Connect

    Klumpp, S.A.; Clarkson, T.B.

    1986-03-01

    The basis for atherosclerosis susceptibility of White Carneau (WC) and resistance of Show Racer (SR) pigeons is not known. Body weight (BW), total serum cholesterol (TSC), growth of the aorta and replication of endothelial cells of the distal thoracic aorta (lesion prone site) of 1, 2 and 4 week old squabs were studied. Aortic measurements were determined morphometrically, and endothelial cell replication was quantitated by 24-hour /sup 3/H-thymidine labeling and whole-mount SEM autoradiography. From hatching to 4 weeks, BW increased more in WC than SR (22 to 473 gm in WC vs 19 to 416 gm in SR, p < 0.05) in WC than SR (197, 243 and 338 mg/dl in WC and 125, 194 and 282 mg/dl in SR). Surface area of the aorta between 1 and 4 weeks increased by 63% (109, 154 and 178 mm/sup 2/) in WC and 44% (101, 140 and 146 mm/sup 2/) in SR. Aortic surface area was significantly larger (0 = 0.002) in the 4 week WC than 4 week SR. /sup 3/H-thymidine labeled endothelial cells at 1, 2 and 4 weeks were 783, 387 and 53 in WC and 674, 283 and 27 cells/mm/sup 2/ in SR. Endothelial replication in the 4 week WC was twice that of the SR and significantly different between breeds at 2 and 4 weeks (p = 0.04; p = 0.02, respectively). Higher TSC, endothelial cell replication and larger aortic surface area in the WC may be contributing factors to increased atherosclerosis susceptibility.

  11. 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

  12. P2X7R is involved in the progression of atherosclerosis by promoting NLRP3 inflammasome activation

    PubMed Central

    PENG, KUANG; LIU, LUSHAN; WEI, DANGHENG; LV, YUNCHENG; WANG, GANG; XIONG, WENHAO; WANG, XIAOQING; ALTAF, AFRASYAB; WANG, LILI; HE, DAN; WANG, HONGYAN; QU, PENG

    2015-01-01

    Purinergic 2X7 receptor (P2X7R) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) are expressed in macrophages in atherosclerotic lesions. However, the mechanisms through which P2X7R participates in the inflammatory response in atherosclerosis remain largely unknown. The aim of the present study was to investigate the role of P2X7R in atherosclerosis and the mechanisms of action of the NLRP3 inflammasome following stimulation with oxidized low-density lipoprotein (oxLDL). We observed the expression and distribution of P2X7R in the atherosclerotic plaque in the coronary arteries from an autopsy specimen and in that of the aortic sinuses of apoE?/? mice by immunohistochemistry and immunofluorescence staining. The specificity of short interfering RNA (siRNA) was used to suppress P2X7R and NLRP3 mRNA expression. RT-qPCR and western blot analysis were used to analyze mRNA and protein expression, respectively. Co-immunoprecipitation was used to examine the interaction between protein kinase R (PKR) phosphorylation and NLRP3. P2X7R and NLRP3 were expressed at high levels in the atherosclerotic plaque in the coronary arteries. Stimulation with oxLDL upregulated P2X7R, NLRP3 and interleukin (IL)-1? expression. P2X7R knockdown by siRNA suppressed NLRP3 inflammasome activation by inhibiting the PKR phosphorylation mediated by oxLDL. In the atherosclerotic lesions in the aortic sinuses of apoE?/? mice, P2X7R expression was found at high levels. Moreover, P2X7R siRNA attenuated the development of atherosclerosis in the apoE?/? mice. In conclusion, our results demonstrate that P2X7R plays a significant role in the development of atherosclerosis and regulates NLRP3 inflammasome activation by promoting PKR phosphorylation. PMID:25761252

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

    PubMed

    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

  14. 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

  15. 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

  16. Association of blood lactate with carotid atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study

    PubMed Central

    Subash Shantha, Ghanshyam Palamaner; Wasserman, Bruce; Astor, Brad C.; Coresh, Josef; Brancati, Fredrick; Sharrett, A. Richey; Young, J. Hunter

    2013-01-01

    Objectives Cardiovascular risk factors such as aging, smoking, and insulin resistance may lead to atherosclerosis through various mechanisms of which their association with mitochondrial dysfunction may be one of them. In order to examine this hypothesis, we assessed the association between elevated blood lactate, a marker of mitochondrial dysfunction, and carotid atherosclerosis. Methods From a total of 2066 participants from the Atherosclerosis Risk In Communities Carotid MRI study, 1496 were included for this analysis. Wall Thickness and Lipid core presence were measured using gadolinium-enhanced MRI. Blood lactate was categorized into quartiles (Q1: < 5.9 mg/dl, Q2: 5.9 to 7.2mg/dl, Q3: 7.3 to 9.2 mg/dl, and Q4: >9.2 mg/dl). Results Of the 1496 study participants, 763 (51%) were females, 296 (19.8%) African American, 539 (36%) obese and 308 (20.6%) had diabetes. There was a strong and graded association between lactate and wall thickness [Q1: 1.08 mm (95% CI: 1.01 mm 1.15 mm), Q2: 1.33 mm (95% CI: 1.19 mm 1.47 mm), Q3: 1.44 (95% CI: 1.34 mm 1.54 mm) and Q4: 1.62 (95% CI: 1.53 mm 1.71 mm); p for trend <0.001] after adjusting for age, gender, ethnicity, stature, body mass index (BMI), waist circumference, LDL, High sensitivity C reactive protein (HsCRP), statin use, thiazolodinedione use, hypertension, and diabetes. This association was attenuated, but still significant, after adjusting for a marker of insulin resistance, the triglyceride/HDL ratio, [Q1: 0.96 mm (95% CI: 0.82 mm 1.10 mm), Q2: 1.17 mm (95% CI: 1.08 mm 1.26 mm), Q3: 1.18 mm (95% CI: 1.07 mm 1.29 mm), Q4: 1.22 mm (95% CI: 1.13 mm 1.31 mm), p for linear trend 0.039]. There was no association of lactate with lipid core presence after adjustment for wall thickness. Conclusions Blood lactate is associated with carotid atherosclerosis. Attenuation of the association with adjustment for triglyceride/HDL ratio, a marker of insulin resistance, suggests that lactates association with carotid atherosclerosis may be related to insulin resistance. PMID:23510829

  17. 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

  18. NR4A Nuclear Receptors in Immunity and Atherosclerosis

    PubMed Central

    Hamers, Anouk A.J.; Hanna, Richard N.; Nowyhed, Heba; Hedrick, Catherine C.; de Vries, Carlie J.M.

    2015-01-01

    Purpose of review To understand chronic inflammatory diseases such as atherosclerosis, we require in-depth knowledge on immune cell differentiation, function of specific immune cell subsets and endothelial cell-mediated extravasation. In this review we summarize a number of very recent observations on the pivotal function of NR4A nuclear receptors in immunity and atherosclerosis. Recent findings NR4A nuclear receptors are involved in negative selection of thymocytes, Treg differentiation and the development of Ly6C? monocytes has recently been shown to be dependent on the subfamily member Nur77. Nur77 and Nurr1 attenuate atherosclerosis in mice whereas NOR1 aggravates vascular lesion formation. Summary These exciting, novel insights on the function of NR4A nuclear receptors in immunity, vascular cells and atherosclerosis, will initiate a plethora of studies to understand the underlying molecular mechanisms, which will accumulate in the identification of novel targets to modulate chronic inflammatory disease. PMID:24005216

  19. Local Bone Marrow Renin-Angiotensin System and Atherosclerosis

    PubMed Central

    Beyazit, Yavuz; Purnak, Tugrul; Guven, Gulay Sain; Haznedaroglu, Ibrahim C.

    2011-01-01

    Local hematopoietic bone marrow (BM) renin-angiotensin system (RAS) affects the growth, production, proliferation differentiation, and function of hematopoietic cells. Angiotensin II (Ang II), the dominant effector peptide of the RAS, regulates cellular growth in a wide variety of tissues in pathobiological states. RAS, especially Ang II and Ang II type 1 receptor (AT1R), has considerable proinflammatory and proatherogenic effects on the vessel wall, causing progression of atherosclerosis. Recent investigations, by analyzing several BM chimeric mice whose BM cells were positive or negative for AT1R, disclosed that AT1R in BM cells participates in the pathogenesis of atherosclerosis. Therefore, AT1R blocking not only in vascular cells but also in the BM could be an important therapeutic approach to prevent atherosclerosis. The aim of this paper is to review the function of local BM RAS in the pathogenesis of atherosclerosis. PMID:21234405

  20. Overexpression of lysosomal acid lipase and other proteins in atherosclerosis.

    PubMed

    Zschenker, Oliver; Illies, Till; Ameis, Detlev

    2006-07-01

    Atherosclerosis is one of the major causes of morbidity and mortality in the western world. The existing data of elevated expression levels of proteins like DNA damage and DNA repair enzymes in human atherosclerotic plaques are reviewed. From the literature, the effect of overexpression of different proteins using adenoviral vectors or the model of transgenic mice on the development of atherosclerosis will be discussed. Special focus is placed on the lysosomal acid lipase (LAL), because LAL connects extra-cellular with intra-cellular lipid metabolism and is the only hydrolase for cleavage of cholesteryl esters delivered to the lysosomes. Patients with a deficiency of LAL show an accumulation of lipids in the cells and develop pre-mature atherosclerosis. To answer the question of the influence of LAL in atherosclerosis if overexpressed, we show for the first time data of transgenic mice overexpressing LAL and the effect on the lipid level. PMID:16877765

  1. 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

  2. Children and Heart Disease (Atherosclerosis) (Beyond the Basics)

    MedlinePLUS

    ... adults. In addition, there is increasing evidence that childhood obesity makes it more likely to have other risk ... their risk. (See "Diseases associated with atherosclerosis in childhood" .) Is ... high blood pressure ● Medical diseases associated ...

  3. Mild Renal Dysfunction and Metabolites Tied to Low HDL Cholesterol Are Associated With Monocytosis and Atherosclerosis

    PubMed Central

    Ganda, Anjali; Magnusson, Martin; Yvan-Charvet, Laurent; Hedblad, Bo; Engström, Gunnar; Ai, Ding; Wang, Thomas J.; Gerszten, Robert E.; Melander, Olle; Tall, Alan R.

    2014-01-01

    Background The number of circulating blood monocytes impacts atherosclerotic lesion size, and in mouse models, elevated levels of high-density lipoprotein cholesterol suppress blood monocyte counts and atherosclerosis. We hypothesized that individuals with mild renal dysfunction at increased cardiovascular risk would have reduced high-density lipoprotein levels, high blood monocyte counts, and accelerated atherosclerosis. Methods and Results To test whether mild renal dysfunction is associated with an increase in a leukocyte subpopulation rich in monocytes that has a known association with future coronary events, we divided individuals from the Malmö Diet and Cancer study (MDC) into baseline cystatin C quintiles (n=4757). Lower levels of renal function were accompanied by higher monocyte counts, and monocytes were independently associated with carotid bulb intima-media thickness cross-sectionally (P=0.02). Cystatin C levels were positively and plasma high-density lipoprotein cholesterol levels negatively associated with monocyte counts at baseline, after adjustment for traditional risk factors. Several amino acid metabolites tied to low levels of high-density lipoprotein cholesterol and insulin resistance measured in a subset of individuals (n=752) by use of liquid chromatography–mass spectrometry were independently associated with a 22% to 34% increased risk of being in the top quartile of monocytes (P<0.05). Conclusions A low high-density lipoprotein cholesterol, insulin resistance phenotype occurs in subjects with mild renal dysfunction and is associated with elevated monocytes and atherosclerosis. High blood monocyte counts may represent a previously unrecognized mechanism underlying the strong relationship between cystatin C and cardiovascular risk. PMID:23378299

  4. Chemokines control mobilization, recruitment, and fate of monocytes in atherosclerosis.

    PubMed

    Drechsler, Maik; Duchene, Johan; Soehnlein, Oliver

    2015-05-01

    Atherosclerosis is a chronic inflammatory disease of large arteries and, among others, characterized by continuous influx of monocytes into the subendothelial space, subsequent macrophage accumulation, and foam cell formation. Chemokines and their receptors tightly orchestrate monocyte trafficking and fate from birth to death. This brief review summarizes our current understanding of the interplay between monocytes and chemokines entertaining crucial processes in atherosclerosis development, progression, and regression. PMID:25792446

  5. 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

  6. A major role for RCAN1 in atherosclerosis progression

    PubMed Central

    Mndez-Barbero, Nerea; Esteban, Vanesa; Villahoz, Silvia; Escolano, Amelia; Urso, Katia; Alfranca, Arantzazu; Rodrguez, Cristina; Snchez, Susana A; Osawa, Tsuyoshi; Andrs, Vicente; Martnez-Gonzlez, Jos; Minami, Takashi; Redondo, Juan Miguel; Campanero, Miguel R

    2013-01-01

    Atherosclerosis is a complex inflammatory disease involving extensive vascular vessel remodelling and migration of vascular cells. As RCAN1 is implicated in cell migration, we investigated its contribution to atherosclerosis. We show RCAN1 induction in atherosclerotic human and mouse tissues. Rcan1 was expressed in lesional macrophages, endothelial cells and vascular smooth muscle cells and was induced by treatment of these cells with oxidized LDLs (oxLDLs). Rcan1 regulates CD36 expression and its genetic inactivation reduced atherosclerosis extension and severity in Apoe?/? mice. This effect was mechanistically linked to diminished oxLDL uptake, resistance to oxLDL-mediated inhibition of macrophage migration and increased lesional IL-10 and mannose receptor expression. Moreover, Apoe?/?Rcan1?/? macrophages expressed higher-than-Apoe?/? levels of anti-inflammatory markers. We previously showed that Rcan1 mediates aneurysm development and that its expression is not required in haematopoietic cells for this process. However, transplantation of Apoe?/?Rcan1?/? bone-marrow (BM) cells into Apoe?/? recipients confers atherosclerosis resistance. Our data define a major role for haematopoietic Rcan1 in atherosclerosis and suggest that therapies aimed at inhibiting RCAN1 expression or function might significantly reduce atherosclerosis burden. PMID:24127415

  7. Human aldose reductase expression accelerates diabetic atherosclerosis in transgenic mice

    PubMed Central

    Vikramadithyan, Reeba K.; Hu, Yunying; Noh, Hye-Lim; Liang, Chien-Ping; Hallam, Kellie; Tall, Alan R.; Ramasamy, Ravichandran; Goldberg, Ira J.

    2005-01-01

    Direct evidence that hyperglycemia, rather than concomitant increases in known risk factors, induces atherosclerosis is lacking. Most diabetic mice do not exhibit a higher degree of atherosclerosis unless the development of diabetes is associated with more severe hyperlipidemia. We hypothesized that normal mice were deficient in a gene that accelerated atherosclerosis with diabetes. The gene encoding aldose reductase (AR), an enzyme that mediates the generation of toxic products from glucose, is expressed at low levels in murine compared with human tissues. Mice in which diabetes was induced through streptozotocin (STZ) treatment, but not nondiabetic mice, expressing human AR (hAR) crossed with LDL receptor–deficient (Ldlr–/–) C57BL/6 male mice had increased aortic atherosclerosis. Diabetic hAR-expressing heterozygous LDL receptor–knockout mice (Ldlr+/–) fed a cholesterol/cholic acid–containing diet also had increased aortic lesion size. Lesion area at the aortic root was increased by STZ treatment alone but was further increased by hAR expression. Macrophages from hAR-transgenic mice expressed more scavenger receptors and had greater accumulation of modified lipoproteins than macrophages from nontransgenic mice. Expression of genes that regulate regeneration of glutathione was reduced in the hAR-expressing aortas. Thus, hAR increases atherosclerosis in diabetic mice. Inhibitors of AR or other enzymes that mediate glucose toxicity could be useful in the treatment of diabetic atherosclerosis. PMID:16127462

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

    PubMed Central

    Damiani, Mario Francesco; Zito, Annapaola; Carrat, 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

  9. 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

  10. Aortic Atherosclerosis in Systemic Lupus Erythematosus

    PubMed Central

    Roldan, Paola C; Ratliff, Michelle; Snider, Richard; Macias, Leonardo; Rodriguez, Rodrigo; Sibbitt, Wilmer; Roldan, Carlos A.

    2014-01-01

    Aortic atherosclerosis (AoA) defined as intima-media thickening or plaques and aortic stiffness (AoS) also considered an atherosclerotic process and defined as decreased vessel distensibility (higher pulse pressure to achieve similar degree of vessel distension) are common in patients with SLE. Immune-mediated inflammation, thrombogenesis, traditional atherogenic factors, and therapy-related metabolic abnormalities are the main pathogenic factors of AoA and AoS. Pathology of AoA and AoS suggests an initial subclinical endothelialitis or vasculitis, which is exacerbated by thrombogenesis and atherogenic factors and ultimately resulting in AoA and AoS. Computed tomography (CT) for detection of arterial wall calcifications and arterial tonometry for detection of increased arterial pulse wave velocity are the most common diagnostic methods for detecting AoA and AoS, respectively. MRI may become a more applicable and accurate technique than CT. Although transesophageal echocardiography accurately detects earlier and advanced stages of AoA and AoS, it is semi-invasive and cannot be used as a screening method. Although imaging techniques demonstrate highly variable prevalence rates, on average about one third of adult SLE patients may have AoA or AoS. Age at SLE diagnosis; SLE duration; activity and damage; corticosteroid therapy; metabolic syndrome; chronic kidney disease; and mitral annular calcification are common independent predictors of AoA and AoS. Also, AoA and AoS are highly associated with carotid and coronary atherosclerosis. Earlier stages of AoA and AoS are usually subclinical. However, earlier stages of disease may be causally related or contribute to peripheral or cerebral embolism, pre-hypertension and hypertension, and increased left ventricular afterload resulting in left ventricular hypertrophy and diastolic dysfunction. Later stages of disease predisposes to visceral ischemia, aortic aneurysms and aortic dissection. Even earlier stages of AoA and AoS have been associated with increased cardiovascular and cerebrovascular morbidity and mortality of SLE patients. Aggressive non-steroidal immunosuppressive therapy and non-pharmacologic and pharmacologic interventions for control of atherogenic risk factors may prevent the development or progression of AoA and AoS and may decrease cardiovascular and cerebrovascular morbidity and mortality in SLE. PMID:25593786

  11. Purification, structure features and anti-atherosclerosis activity of a Laminaria japonica polysaccharide.

    PubMed

    Peng, Fu-Hua; Zha, Xue-Qiang; Cui, Shao-Hua; Asghar, Muhammad-Naeem; Pan, Li-Hua; Wang, Jun-Hui; Luo, Jian-Ping

    2015-11-01

    A homogeneous polysaccharide (LJP12) was isolated from Laminaria japonica by diethylaminoethyl-cellulose and Sephacryl S-500 chromatography, with a molecular weight of 2.3110(6)Da. Monosaccharide analysis showed that LJP12 was mainly composed of arabinose, xylose, mannose, glucose and galactose in a molar ratio of 1:0.17:1.54:2.64:0.18. For these monosaccharides, mannose was suggested to be 1,4-linked and 1,3,6-linked while glucose was linked by 1,6-glycosidic bond. The xylose, arabinose and galactose were suggested to be the terminal residues. To study the effects of LJP12 on protecting against atherosclerosis, LJP12 was administered to LDL receptor-deficient (LDLr(-/-)) mice (50, 100 and 200mg/kg/day, n=30 for each experimental group). Results showed that LJP12 exhibited the ability to inhibit high-fat-cholesterol diet (HFD)-induced formation of atherosclerotic plaques and plasma lipid levels in a dose-dependent manner. Meanwhile, both the HFD-induced systemic inflammation and local inflammation at the site of atherosclerotic lesion were significantly attenuated by LJP12, which were accompanied by the suppression of the activation of nuclear factor kappa-B (NF-?B) and mitogen-activated protein kinases (MAPKs) signaling pathways. Taken together, we concluded that long-term oral administration of LJP12 protects against atherosclerosis in LDLr(-/-) mice via inhibiting NF-?B/MAPKs-mediated inflammatory responses. PMID:26394383

  12. Effects of murine norovirus on atherosclerosis in ldlr(-/-) mice depends on the timing of infection.

    PubMed

    Paik, Jisun; Kwok, Fiona; Seamons, Audrey; Brabb, Thea; Kim, Jinkyu; Sullivan, Brittany; Hsu, Charlie; O'Brien, Kevin D; Maggio-Price, Lillian

    2015-04-01

    We previously reported that murine norovirus (MNV), a virus prevalent in United States research institutions, increased atherosclerotic lesion size in Ldlr(-/-) mice when the mice were infected 8 wk after feeding an atherogenic diet. To determine whether the timing of MNV infection relative to atherosclerosis development altered the disease phenotype and to examine potential mechanisms by which MNV influences the disease process, we fed Ldlr(-/-) mice an atherogenic diet for 16 wk. Three days after initiating the atherogenic diet, half of the mice received MNV4 and the other half vehicle only (clarified cell-culture lysate; controls). Both groups of mice developed large aortic sinus lesions (control compared with MNV4: 133 8 10 ?m compared with 140 7 10 ?m) that were not significantly different in size. Because the timing of MNV infection relative to atherosclerosis development and hypercholesterolemia differed between our previous and the current studies, we examined whether hypercholesterolemia altered MNV4-induced changes in bone-marrow-derived macrophages. MNV4 infection increased the potential of macrophages to take up and store cholesterol by increasing CD36 expression while suppressing the ABCA1 transporter. Thus, the effects of MNV4 infection on atherosclerotic lesion size appear to be dependent on the timing of the infection: MNV4 infection promotes only established lesions. This effect may be due to MNV4's ability to increase cholesterol uptake and decrease efflux by regulating CD36 and ABCA1 protein expression. PMID:25926396

  13. 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

  14. 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

  15. 3-Nitrotyrosine Modified Proteins in Atherosclerosis

    PubMed Central

    2015-01-01

    Cardiovascular disease is the leading cause of premature death worldwide, and atherosclerosis is the main contributor. Lipid-laden macrophages, known as foam cells, accumulate in the subendothelial space of the lesion area and contribute to consolidate a chronic inflammatory environment where oxygen and nitrogen derived oxidants are released. Oxidatively modified lipids and proteins are present both in plasma as well as atherosclerotic lesions. A relevant oxidative posttranslational protein modification is the addition of a nitro group to the hydroxyphenyl ring of tyrosine residues, mediated by nitric oxide derived oxidants. Nitrotyrosine modified proteins were found in the lesion and also in plasma from atherosclerotic patients. Despite the fact of the low yield of nitration, immunogenic, proatherogenic, and prothrombotic properties acquired by 3-nitrotyrosine modified proteins are in agreement with epidemiological studies showing a significant correlation between the level of nitration found in plasma proteins and the prevalence of cardiovascular disease, supporting the usefulness of this biomarker to predict the outcome and to take appropriate therapeutic decisions in atherosclerotic disease. PMID:25814781

  16. Pathogenesis of atherosclerosis: state of the art.

    PubMed

    Haudenschild, C C

    1990-08-01

    The practical implementation of the results of large, well-controlled clinical and epidemiologic studies has led to substantial progress in the prevention of atherosclerosis. Now, daring and aggressive interventions, as well as a new understanding of cellular and molecular mechanisms of atherogenesis, also provide new possibilities of effective treatments at an advanced, symptomatic stage of the disease. An abundance of new information has come from an increasing number of seemingly unrelated scientific fields, ranging from laser optics to genetic engineering. This short study examines how some selected new findings and concepts fit into the traditional theories of atherogenesis: encrustation, infiltration, and response to injury. Endothelial and smooth muscle cells, platelets, and leukocytes are viewed in their dual capability of promoting as well as inhibiting the atherogenic process. Mechanisms of vascular healing and intimal hyperplasia after physical interventions are distinguished from those leading to complicated spontaneous atherosclerotic plaques, and the impact of some new ideas on potential pharmacologic interventions is brought to the reader's attention. PMID:2076414

  17. 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

  18. Shear stress, arterial identity and atherosclerosis.

    PubMed

    Lehoux, Stephanie; Jones, Elizabeth A

    2016-02-29

    In the developing embryo, the vasculature first takes the form of a web-like network called the vascular plexus. Arterial and venous differentiation is subsequently guided by the specific expression of genes in the endothelial cells that provide spatial and temporal cues for development. Notch1/4, Notch ligand delta-like 4 (Dll4), and Notch downstream effectors are typically expressed in arterial cells along with EphrinB2, whereas chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and EphB4 characterise vein endothelial cells. Haemodynamic forces (blood pressure and blood flow) also contribute importantly to vascular remodelling. Early arteriovenous differentiation and local blood flow may hold the key to future inflammatory diseases. Indeed, despite the fact that atherosclerosis risk factors such as smoking, hypertension, hypercholesterolaemia, and diabetes all induce endothelial cell dysfunction throughout the vasculature, plaques develop only in arteries, and they localise essentially in vessel branch points, curvatures and bifurcations, where blood flow (and consequently shear stress) is low or oscillatory. Arterial segments exposed to high blood flow (and high laminar shear stress) tend to remain plaque-free. These observations have led many to investigate what particular properties of arterial or venous endothelial cells confer susceptibility or protection from plaque formation, and how that might interact with a particular shear stress environment. PMID:26676959

  19. Tooth loss and atherosclerosis: the Nagahama Study.

    PubMed

    Asai, K; Yamori, M; Yamazaki, T; Yamaguchi, A; Takahashi, K; Sekine, A; Kosugi, S; Matsuda, F; Nakayama, T; Bessho, K

    2015-03-01

    Several epidemiologic studies have suggested that oral disease is a risk factor for cardiovascular disease (CVD). However, whether a clinically significant association exists between the 2 disorders remains controversial. Here, we investigated the association between tooth loss, as an indicator of oral disease, and arterial stiffness, as a marker of atherosclerosis, in Japanese adults. Cross-sectional data were collected for 8,124 persons aged 30 to 75 y with no history of tooth loss for noninflammatory reasons, such as orthodontic treatment, malposition, and trauma. Participants received a comprehensive dental examination and extensive in-person measurements of CVD risk factors, and arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI). We examined the association between CAVI and tooth loss using general linear models with adjustment for age, sex, body mass index, smoking status, hemoglobin A1c, and a history of insulin or hypoglycemic medication depending on the model. In addition, we performed an analysis that included interaction terms of the centered variables tooth loss, sex, and age. The results of the multiple regression analysis that included the interaction terms detected that the relationship between CAVI and tooth loss was dependent on sex, with only men showing a positive correlation (β for interaction = 0.04; 95% confidence interval, 0.02-0.06). The findings from this study suggest that a linear relationship exists between tooth loss and degree of arterial stiffness and that the association differed depending on sex. PMID:25406168

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. Pro-inflammatory genetic markers of atherosclerosis.

    PubMed

    Incalcaterra, Egle; Accardi, Giulia; Balistreri, Carmela Rita; Caimi, Gregorio; Candore, Giuseppina; Caruso, Marco; Caruso, Calogero

    2013-06-01

    Atherosclerosis (AS) is a chronic, progressive, multifactorial disease mostly affecting large and medium-sized elastic and muscular arteries. It has formerly been considered a bland lipid storage disease. Currently, multiple independent pathways of evidence suggest this pathological condition is a peculiar form of inflammation, triggered by cholesterol-rich lipoproteins and influenced both by environmental and genetic factors. The Human Genome Project opened up the opportunity to dissect complex human traits and to understand basic pathways of multifactorial diseases such as AS. Population-based association studies have emerged as powerful tools for examining genes with a role in common multifactorial diseases that have a strong environmental component. These association studies often estimate the risk of developing a certain disease in carriers and non-carriers of a particular genetic polymorphism. Dissecting out the influence of pro-inflammatory genes within the complex pathophysiology of AS and its complications will help to provide a more complete risk assessment and complement known classical cardiovascular risk factors. The detection of a risk profile will potentially allow both the early identification of individuals susceptible to disease and the possible discovery of potential targets for drug or lifestyle modification; i.e. it will open the door to personalized medicine. PMID:23591672

  5. 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.

  6. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis

    NASA Astrophysics Data System (ADS)

    Moulton, Karen S.; Vakili, Khashayar; Zurakowski, David; Soliman, Mohsin; Butterfield, Catherine; Sylvin, Erik; Lo, Kin-Ming; Gillies, Stephen; Javaherian, Kashi; Folkman, Judah

    2003-04-01

    Plaque angiogenesis promotes the growth of atheromas, but the functions of plaque capillaries are not fully determined. Neovascularization may act as a conduit for the entry of leukocytes into sites of chronic inflammation. We observe vasa vasorum density correlates highly with the extent of inflammatory cells, not the size of atheromas in apolipoprotein E-deficient mice. We show atherosclerotic aortas contain activities that promote angiogenesis. The angiogenesis inhibitor angiostatin reduces plaque angiogenesis and inhibits atherosclerosis. Macrophages in the plaque and around vasa vasorum are reduced, but we detect no direct effect of angiostatin on monocytes. After angiogenesis blockade in vivo, the angiogenic potential of atherosclerotic tissue is suppressed. Activated macrophages stimulate angiogenesis that can further recruit inflammatory cells and more angiogenesis. Our findings demonstrate that late-stage inhibition of angiogenesis can interrupt this positive feedback cycle. Inhibition of plaque angiogenesis and the secondary reduction of macrophages may have beneficial effects on plaque stability.

  7. [Experimental models of atherosclerosis. Contribution, limits and trends].

    PubMed

    Hadjiisky, P; Bourdillon, M C; Grosgogeat, Y

    1991-11-01

    Experimental approaches to the problem of atherosclerosis involve animal or cellular models and procedures of lesional induction. Relevant animal models are rare. The rat, the mouse and the dog are free of "natural" atherosclerosis and only develop diffuse lipidosis after high cholesterol diet and thyroid block. They are more appropriate models of experimental arteriosclerosis and intimal proliferation induced by different procedures. The rabbit, also free of spontaneous atherosclerosis, is extremely sensitive to lipid-rich diets, but the lesions induced resemble more a xanthomatosis than an atherosclerosis. Immunological procedures in this model result in a generalised immune arteriosclerotic arteriopathy. The monkey and pig, which are phylogenetically close to man, develop spontaneous atherosclerosis exacerbated by lipid-rich diets or other procedures: hormones, psychosocial stress. The cost and problems of upkeep make these two models inaccessible to most laboratories. Although the hen, turkey and pigeon are grain-eating, they develop natural atherosclerosis, are sensitive to atherogenic diets, and provide satisfactory replacement models, especially for research into the viral and tumoral theories of atherogenesis. The pigeon is particularly suitable for studying cellular, biochemical and genetic aspects of atherosclerosis: these spontaneous plaques, similar to those in man, are ontogenetically and topographically predictable. The species include genetic types both sensitive and resistant to the disease. Moderately lipid-rich diets induce lesions even in very young pigeons. They also lend themselves well to the study of the antiatherosclerotic effects of pharmacological agents. Endothelial, smooth muscle and macrophage cell cultures are widely used to study the factors influencing cellular modulation and proliferation, lipid metabolism and movement of cholesterol, cellular biosynthesis and cell-cell and cell-matrix interactions. PMID:1763926

  8. Immune Mechanisms in Atherosclerosis, Especially in Diabetes Type 2

    PubMed Central

    Frostegrd, 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 1? (IL-1?), 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

  9. Beyond cholesterol: the enigma of atherosclerosis revisited.

    PubMed

    Bhakdi, Sucharit; Lackner, Karl J; Han, Shan-Rui; Torzewski, Michael; Husmann, Matthias

    2004-04-01

    Atherosclerosis is widely regarded as a chronic inflammatory disease that develops as a consequence of entrapment of low density lipoprotein (LDL) in the arterial intima. Native LDL lacks inflammatory properties, so the lipoprotein must undergo biochemical alterations in order to become atherogenic. Modification is commonly regarded as being dangerous because it bestows inflammatory properties onto the lipoprotein. Most current models consider oxidation to be the decisive modifying event. Here, we submit a different concept for discussion. We propose that modification of tissue-entrapped LDL is required because it enables the lipoprotein to signal to the immune system and effect its own removal. Oxidation would be too haphazard to fulfill this function. We summarize the evidence indicating that modification occurs through the action of ubiquitous hydrolytic enzymes. Enzymatically remodeled LDL binds C-reactive protein. C-reactive protein bound to remodeled LDL not only activates complement but also regulates it by inhibiting activation of the terminal complement cascade. Simultaneously, epitopes are exposed to enable the lipoprotein to be recognized and taken up by macrophages. The high density lipoprotein-dependent reverse transport pathway concludes the sequence of events that clear tissues of cholesterol in a non-inflammatory manner very similar to what has been described for the removal of apoptotic cells. It is proposed that these physiological processes occur throughout life without harm, pathology evolving only when the machinery suffers overload. Detrimental effects are then evoked primarily by the unreigned activation of complement, macrophages, and other effectors of the immune system in the lesions. PMID:15045123

  10. Hemodynamic sequelae of regression of experimental atherosclerosis.

    PubMed Central

    Armstrong, M L; Heistad, D D; Marcus, M L; Piegors, D J; Abboud, F M

    1983-01-01

    Regression of experimental atherosclerosis is characterized by decreased intimal thickness and luminal enlargement, but intimal fibrosis becomes more dense. We tested the hypothesis that fibrosis of arteries during regression might limit vasodilator capacity and restrict hemodynamic improvement despite luminal improvement. We studied limb, coronary, and cerebral hemodynamics in 11 normal cynomolgus monkeys, 10 monkeys given an atherogenic diet for 20 mo and 8 monkeys given a regression diet for an additional 18 mo. The atherogenic diet induced lesions of moderate severity (50-60% stenosis); owing to characteristic vessel growth during the atherogenic period, luminal size did not decrease correspondingly. Regression monkeys showed typical changes of regression with luminal enlargement but increased fibrosis. The iliac artery was perfused at constant blood flow and maximal vasodilatation was produced with papaverine. Blood flow was measured with microspheres during maximal vasodilatation in the coronary bed (adenosine) and cerebral bed (hypercapnia). In normal monkeys, minimal vascular resistances were 1.95 +/- 0.19 mm Hg/ml/min X 100 g (mean +/- SE) (limb), 0.13 +/- 0.01 (coronary), and 0.44 +/- 0.02 (cerebral). In atherosclerotic monkeys minimal resistance increased (P less than 0.05) 108, 62, and 166% in the limb, coronary, and cerebral beds, respectively. In regression monkeys, minimal resistance increased from values found in atherosclerotic animals in the limb (+22%), decreased inconsistently in the coronary bed (-19%), and decreased significantly in the cerebral bed (-44%, P less than 0.05). Thus morphologic regression was accompanied by significant hemodynamic improvement during maximal dilatation only in cerebral vessels. We conclude that increases in luminal size during regression of atherosclerotic lesions may not be associated with increases in vasodilator capacity, as intimal fibrosis may limit physiologically important hemodynamic improvement. PMID:6848553

  11. Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging.

    PubMed

    McCully, Kilmer S

    2015-01-01

    The importance of homocysteine in vascular function and arteriosclerosis was discovered by demonstration of arteriosclerotic plaques in children with homocystinuria caused by inherited enzymatic deficiencies of cystathionine synthase, methionine synthase, or methylene-tetrahydrofolate reductase. According to the homocysteine theory of arteriosclerosis, an elevated blood homocysteine level is an important risk factor for atherosclerosis in subjects without these rare enzymatic abnormalities. The homocysteine theory is supported by demonstration of arterial plaques in experimental animals with hyperhomocysteinemia, by discovery of a pathway for conversion of homocysteine thiolactone to sulfate in cell cultures from children with homocystinuria, and by demonstration of growth promotion by homocysteic acid in normal and hypophysectomized animals. Studies with cultured malignant cells revealed abnormal homocysteine thiolactone metabolism, resulting in homocysteinylation of proteins, nucleic acids, and glycosaminoglycans, explaining the abnormal oxidative metabolism, abnormalities of cellular membranes, and altered genetic expression observed in malignancy. Abnormal homocysteine metabolism in malignant cells is attributed to deficiency of thioretinamide, the amide synthesized from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide combine with cobalamin to form thioretinaco. Based on the molecular structure of thioretinaco, a theory of oxidative phosphorylation was proposed, involving oxidation to a disulfonium derivative by ozone, and binding of oxygen, nicotinamide adenine dinucleotide and phosphate as the active site of adenosine triphosphate synthesis in mitochondria. Obstruction of vasa vasorum by aggregates of microorganisms with homocysteinylated low-density lipoproteins is proposed to cause ischemia of arterial wall and a microabscess of the intima, the vulnerable atherosclerotic plaque. 2016 American Physiological Society. Compr Physiol 6:471-505, 2016. PMID:26756640

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

    PubMed

    Pramo, Jos A; Beloqui, Oscar; Orbe, Josune

    2006-05-27

    It is now widely accepted that atherosclerosis is a complex chronic inflammatory disorder of the arterial tree associated with several risk factors. From the initial phases to eventual rupture of vulnerable atherosclerotic plaques, a low-grade inflammation, also termed microinflammation, appears to play a key pathogenetic role. Systemic inflammatory markers (C reactive protein, cytokines adhesion molecules) also play a role in this process. Experimental and clinical evidence suggests that cyclooxygenase-2 (COX-2), an enzyme which catalyzes the generation of prostaglandins from arachidonic acid, also contributes to lesion formation. Recent reports by our group have demonstrated increased monocyte COX-2 activity and the production of prostaglandin E2 in relation to cardiovascular risk factors and subclinical atherosclerosis in asymptomatic subjects. Our findings support the notion that the COX-2/prostaglandin E2 axis may have a role, raising the question as to whether its selective inhibition might be an attractive therapeutic target in atherosclerosis. COX-2 inhibitors, collectively called "coxibs" (celecoxib, rofecoxib, valdecoxib, lumiracoxib, etc), held a promise as anti-inflammatory drugs without the some of the side effects of aspirin or non steroidal antiinflammatory agents. However, clinical studies raise several clinically relevant questions as to their beneficial role in atherosclerosis prevention, because of increased thrombogenicity and cardiovascular risk, and therefore coxibs should be restricted in atherosclerosis-prone patients. PMID:16792983

  13. Contrast-enhanced ultrasound: clinical applications in patients with atherosclerosis.

    PubMed

    Schinkel, Arend F L; Kaspar, Mathias; Staub, Daniel

    2016-01-01

    Contrast-enhanced ultrasound (CEUS) is increasingly being used to evaluate patients with known or suspected atherosclerosis. The administration of a microbubble contrast agent in conjunction with ultrasound results in an improved image quality and provides information that cannot be assessed with standard B-mode ultrasound. CEUS is a high-resolution, noninvasive imaging modality, which is safe and may benefit patients with coronary, carotid, or aortic atherosclerosis. CEUS allows a reliable assessment of endocardial borders, left ventricular function, intracardiac thrombus and myocardial perfusion. CEUS results in an improved detection of carotid atherosclerosis, and allows assessment of high-risk plaque characteristics including intraplaque vascularization, and ulceration. CEUS provides real-time bedside information in patients with a suspected or known abdominal aortic aneurysm or aortic dissection. The absence of ionizing radiation and safety of the contrast agent allow repetitive imaging which is particularly useful in the follow-up of patients after endovascular aneurysm repair. New developments in CEUS-based molecular imaging will improve the understanding of the pathophysiology of atherosclerosis and may in the future allow to image and directly treat cardiovascular diseases (theragnostic CEUS). Familiarity with the strengths and limitations of CEUS may have a major impact on the management of patients with atherosclerosis. PMID:26206524

  14. Lanatoside C Promotes Foam Cell Formation and Atherosclerosis.

    PubMed

    Shi, Huairui; Mao, Xiaobo; Zhong, Yucheng; Liu, Yuzhou; Zhao, Xiaoqi; Yu, Kunwu; Zhu, Ruirui; Wei, Yuzhen; Zhu, Jianghao; Sun, Haitao; Mao, Yi; Zeng, Qiutang

    2016-01-01

    Lanatoside C's impact on atherosclerosis is poorly understood. The present study was conducted to determine whether lanatoside C affects the development of atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice. ApoE(-/-) mice were administered either phosphate-buffered saline (PBS) containing 0.1% DMSO (the vehicle control group) or lanatoside C at low (1?mg/kg per day) or high (2?mg/kg per day) doses, and fed a Western diet for 12 weeks. Lanatoside C dose-dependently aggravated the development of atherosclerosis in the ApoE(-/-) mice compared with the vehicle control group. In an effort to determine the mechanism by which lanatoside C increased atherosclerosis, we found that lanatoside C significantly promoted the uptake of oxidised low-density lipoprotein (oxLDL) and increased foam-cell formation by upregulation of scavenger receptor class A (SR-A) and the class B scavenger receptor (CD36) in macrophages. Meanwhile, the effects of lanatoside C were abolished using small interfering RNA (siRNA) inhibition of peroxisome proliferator-activated receptors ?/? (PPAR?/?). Overall, our data demonstrate that lanatoside C aggravates the development of atherosclerosis by inducing PPAR?/? expression, which mediates upregulation of SR-A and CD36, and promotes oxLDL uptake and foam-cell formation. PMID:26821916

  15. Lanatoside C Promotes Foam Cell Formation and Atherosclerosis

    PubMed Central

    Shi, Huairui; Mao, Xiaobo; Zhong, Yucheng; Liu, Yuzhou; Zhao, Xiaoqi; Yu, Kunwu; Zhu, Ruirui; Wei, Yuzhen; Zhu, Jianghao; Sun, Haitao; Mao, Yi; Zeng, Qiutang

    2016-01-01

    Lanatoside Cs impact on atherosclerosis is poorly understood. The present study was conducted to determine whether lanatoside C affects the development of atherosclerosis in apolipoprotein E-deficient (ApoE/) mice. ApoE/ mice were administered either phosphate-buffered saline (PBS) containing 0.1% DMSO (the vehicle control group) or lanatoside C at low (1?mg/kg per day) or high (2?mg/kg per day) doses, and fed a Western diet for 12 weeks. Lanatoside C dose-dependently aggravated the development of atherosclerosis in the ApoE/ mice compared with the vehicle control group. In an effort to determine the mechanism by which lanatoside C increased atherosclerosis, we found that lanatoside C significantly promoted the uptake of oxidised low-density lipoprotein (oxLDL) and increased foam-cell formation by upregulation of scavenger receptor class A (SR-A) and the class B scavenger receptor (CD36) in macrophages. Meanwhile, the effects of lanatoside C were abolished using small interfering RNA (siRNA) inhibition of peroxisome proliferator-activated receptors ?/? (PPAR?/?). Overall, our data demonstrate that lanatoside C aggravates the development of atherosclerosis by inducing PPAR?/? expression, which mediates upregulation of SR-A and CD36, and promotes oxLDL uptake and foam-cell formation. PMID:26821916

  16. Heat Shock Protein 60 and Immune Inflammatory Responses in Atherosclerosis

    PubMed Central

    Grundtman, Cecilia; Kreutmayer, Simone B.; Almanzar, Giovanni; Wick, Marius C.; Wick, Georg

    2011-01-01

    Hallmarks of inflammation in various cardiovascular diseases, notably atherosclerosis, have been observed for a long time. However, evidence for an (auto)antigen-driven process at these sites of inflammation has come forward only recently. Heat shock proteins (HSPs) have been identified as playing either immunologically mediated disease promoting or protective roles. HSP60 has been shown to trigger innate and adaptive immune responses that initiate the earliest still reversible inflammatory stage of atherosclerosis. HSP60 is structurally highly conserved and abundantly expressed by prokaryotic and eukaryotic cells under stressful conditions. Beneficial protective immunity to microbial HSP60 acquired by infection or vaccination and bona fide autoimmunity to biochemically altered autologous HSP60 is present in all humans. In vitro and in vivo experiments have demonstrated that classical atherosclerosis risk factors can act as endothelial stressors that provoke the simultaneous expression of adhesion molecules and of HSP60 in mitochondria, in cytoplasm, and on the cell surface, where it acts as a danger signal for cellular and humoral immune reactions. Hence, protective, preexisting anti-HSP60 immunity may have to be paid for by harmful (auto)immune cross-reactive attack on arterial endothelial cells maltreated by atherosclerosis risk factors. These experimentally and clinically proven findings are the basis for the autoimmune concept of atherosclerosis. PMID:21508342

  17. Antigen-Induced Immunomodulation in the Pathogenesis of Atherosclerosis

    PubMed Central

    Milioti, Natalia; Bermudez-Fajardo, Alexandra; Penichet, Manuel L.; Oviedo-Orta, Ernesto

    2008-01-01

    Atherosclerosis is a chronic inflammatory disorder characterised by the accumulation of monocytes/macrophages, smooth muscle cells, and lymphocytes within the arterial wall in response to the release of proinflammatory molecules. Such accumulation results in the formation of the atherosclerotic plaque, which would eventually evolve to complications such as total artery occlusion, rupture, calcification, or aneurysm. Although the molecular mechanism responsible for the development of atherosclerosis is not completely understood, it is clear that the immune system plays a key role in the development of the atherosclerotic plaque and in its complications. There are multiple antigenic stimuli that have been associated with the pathogenesis of atherosclerosis. Most of these stimuli come from modified self-molecules such as oxidised low-density lipoproteins (oxLDLs), beta2glycoprotein1 (?2GP1), lipoprotein a (LP(a)), heat shock proteins (HSPs), and protein components of the extracellular matrix such as collagen and fibrinogen in the form of advanced glycation-end (AGE) products. In addition, several foreign antigens including bacteria such as Porphyromonas gingivalis and Chlamydia pneumoniae and viruses such as enterovirus and cytomegalovirus have been associated with atherosclerosis as potentially causative or bystander participants, adding another level of complexity to the analysis of the pathophysiology of atherosclerosis. The present review summarises the most important scientific findings published within the last two decades on the importance of antigens, antigen stimulation, and adaptive immune responses in the development of atherosclerotic plaques. PMID:18551190

  18. The role of infection and immunity in atherosclerosis.

    PubMed

    Gurfinkel, E; Lernoud, V

    2006-01-01

    Cardiovascular diseases account for 20% of deaths worldwide, rising to 50% in developed countries. Current understanding of atherosclerosis derives from a combination of research in animals and cell cultures, analysis of human lesions, clinical investigations of patients with acute coronary syndromes and epidemiological studies of coronary artery disease. By measuring serologic titers in the serum of patients after cardiovascular events, it was observed that the greater the infectious exposure of a patient, the larger the atherosclerotic lesion extension. In addition, gene targeting or pharmacological inhibition of certain cytokines aggravates atherosclerosis in animal experiments. Other animal experiments have succeeded in proving that B cells play a protective role in atherosclerosis through induced immunity against oxidized low-density lipoprotein and other epitopes. Molecular mimicry might respond to the question of how infection may trigger vulnerability in previously stable atherosclerotic lesions. The FLU Vaccination Acute Coronary Syndromes trial enhanced the debate on atherosclerosis prevention by the application of antiflu vaccine. So far, antibiotics have failed to reduce cardiovascular risk, as recent trials could not demonstrate a statistically significant risk reduction. Having assumed atherosclerosis to be an inflammatory disease, the WHO considered the possible role of secondary prevention with antiflu vaccine. PMID:16375635

  19. 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

  20. A novel dilute and shoot HPLC assay method for quantification of irbesartan and hydrochlorothiazide in combination tablets and urine using second generation C18-bonded monolithic silica column with double gradient elution.

    PubMed

    Koyuturk, Sema; Can, Nafiz Oncu; Atkosar, Zeki; Arli, Goksel

    2014-08-01

    Irbesartan (IRB) and hydrochlorothiazide (HCT) are angiotensin-II receptor antagonist and thiazide-class diuretic compounds, respectively, which are in use in the treatment of hypertension. A novel dilute-and-shoot HPLC assay method for simultaneous quantification of IRB and HCT in fixed-dose combination tablets and urine samples was described. The separation of IRB, HCT and agomelatine (internal standard) was carried out using a second generation C18-bonded monolithic silica column (Chromolith() High Resolution RP-18e, 1004.6mm, Merck KGaA), utilizing both mobile phase and flow rate gradient elution programs. The analytes were detected at 230 nm wavelength using photodiode array detector within 24 minutes with high resolution, observing about 50 percent more peak capacity when using second generation C18-bonded monolithic silica column. Urine samples were introduced into the system effortlessly, with only filtration and subsequent dilution. Validation studies were performed according to the official recommendations of USP and ICH, and the developed method was successfully applied to pharmaceutical tablets and urine samples. PMID:24876066

  1. 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

  2. In Vivo ?F-FDG-PET Imaging in Mouse Atherosclerosis.

    PubMed

    Mateo, Jess; Bilbao, Izaskun; Vaquero, Juan Jos; Ruiz-Cabello, Jess; Espaa, Samuel

    2015-01-01

    Positron emission tomography (PET) is an important technique in cardiovascular research. Vascular inflammation detected by fluorodeoxyglucose (FDG)-PET has been shown to predict cardiovascular (CV) events independent of traditional risk factors and is also highly associated with overall burden of atherosclerosis. The use of PET imaging in mouse models of atherosclerosis is challenged by the reduced size of the scanned organs. However, the last generation of dedicated PET scanners has an improved spatial resolution (<1 mm) and increased sensitivity allowing those studies to be performed. Here, we describe a procedure to perform FDG-PET experiments in atherosclerosis mouse models, the required equipment for animal handling and imaging, and the tools and procedures for image analysis and validation of the results. PMID:26445805

  3. Nuclear Receptors in atherosclerosis: a superfamily with many 'Goodfellas'.

    PubMed

    Kurakula, Kondababu; Hamers, Anouk A J; de Waard, Vivian; de Vries, Carlie J M

    2013-04-10

    Nuclear Receptors form a superfamily of 48 transcription factors that exhibit a plethora of functions in steroid hormone signaling, regulation of metabolism, circadian rhythm and cellular differentiation. In this review, we describe our current knowledge on the role of Nuclear Receptors in atherosclerosis, which is a multifactorial disease of the vessel wall. Various cell types are involved in this chronic inflammatory pathology in which multiple cellular processes and numerous genes are dysregulated. Systemic risk factors for atherosclerosis are among others adverse blood lipid profiles, enhanced circulating cytokine levels, as well as increased blood pressure. Since many Nuclear Receptors modulate lipid profiles or regulate blood pressure they indirectly affect atherosclerosis. In the present review, we focus on the functional involvement of Nuclear Receptors within the atherosclerotic vessel wall, more specifically on their modulation of cellular functions in endothelial cells, smooth muscle cells and macrophages. Collectively, this overview shows that most of the Nuclear Receptors are athero-protective in atherosclerotic lesions. PMID:22664910

  4. Redox balance and blood elemental levels in atherosclerosis

    NASA Astrophysics Data System (ADS)

    Napoleão, P.; Lopes, P. A.; Santos, M.; Steghens, J.-P.; Viegas-Crespo, A. M.; Pinheiro, T.

    2006-08-01

    Oxidation of lipids and proteins represents a causative event for atherogenesis, which can be opposed by antioxidant activity. Elements, such as, Fe, Cu, Zn and Se can be involved in both mechanisms. Thus, evaluation of blood elemental levels, easily detected by PIXE, and of redox parameters may be useful in assessing the risk of atherosclerosis. A group of stable patients suffering from atherosclerosis, was matched with a cohort of normo-tensive and -lipidemic volunteers. Although no major discrepancies were observed for trace elemental levels in blood, increased concentrations of K and Ca were found in atherosclerotic group. Patients presented enhance levels of antioxidant (α-tocopherol) and decreased of protein oxidation (protein carbonyls), while for the lipid oxidation marker (malondialdehyde) no variation was observed. This study contributes to a better understanding of atherosclerosis development and its relationship with blood elemental levels, and set basis for further clinical trials with pathological groups in acute phase.

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

    SciTech Connect

    Qiao, Wang; Chaoshu, Tang; Key Laboratory of Molecular Cardiovascular Medicine, Ministry of Education ; 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.

  6. Symptomatic atherosclerosis is associated with an altered gut metagenome

    PubMed Central

    Karlsson, Fredrik H.; Fåk, Frida; Nookaew, Intawat; Tremaroli, Valentina; Fagerberg, Björn; Petranovic, Dina; Bäckhed, Fredrik; Nielsen, Jens

    2012-01-01

    Recent findings have implicated the gut microbiota as a contributor of metabolic diseases through the modulation of host metabolism and inflammation. Atherosclerosis is associated with lipid accumulation and inflammation in the arterial wall, and bacteria have been suggested as a causative agent of this disease. Here we use shotgun sequencing of the gut metagenome to demonstrate that the genus Collinsella was enriched in patients with symptomatic atherosclerosis, defined as stenotic atherosclerotic plaques in the carotid artery leading to cerebrovascular events, whereas Roseburia and Eubacterium were enriched in healthy controls. Further characterization of the functional capacity of the metagenomes revealed that patient gut metagenomes were enriched in genes encoding peptidoglycan synthesis and depleted in phytoene dehydrogenase; patients also had reduced serum levels of β-carotene. Our findings suggest that the gut metagenome is associated with the inflammatory status of the host and patients with symptomatic atherosclerosis harbor characteristic changes in the gut metagenome. PMID:23212374

  7. 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 ...

  8. 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 (? ? 0.36). There was no significant evidence for a main effect for the MAOA genotype (? = 0.02, p = 0.82) or childhood trauma (0.005 < ? < 0.10, p > 0.54) on early atherosclerosis. However, a significant interaction was observed between MAOA genotype and physical (?interaction = 0.37, p = 0.026) or emotional abuse (?interaction = 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

  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. 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

  11. Human Genetic Evidence for Involvement of CD137 in Atherosclerosis

    PubMed Central

    Sderstrm, Leif ; Gertow, Karl; Folkersen, Lasse; Sabater-Lleal, Maria; Sundman, Eva; Sheikine, Yuri; Goel, Anuj; Baldassarre, Damiano; Humphries, Steve E; de Faire, Ulf; Watkins, Hugh; Tremoli, Elena; Veglia, Fabrizio; Hamsten, Anders; Hansson, Gran K; Olofsson, Peder S

    2014-01-01

    Atherosclerosis is an inflammatory disease and the main cause of cardiovascular disease. Inflammation promotes plaque instability and clinical disease, such as myocardial infarction, stroke and peripheral vascular disease. Subclinical atherosclerosis begins with thickening of the arterial intimal layer, and increased intima-media thickness (IMT) in the carotid artery is a widely used measurement of subclinical atherosclerosis. Activation of CD137 (tumor necrosis factor receptor super family 9) promotes inflammation and disease development in murine atherosclerosis. CD137 is expressed in human atherosclerosis, but its role is largely unknown. This study uses a genetic approach to investigate CD137 in human atherosclerotic disease. In publicly available data on genotype and gene expression from the HapMap project, the minor T allele of rs2453021, a single nucleotide polymorphism in CD137, was significantly associated with CD137 gene expression. In the PROCARDIS and Wellcome Trust Case Control Consortium (WTCCC) cohorts of 13,029 cases and controls, no significant association was detected between the minor T allele of rs2453021 and risk for coronary artery disease or myocardial infarction. However, in the IMPROVE multicenter study of 3,418 individuals, the minor T allele of rs2453021 was associated with increased IMT of the common carotid artery (CCA), as measured by ultrasonography, with presence of plaque in CCA and with increased incidence of adverse noncardiac vascular events. Taken together, this study shows that the minor T allele of rs2453021 is associated with increased IMT in the CCA and increased risk of incident noncardiac vascular events, thus providing the first human genetic evidence for involvement of CD137 in atherosclerosis. PMID:25032953

  12. Changes in transcriptome of macrophages in atherosclerosis

    PubMed Central

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

    2015-01-01

    Macrophages display significant phenotypic heterogeneity. Two growth factors, macrophage colony-stimulating factor and chemokine (C-X-C motif) ligand 4, drive terminal differentiation of monocytes to M0 and M4 macrophages respectively. Compared to M0 macrophages, M4 cells have a unique transcriptome, with expression of surface markers such as S100A8, mannose receptor CD206 and matrix metalloproteinase 7. M4 macrophages did not express CD163, a scavenger receptor for haemoglobin/haptoglobin complex. Depending on the stimuli, M0 macrophages could polarize towards the proinflammatory M1 subset by treatment with lipopolysaccharide or interferon-?. These macrophages produce a range of proinflammatory cytokines, nitric oxide, reactive oxygen species and exhibit high chemotactic and phagocytic activity. The alternative M2 type could be induced from M0 macrophage by stimulation with interleukin (IL)-4. M2 macrophages express high levels of CD206 and produce anti-inflammatory cytokines IL-10 and transforming growth factor-?. M1, M2 and M4 macrophages could be found in atherosclerotic plaques. In the plaque, macrophages are subjected to the intensive influence not only by cytokines and chemokines but also with bioactive lipids such as cholesterol and oxidized phospholipids. Oxidized phospholipids induce a distinct Mox phenotype in murine macrophages that express a unique panel of antioxidant enzymes under control of the redox-regulated transcription factor Klf2, resistant to lipid accumulation. In unstable human lesions, atheroprotective M(Hb) and HA-mac macrophage subsets could be found. These two subsets are induced by the haemoglobin/haptoglobin complex, highly express haeme oxygenase 1 and CD163, and are implicated in clearance of haemoglobin and erythrocyte remnants. In atherogenesis, the macrophage phenotype is plastic and could therefore be switched to proinflammatory (i.e. proatherogenic) and anti-inflammatory (i.e. atheroprotective). The aim of this review was to characterize changes in macrophage transcriptome in atherosclerosis and discuss key markers that characterize different phenotypes of macrophages present in atherosclerotic lesions. PMID:25973901

  13. Angiography Underestimates Peripheral Atherosclerosis: Lumenography Revisited

    PubMed Central

    Kashyap, Vikram S.; Pavkov, Mircea L.; Bishop, Paul D.; Nassoiy, Sean P.; Eagleton, Matthew J.; Clair, Daniel G.; Ouriel, Kenneth

    2008-01-01

    Abstract Purpose: To compare angiograms, considered the gold standard for diagnostic imaging of peripheral arterial disease (PAD), to the corresponding histological sections of popliteal and tibial vessels obtained after amputation to determine if angiography fails to define atheroma burden in normal appearing arteries in patients with PAD. Methods: Between 2004 and 2006, 69 patients underwent amputation of a lower extremity for severe tissue loss, gangrene, or pedal sepsis precluding limb salvage. Popliteal and tibial vessels were harvested, perfusion-fixed, and analyzed histologically. Thirty-four of these patients had pre-amputation angiography during attempted salvage procedures. Angiograms with patent or minimally diseased vessel segments (n?=?19) were assessed for stenoses, diameter, and calcification by 3 vascular surgeons (n?=?72 evaluations). These results were compared to corresponding cross-sectional histological slides (n?=?66) in a blinded manner. Results: Angiograms performed prior to above-knee (n?=?9) or below-knee (n?=?10) amputation revealed 24 stenoses with a mean (SD) diameter-reducing stenosis of 19.5%15.2%. Corresponding histological cross sections revealed greater linear stenoses measured via boundaries of the internal elastic lamina (IEL stenosis, 28.9%20.2%, p?=?0.003 versus angiography) or via boundaries of the external elastic membrane (vessel stenosis, 43.1%15.2%, p<0.0001). Stenosis calculated by area methods (IEL area) were greater and measured 39.2%24.2% (p<0.0001) and 60.9%15.2% (vessel area, p<0.0001). Popliteal arteries had greater discrepancy in stenosis measurement than tibial arteries (18.5%14.6% versus 34.9%21.0%, p?=?0.0005). However, evaluations of tibial arteries for concentricity of plaque (44% versus 69%, p?=?0.08) and calcification grade (1.6 versus 2.2, p?=?0.002) by angiography were discordant with histological analyses. Measurement of arterial diameter by histology for popliteal arteries (6.20.9 mm) and tibial arteries (3.10.7 mm) was greater than angiographic diameter determination (p<0.001). Conclusion: Angiography provides information on luminal characteristics of peripheral arteries but severely underestimates the extent of atherosclerosis in patients with PAD even in normal appearing vessels. PMID:18254670

  14. Recent insights into the cellular biology of atherosclerosis

    PubMed Central

    García-Cardeña, Guillermo; Owens, Gary K.

    2015-01-01

    Atherosclerosis occurs in the subendothelial space (intima) of medium-sized arteries at regions of disturbed blood flow and is triggered by an interplay between endothelial dysfunction and subendothelial lipoprotein retention. Over time, this process stimulates a nonresolving inflammatory response that can cause intimal destruction, arterial thrombosis, and end-organ ischemia. Recent advances highlight important cell biological atherogenic processes, including mechanotransduction and inflammatory processes in endothelial cells, origins and contributions of lesional macrophages, and origins and phenotypic switching of lesional smooth muscle cells. These advances illustrate how in-depth mechanistic knowledge of the cellular pathobiology of atherosclerosis can lead to new ideas for therapy. PMID:25869663

  15. The Influence of Innate and Adaptive Immune Responses on Atherosclerosis

    PubMed Central

    Witztum, Joseph L.; Lichtman, Andrew H.

    2014-01-01

    Both the chronic development of atherosclerotic lesions and the acute changes in lesion phenotype that lead to clinical cardiovascular events are significantly influenced by the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall. The rapid pace of discovery of mechanisms of immunologic recognition, effector functions, and regulation has significantly influenced the study of atherosclerosis, and our new knowledge is beginning to affect how we treat this ubiquitous disease. In this review, we discuss recent advances in our understanding of how innate and adaptive immunity contribute to atherosclerosis, as well as therapeutic opportunities that arise from this knowledge. PMID:23937439

  16. 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

  17. Management of radiation-induced accelerated carotid atherosclerosis

    SciTech Connect

    Loftus, C.M.; Biller, J.; Hart, M.N.; Cornell, S.H.; Hiratzka, L.F.

    1987-07-01

    Patients with long survival following cervical irradiation are at risk for accelerated carotid atherosclerosis. The neurologic presentation in these patients mimics naturally occurring atheromatous disease, but patients often present at younger ages and with less concurrent coronary or systemic vascular disease. Hypercholesterolemia also contributes to this accelerated arteriosclerosis. Angiographic findings in this disorder include disproportionate involvement of the distal common carotid artery and unusually long carotid lesions. Pathologic findings include destruction of the internal elastic lamina and replacement of the normal intima and media with fibrous tissue. This article describes two surgical patients with radiation-induced accelerated carotid atherosclerosis who typify the presentation and characteristics of this disease.

  18. Cardiorespiratory Fitness and Atherosclerosis: Recent Data and Future Directions.

    PubMed

    Mehanna, Emile; Hamik, Anne; Josephson, Richard A

    2016-05-01

    Historically, the relationship between exercise and the cardiovascular system was viewed as unidirectional, with a disease resulting in exercise limitation and hazard. This article reviews and explores the bidirectional nature, delineating the effects, generally positive, on the cardiovascular system and atherosclerosis. Exercise augments eNOS, affects redox potential, and favorably affects mediators of atherosclerosis including lipids, glucose homeostasis, and inflammation. There are direct effects on the vasculature as well as indirect benefits related to exercise-induced changes in body composition and skeletal muscle. Application of aerobic exercise to specific populations is described, with the hope that this knowledge will move the science forward and improve individual patient outcome. PMID:27005804

  19. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure

    PubMed Central

    Swirski, Filip K.; Nahrendorf, Matthias

    2013-01-01

    Cardiovascular diseases claim more lives worldwide than any other. Etiologically, the dominant trajectory involves atherosclerosis, a chronic inflammatory process of lipid-rich lesion growth in the vascular wall that can cause life-threatening myocardial infarction (MI). Those who survive MI can develop congestive heart failure, a chronic condition of inadequate pump activity that is frequently fatal. Leukocytes – white blood cells – are important participants at the various stages of cardiovascular disease progression and complication. This review will discuss leukocyte function in atherosclerosis, myocardial infarction, and heart failure. PMID:23307733

  20. Recent insights into the cellular biology of atherosclerosis.

    PubMed

    Tabas, Ira; García-Cardeña, Guillermo; Owens, Gary K

    2015-04-13

    Atherosclerosis occurs in the subendothelial space (intima) of medium-sized arteries at regions of disturbed blood flow and is triggered by an interplay between endothelial dysfunction and subendothelial lipoprotein retention. Over time, this process stimulates a nonresolving inflammatory response that can cause intimal destruction, arterial thrombosis, and end-organ ischemia. Recent advances highlight important cell biological atherogenic processes, including mechanotransduction and inflammatory processes in endothelial cells, origins and contributions of lesional macrophages, and origins and phenotypic switching of lesional smooth muscle cells. These advances illustrate how in-depth mechanistic knowledge of the cellular pathobiology of atherosclerosis can lead to new ideas for therapy. PMID:25869663

  1. 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 Administrations 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

  2. Molecular mechanisms linking diabetes to the accelerated development of atherosclerosis.

    PubMed

    Zeadin, Melec G; Petlura, Christina I; Werstuck, Geoff H

    2013-10-01

    Diabetes mellitus is a major independent risk factor for the development of cardiovascular disease, and both type 1 and type 2 diabetes have been shown to accelerate the development of atherosclerosis, the underlying cause of most myocardial infarctions. Despite the profound clinical importance of vascular disease in patients with diabetes mellitus, our understanding of the relative contributions of insulin resistance and hyperglycemia to atherogenesis is not complete. Furthermore, the molecular and cellular pathways that are involved in disease progression are not clear. In this review, we summarize our current understanding of the potential mechanisms that link diabetes to atherosclerosis and indicate existing gaps in our knowledge. PMID:24500563

  3. 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

  4. The Role of Oxidative Stress and Autophagy in Atherosclerosis

    PubMed Central

    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

  5. 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

  6. Novel approaches for predicting risk factors of atherosclerosis.

    PubMed

    Rao, V S H; Kumar, M N

    2013-01-01

    Coronary heart disease (CHD) caused by hardening of artery walls due to cholesterol known as atherosclerosis is responsible for large number of deaths world-wide. The disease progression is slow, asymptomatic and may lead to sudden cardiac arrest, stroke or myocardial infraction. Presently, imaging techniques are being employed to understand the molecular and metabolic activity of atherosclerotic plaques to estimate the risk. Though imaging methods are able to provide some information on plaque metabolism they lack the required resolution and sensitivity for detection. In this paper we consider the clinical observations and habits of individuals for predicting the risk factors of CHD. The identification of risk factors helps in stratifying patients for further intensive tests such as nuclear imaging or coronary angiography. We present a novel approach for predicting the risk factors of atherosclerosis with an in-built imputation algorithm and particle swarm optimization (PSO). We compare the performance of our methodology with other machine learning techniques on STULONG dataset which is based on longitudinal study of middle aged individuals lasting for twenty years. Our methodology powered by PSO search has identified physical inactivity as one of the risk factor for the onset of atherosclerosis in addition to other already known factors. The decision rules extracted by our methodology are able to predict the risk factors with an accuracy of 99:73% which is higher than the accuracies obtained by application of the state-of-theart machine learning techniques presently being employed in the identification of atherosclerosis risk studies. PMID:23193312

  7. 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.

  8. 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.

  9. New indole-thiazolidine attenuates atherosclerosis in LDLr(-/-) mice.

    PubMed

    Csar, Fernanda A; Rudnicki, Martina; de Las Heras, Beatriz; Bosc, Lisardo; Lima, Maria C A; Pitta, Ivan R; Abdalla, Dulcineia S P

    2015-08-01

    Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor ? (PPAR?) agonists that improve insulin-mediated glucose uptake and possess beneficial vasculoprotective actions. However, because undesirable side effects are associated with these drugs, novel TZDs are under development. In this study, we evaluated the biological activity of LYSO-7, a new indole-thiazolidine, on PPAR activation, inflammation and atherogenesis using a gene reporter assay, lipopolysaccharide (LPS)-activated RAW 264.7 cell culture, and a low-density lipoprotein receptor knockout (LDLr(-/-)) mouse model of atherosclerosis. LYSO-7 shows low cytotoxicity in RAW 264.7 cells and at 2.5?mol/L induces PPAR? and PPAR? transactivation as well as inhibits LPS-induced nitrite production and the mRNA gene expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). In addition, treatment with LYSO-7 reduces the development of atherosclerosis in LDLr(-/-) mice, improves the lipid profile, blood glucose levels, and downregulates CD40 and CD40L expression without affecting the body weight of the animals. Altogether, our data show that LYSO-7 possesses anti-inflammatory properties and that treatment with this TZD attenuates atherosclerosis progression in LDLr(-/-) mice by modulating lipid metabolism and inflammation. Thus, LYSO-7 shows potential as a new drug candidate for the treatment of atherosclerosis. PMID:25869519

  10. Endothelial function and atherosclerosis: circulatory markers with clinical usefulness.

    PubMed

    Ribeiro, Fernando; Alves, Alberto J; Teixeira, Madalena; Ribeiro, Vasco; Duarte, Jos A; Oliveira, Jos

    2009-10-01

    The healthy endothelium secretes and expresses at the surface various molecules which help maintain vascular wall structure and vascular homeostasis, as well as regulating vascular tone and leukocyte traffic. In response to various aggressive stimuli, the endothelial cell modulates its properties to restore vascular homeostasis. Usually, changes in the endothelial cell phenotype are transient and do not compromise the subsequent re-establishment of endothelial function. However, in certain pathological conditions, such as atherosclerosis, endothelial function is chronically disturbed, and this alteration is a critical step in the progression of the disease. In recent years, advances in knowledge have improved our understanding of the physiopathology of atherosclerosis, which is now known to be a dynamic and progressive process proceeding from endothelial dysfunction and inflammation of the vascular wall. The evolution and prognosis of atherosclerosis, along with the efficacy of therapeutic modalities, can be assessed by measuring the circulating levels of various biomarkers expressed or released by the endothelium. The purpose of this review is to reappraise the evidene concerning endothelial function under physiological conditions and in atherosclerosis, and to analyze markers of endothelial function with clinical applicability. PMID:20058778

  11. CXCR4 blockade induces atherosclerosis by affecting neutrophil function

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Berbe, Jimmy F. P.; Boon, Maritte 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 ?3-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

  13. CD36, a scavenger receptor implicated in atherosclerosis

    PubMed Central

    Park, Young Mi

    2014-01-01

    CD36 is a membrane glycoprotein that is present on various types of cells, including monocytes, macrophages, microvascular endothelial cells, adipocytes and platelets. Macrophage CD36 participates in atherosclerotic arterial lesion formation through its interaction with oxidized low-density lipoprotein (oxLDL), which triggers signaling cascades for inflammatory responses. CD36 functions in oxLDL uptake and foam cell formation, which is the initial critical stage of atherosclerosis. In addition, oxLDL via CD36 inhibits macrophage migration, which may be a macrophage-trapping mechanism in atherosclerotic lesions. The role of CD36 was examined in in vitro studies and in vivo experiments, which investigated various functions of CD36 in atherosclerosis and revealed that CD36 deficiency reduces atherosclerotic lesion formation. Platelet CD36 also promotes atherosclerotic inflammatory processes and is involved in thrombus formation after atherosclerotic plaque rupture. Because CD36 is an essential component of atherosclerosis, defining the function of CD36 and its corresponding signaling pathway may lead to a new treatment strategy for atherosclerosis. PMID:24903227

  14. Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation.

    PubMed

    Rohwedder, Ina; Montanez, Eloi; Beckmann, Karsten; Bengtsson, Eva; Dunér, Pontus; Nilsson, Jan; Soehnlein, Oliver; Fässler, Reinhard

    2012-07-01

    Atherosclerotic lesions are asymmetric focal thickenings of the intima of arteries that consist of lipids, various cell types and extracellular matrix (ECM). These lesions lead to vascular occlusion representing the most common cause of death in the Western world. The main cause of vascular occlusion is rupture of atheromatous lesions followed by thrombus formation. Fibronectin (FN) is one of the earliest ECM proteins deposited at atherosclerosis-prone sites and was suggested to promote atherosclerotic lesion formation. Here, we report that atherosclerosis-prone apolipoprotein E-null mice lacking hepatocyte-derived plasma FN (pFN) fed with a pro-atherogenic diet display dramatically reduced FN depositions at atherosclerosis-prone areas, which results in significantly smaller and fewer atherosclerotic plaques. However, the atherosclerotic lesions from pFN-deficient mice lacked vascular smooth muscle cells and failed to develop a fibrous cap. Thus, our results demonstrate that while FN worsens the course of atherosclerosis by increasing the atherogenic plaque area, it promotes the formation of the protective fibrous cap, which in humans prevents plaques rupture and vascular occlusion. PMID:22514136

  15. 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

  16. 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

  17. p110Delta Inhibits Monocyte Infiltration by Thioglycollate-Induced Periotoneal Inflammation but Not HCD-Induced Inflammation and Atherosclerosis in APOE KO Mice.

    PubMed

    Tang, Futian; Li, Xiaoqiang; Gui, Yali; Qi, Cuiling; Lu, Meili; Dai, Chunmei; Wang, Hongxin; Wang, Lijing

    2015-09-01

    We have previously reported that phosphoinositide 3-kinase p110? knockout (p110? KO) diminished the adhesion of leukocytes to capillary venules and suppressed the peritoneal infiltration of leukocytes, both functions that play important roles in atherosclerosis. Therefore, we hypothesized that p110? deficiency might be protective against atherosclerosis. Apolipoprotein E knockout (ApoE KO) mice were crossed with p110? KO mice to generate homozygous double knockout mice (ApoE/p110? DKO). The present study showed that ApoE/p110? DKO mice fed with a high cholesterol diet (HCD) demonstrated less peritoneal infiltration of leukocytes and monocytes compared with ApoE KO mice after intraperitoneal injection of thioglycollate, an inducer of acute peritoneal inflammation. Unexpectedly, atherosclerosis in the aortic root and in the entire aorta was similar between the ApoE/p110? DKO and ApoE KO groups. No difference in Mac-3 expression, indicative of macrophage infiltration, was found between the two groups. Further analysis showed that ApoE KO mice chronically fed with HCD had increased levels of total cholesterol, low-density lipoprotein in the blood and counts and percentages of circulating monocytes compared with ApoE KO mice fed with a normal diet. Consistently, the deficiency of p110? affected neither the counts nor the percentages of monocytes nor the lipid profiles in the blood. The results suggested that p110? plays an important role in acute but not in chronic inflammation, the latter being included in the early characteristics of atherosclerosis, which might explain the finding that p110? deficiency fails to inhibit early atherosclerosis. PMID:25964052

  18. 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

  19. 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

  20. Fatty acyl composition of lysophosphatidylcholine is important in atherosclerosis.

    PubMed

    Akerele, O A; Cheema, S K

    2015-12-01

    Atherosclerosis is a major cause of death for mankind. Although the pathophysiology of atherosclerosis is a complex and multifactorial process, growing body of evidence has identified phospholipids-mediated signaling as an important factor in the induction and progression of atherosclerosis. Lysophosphatidylcholine (LPC) is a major phospholipid in oxidized low-density lipoprotein, and is generally considered to be atherogenic. However, some studies have shown anti-atherogenic properties of LPC. The controversial findings surrounding the pro- or anti-atherogenic properties of LPC appear to be due to the chain length and the degree of saturation of the fatty acyl moiety of LPC. Studies have suggested that the presence of omega (n)-polyunsaturated fatty acids (PUFA) at the sn-1 position of LPC modulates the inflammatory response thereby making LPC anti-atherogenic. We have recently shown that feeding a diet high in n-3 PUFA resulted in the enrichment of LPC in both plasma and liver of C57BL/6 mice with n-3 PUFA. Others have also shown that supplementation with fish oil leads to preferential incorporation of n-3 PUFA into LPC. We also found that plasma obtained from mice fed a diet high in n-3 PUFA showed higher cholesterol efflux capacity compared to animals fed a low n-3 PUFA diet, despite no changes in high-density lipoprotein concentrations. We are therefore hypothesizing that n-3 PUFA enriched LPC has anti-atherogenic properties by promoting cholesterol efflux from macrophages and by reducing inflammation. Our anticipated long term objective is to establish that the fatty acyl moiety of LPC can be used as a potential biomarker for the risk of developing atherosclerosis. Validating this hypothesis would have a substantial impact on the public health with respect to early diagnosis of cardiovascular risks, and designing dietary based therapeutic strategies for the prevention and management of atherosclerosis and other heart related diseases. PMID:26604024

  1. 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 age (p < 0.001). There was a small increase in aortic wall thickness between 50 and 73 weeks of age, but this was not significant (p > 0.05). The corresponding differences in lumen cross-sectional areas at 20, 50, and 73 weeks of age were not significant. These results were consistent with in-house historical histology data on this strain of rabbits. Conclusions. High-resolution gradient echo MRI can follow disease progression in the WHHL rabbit spontaneous atherosclerosis disease model.

  2. 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

  3. 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

  4. 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

  5. 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 ...

  6. Associations between surface markers on blood monocytes and carotid atherosclerosis in HIV-positive individuals.

    PubMed

    Westhorpe, Clare L V; Maisa, Anna; Spelman, Tim; Hoy, Jennifer F; Dewar, Elizabeth M; Karapanagiotidis, Sofie; Hearps, Anna C; Cheng, Wan-Jung; Trevillyan, Janine; Lewin, Sharon R; Sviridov, Dmitri; Elliott, Julian H; Jaworowski, Anthony; Dart, Anthony M; Crowe, Suzanne M

    2014-02-01

    Chronic HIV infection is associated with increased risk of cardiovascular disease (CVD), including in patients with virological suppression. Persistent innate immune activation may contribute to the development of CVD via activation of monocytes in these patients. We investigated whether changes in monocyte phenotype predict subclinical atherosclerosis in virologically suppressed HIV-positive individuals with low cardiovascular risk. We enroled 51 virologically suppressed HIV-positive individuals not receiving protease inhibitors or statins and 49 age-matched uninfected controls in this study. Carotid artery intima-media thickness (cIMT) was used as a surrogate marker for CVD, and traditional risk factors, including Framingham risk scores, were recorded. Markers of monocyte activation (CD14, CD16, CCR2, CX3CR1, CD38, HLA-DR and CD11b) were measured in whole-blood samples by flow cytometry. Associations were assessed using univariate and multivariate median regressions. Median cIMT was similar between HIV-positive and HIV-negative participants (P=0.3), although HIV-positive patients had significantly higher Framingham risk score (P=0.009) and systemic inflammation. Expression of two monocyte markers, CD11b and CX3CR1, independently predicted carotid artery thickness in HIV-positive individuals after controlling for Framingham risk score (P=0.025 and 0.015, respectively). These markers were not predictive of carotid artery thickening in controls. Our study indicates that monocyte surface markers may serve as novel predictors of CVD in HIV-positive individuals and is consistent with an important role for monocyte activation in the progression of HIV-related cardiovascular pathology. PMID:24296810

  7. Reduced Acute Vascular Injury and Atherosclerosis in Hyperlipidemic Mice Transgenic for Lysozyme

    PubMed Central

    Liu, Huixian; Zheng, Feng; Li, Zhu; Uribarri, Jaime; Ren, Bin; Hutter, Randolph; Tunstead, James R.; Badimon, Juan; Striker, Gary E.; Vlassara, Helen

    2006-01-01

    Hyperlipidemia promotes oxidant stress, inflammation, and atherogenesis in apolipoprotein E-deficient (ApoE(?/?)) mice. Mice transgenic for lysozyme (LZ-Tg) are resistant to acute and chronic oxidative stress and have decreased circulating levels of pro-oxidant advanced glycation end-products (AGEs). Herein we report that TIB-186 macrophages transduced with adenovirus-expressing human LZ (AdV-LZ) containing the AGE-binding domain facilitated AGE uptake and degradation and that AdV-LZ-transduced macrophages and peritoneal macrophages from LZ-Tg mice suppressed the AGE-triggered tumor necrosis factor-? response. We assessed atherosclerosis in LZ-Tg mice crossed with ApoE(?/?) mice (LZ/ApoE(?/?)) and found increased serum LZ levels and decreased AGE and 8-isoprostanes levels, although hyperlipidemia remained similar to ApoE(?/?) controls. Atherosclerotic plaques and neointimal lesions at the aortic root and descending aorta were markedly decreased (by 40% and 80%, respectively) in LZ/ApoE(?/?) versus ApoE(?/?) mice, as were inflammatory infiltrates. The arterial lesions following femoral artery injury in LZ/ApoE(?/?) mice were suppressed (intimal to media ratio decreased by 50%), as were AGE deposits and vascular smooth muscle cell activation, compared to ApoE(?/?) mice. Despite hyperlipidemia, development of atheroma and occlusive, inflammatory arterial neointimal lesions in response to injury was suppressed in LZ/ApoE(?/?) mice. This effect may be due to the antioxidant properties of LZ, which is possibly linked to the AGE-binding domain region of the molecule. PMID:16816382

  8. Apple Polyphenols Decrease Atherosclerosis and Hepatic Steatosis in ApoE-/- Mice through the ROS/MAPK/NF-?B Pathway.

    PubMed

    Xu, Zhe-Rong; Li, Jin-You; Dong, Xin-Wei; Tan, Zhong-Ju; Wu, Wei-Zhen; Xie, Qiang-Min; Yang, Yun-Mei

    2015-08-01

    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 PPAR?, 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-?B 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

  9. Large animal models of atherosclerosis - new tools for persistent problems in cardiovascular medicine.

    PubMed

    Shim, J; Al-Mashhadi, R H; Srensen, C B; Bentzon, J F

    2016-01-01

    Coronary heart disease and ischaemic stroke caused by atherosclerosis are leading causes of illness and death worldwide. Small animal models have provided insight into the fundamental mechanisms driving early atherosclerosis, but it is increasingly clear that new strategies and research tools are needed to translate these discoveries into improved prevention and treatment of symptomatic atherosclerosis in humans. Key challenges include better understanding of processes in late atherosclerosis, factors affecting atherosclerosis in the coronary bed, and the development of reliable imaging biomarker tools for risk stratification and monitoring of drug effects in humans. Efficient large animal models of atherosclerosis may help tackle these problems. Recent years have seen tremendous advances in gene-editing tools for large animals. This has made it possible to create gene-modified minipigs that develop atherosclerosis with many similarities to humans in terms of predilection for lesion sites and histopathology. Together with existing porcine models of atherosclerosis that are based on spontaneous mutations or severe diabetes, such models open new avenues for translational research in atherosclerosis. In this review, we discuss the merits of different animal models of atherosclerosis and give examples of important research problems where porcine models could prove pivotal for progress. Copyright 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:26414760

  10. 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

  11. Flavonoids protect LDL from oxidation and attenuate atherosclerosis.

    PubMed

    Fuhrman, B; Aviram, M

    2001-02-01

    Consumption of some plant-derived flavonoids results in their absorption and appearance in plasma and tissues. The inverse relationship between dietary flavonoids consumption and cardiovascular diseases may be associated with the ability of flavonoids to attenuate LDL oxidation, macrophage foam cell formation and atherosclerosis. The effect of flavonoids on arterial cell-mediated oxidation of LDL is determined by their accumulation in the lipoprotein and in arterial cells, such as macrophages. Flavonoids can reduce LDL lipid peroxidation by scavenging reactive oxygen/nitrogen species, chelation of transition metal ions and sparing of LDL-associated antioxidants. They can also reduce macrophage oxidative stress by inhibition of cellular oxygenases [such as nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase] or by activating cellular antioxidants (such as the glutathione system). Thus, plant flavonoids, as potent natural antioxidants that protect against lipid peroxidation in arterial cells and lipoproteins, significantly attenuate the development of atherosclerosis. PMID:11176202

  12. Defects in regulation of local immune responses resulting in atherosclerosis.

    PubMed

    Ferencík, Miroslav; Stvrtinová, Viera; Hulín, Ivan

    2005-09-01

    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

  13. Nikolai N. Anitschkow and the lipid hypothesis of atherosclerosis.

    PubMed

    Buja, L Maximilian

    2014-01-01

    One hundred years ago, Nikolai N. Anitschkow published his seminal observations that rabbits fed a diet with only high-cholesterol developed atheromatous lesions in association with greatly elevated blood cholesterol. For many years, Anitschkow's observations received little recognition. However, eventually a combination of experimental work, autopsy studies, epidemiological investigation and clinical trials has led to the firm establishment of the essential role of lipids in the response to injury theory of atherosclerosis. The twists and turns in the acceptance of the lipid hypothesis of atherosclerosis is briefly reviewed. Today, it is well worth celebrating the 100th anniversary of the seminal insight into human vascular disease of the brilliant experimental pathologist, Nikolai N. Anitschkow. PMID:24484612

  14. 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

  15. Activation of the human terminal complement pathway in atherosclerosis.

    PubMed

    Niculescu, F; Rus, H G; Vlaicu, R

    1987-11-01

    The presence of the terminal C5b-9 complement complex in tissues indicates that complement activation has occurred in situ with subsequent membrane damage, tissue injury, and inflammatory response mediation. The terminal C5b-9 neoantigens of the complement system, S protein C3c, C3d, and apolipoprotein B deposits were localized in 20 aortic fibrous plaques, 12 aortic intimal thickenings, 8 aortic fatty streak intimae, 14 coronary fibrous plaques, 5 coronary intimal thickenings, and 8 femoral fibrous plaques, using an indirect and double-staining immunoperoxidase technique. The specific granular deposits were present from the early to the advanced stages of atherosclerosis in relation to the degree of fibrosis and necrosis. The different double-staining localization of C5b-9 and S protein may suggest local assembly of the complex as a consequence of complement activation and may sustain its role in the chronic progression of atherosclerosis. PMID:2444373

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

    PubMed

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

    2015-11-01

    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

  17. Probing nanoparticle translocation across the permeable endothelium in experimental atherosclerosis

    PubMed Central

    Kim, YongTae; Lobatto, Mark E.; Kawahara, Tomohiro; Lee Chung, Bomy; Mieszawska, Aneta J.; Sanchez-Gaytan, Brenda L.; Fay, Francois; Senders, Max L.; Calcagno, Claudia; Becraft, Jacob; Tun Saung, May; Gordon, Ronald E.; Stroes, Erik S. G.; Ma, Mingming; Farokhzad, Omid C.; Fayad, Zahi A.; Mulder, Willem J. M.; Langer, Robert

    2014-01-01

    Therapeutic and diagnostic nanomaterials are being intensely studied for several diseases, including cancer and atherosclerosis. However, the exact mechanism by which nanomedicines accumulate at targeted sites remains a topic of investigation, especially in the context of atherosclerotic disease. Models to accurately predict transvascular permeation of nanomedicines are needed to aid in design optimization. Here we show that an endothelialized microchip with controllable permeability can be used to probe nanoparticle translocation across an endothelial cell layer. To validate our in vitro model, we studied nanoparticle translocation in an in vivo rabbit model of atherosclerosis using a variety of preclinical and clinical imaging methods. Our results reveal that the translocation of lipid–polymer hybrid nanoparticles across the atherosclerotic endothelium is dependent on microvascular permeability. These results were mimicked with our microfluidic chip, demonstrating the potential utility of the model system. PMID:24395808

  18. 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

  19. 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

  20. Clinical imaging in anti-atherosclerosis drug development.

    PubMed

    Ehlgen, Alexander; Bylock, Anders; Kreuzer, Jörg; Koslowski, Michael; Gantner, Florian; Niessen, Heiko G

    2015-11-01

    The development of novel drugs for the treatment of atherosclerosis faces many challenges, particularly caused by the need for large and costly outcome trials. When predictive biochemical biomarkers are not available, clinical imaging data can serve as intermediate Phase II endpoints to demonstrate mechanistic and anti-atherosclerotic activity of new compounds. These data can support risk mitigation before continuing development in large Phase III outcome trials. Imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT) and ultrasound [intima-media thickness (IMT) and intravascular ultrasound (IVUS)] can provide detailed information on vascular plaque volume and morphology, whereas functional changes can potentially be captured by positron emission tomography (PET) techniques in the vessel wall. We will review the application and operational aspects of clinical imaging methods and endpoints used in interventional atherosclerosis trials. PMID:26151479

  1. Role of diabetes, hypertension, and cigarette smoking on atherosclerosis

    PubMed Central

    Mathur, Ram K.

    2010-01-01

    Hyperosmolar food causes atherosclerosis. Hyperosmolal food hypothesis encompasses all the factors involved under one heading and, that is, the generation of heat in the body. The involvement of cigarette smoking is obvious. High glycemic index food and diabetes result in high levels of blood glucose, which raises the core body temperature. The ingestion of hyperosmolal salt, glucose, and amino acids singularly or synergistically raise the core body temperature, forcing abdominal aorta to form an insulation wall of fatty material causing atherosclerotic plaques. The osmolarity of food, that is glucose, salt, and amino acids is reduced when water is ingested with food. The incidence of atherosclerosis goes down with increasing intake of water. PMID:20877688

  2. Conjugated linoleic acid and atherosclerosis: studies in animal models.

    PubMed

    Mitchell, Patricia L; McLeod, Roger S

    2008-08-01

    Conjugated linoleic acids (CLA) are isomeric forms of linoleic acid (LA) containing two conjugated sites of unsaturation. The most abundant dietary form of CLA is the cis-9,trans-11 (c-9,t-11) isomer that is found in the fatty tissues and milk of ruminant animals. CLA can also be acquired by ingestion of supplements, which are usually equimolar mixtures of the c-9,t-11 and t-10,c-12 CLA. For more than a decade, the potential for CLA to modify atherosclerosis in animal models has been examined. However, to date, the studies have failed to reach consensus on whether CLA can be effective in reducing the incidence or severity of atherosclerotic lesions, or whether or not plasma lipid and lipoprotein levels can be improved with CLA supplementation. This review will examine the evidence for and against a role for CLA in atherosclerosis, with a focus on the rabbit, the hamster, and the apoE-deficient mouse. PMID:18756324

  3. 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-g/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

  4. Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis.

    PubMed Central

    de Andrade, M; Thandi, I; Brown, S; Gotto, A; Patsch, W; Boerwinkle, E

    1995-01-01

    From the cohort taking part in the Atherosclerosis Risk in Communities (ARIC) study, a multicenter investigation of atherosclerosis and its sequelae in women and men ages 45-64 years, a sample of 145 subjects with significant carotid artery atherosclerosis but without clinically recognized coronary heart disease was identified along with 224 group-matched control subjects. The aim of this paper is to measure the association of the apolipoprotein (apo) E polymorphism with the prevalence of significant carotid artery atherosclerotic disease (CAAD) after considering the contribution of established risk factor variables. The first model used a stepwise selection procedure to define a group of significant physical and lifestyle characteristics and a group of significant plasma lipid, lipoprotein, and apolipoprotein variables that were predictive of CAAD status in this sample. Those variables selected included age (years), body mass index (BMI; kg/m2), consumption of cigarettes (CigYears; number of cigarettes/d x the number of smoking years), hypertension status, high-density lipoprotein (HDL)-cholesterol (mg/dl), total cholesterol (mg/dl), and Lp[a] (micrograms/ml). The second model was built by forcing into the equation an a priori set of demographic, anthropometric, and lipoprotein variables, which were age, BMI, CigYears, hypertensive status, LDL-cholesterol, and HDL-cholesterol. In both models, the apo E genotype epsilon 2/3 was related to CAAD status. For both models, the estimated odds ratio of being a CAAD case associated with the apo E genotype epsilon 2/3 was > 2:1. The mechanism of the observed association between the epsilon 2/3 genotype and carotid atherosclerosis is unknown, but it is likely due to the known effects of the E2 isoform in causing delayed clearance of triglyceride-rich lipoproteins. PMID:7762561

  5. Attenuation of the development of hypercholesterolemic atherosclerosis by thymoquinone

    PubMed Central

    Ragheb, Ahmed; Elbarbry, Fawzy; Prasad, Kailash; Mohamed, Adel; Ahmed, Mohamed S; Shoker, Ahmed

    2008-01-01

    Thymoquinone (TQ), derived from Nigella sativa seed, is an antioxidant. The present study investigated whether TQ attenuates the development of atherosclerosis, and/or reduces the serum lipid levels and oxidative stress in rabbits. New Zealand white female rabbits were assigned to four groups of six animals each: group I, control; group II, 1% cholesterol diet; group III, 1% cholesterol plus TQ (10 mg/kg/day; through a nasogastric tube) diet; and group IV, 1% cholesterol plus TQ (20 mg/kg/day; through a nasogastric tube) diet. Blood samples were collected at baseline and after four and eight weeks on the experimental diets for measurement of serum lipids, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TC/HDL-C ratio and oxidative stress biomarkers (malondialdehyde [MDA] and protein carbonyls). At the end of the eight weeks, the aorta was removed for the assessment of atherosclerotic changes, MDA and protein carbonyls. Group II animals developed atherosclerosis (45%11% of the intimal surface of aorta was covered with atherosclerotic plaques), which was associated with an increase in the serum TC, TG, LDL-C, HDL-C, TC/HDL-C, MDA and protein carbonyls. In group III, TQ decreased serum TC, LDL-C, MDA and protein carbonyls by 26%, 29%, 85% and 62%, respectively, and aortic MDA by 73%, which was associated with a 40% reduction of the development of aortic atherosclerosis. The higher dose of TQ in group IV had effects similar to the lower dose (group III), except that this dose further decreased serum TG. It is concluded that TQ attenuates hypercholesterolemic atherosclerosis and this effect is associated with a decrease in serum lipids and oxidative stress. PMID:22477447

  6. Laser Coronary Endarterectomy: Proposed Treatment for Diffuse Coronary Atherosclerosis

    PubMed Central

    Livesay, James J.; Cooley, Denton A.

    1984-01-01

    A new surgical technique with a hand-held laser is proposed as an adjunct for coronary revascularization. High intensity light energy from a carbon dioxide laser may be used to cut atherosclerotic plaques, to relieve coronary stenosis, and to reopen totally occluded arteries. The recent development of a small, portable CO2 laser provides a practical surgical tool for treatment of diffuse coronary atherosclerosis. PMID:15227061

  7. Fish oil inhibits development of atherosclerosis in rhesus monkeys.

    PubMed

    Davis, H R; Bridenstine, R T; Vesselinovitch, D; Wissler, R W

    1987-01-01

    The effect of feeding fish oil (Menhaden) on the progression of rhesus monkey atherosclerosis was determined by feeding diets containing 2% cholesterol and either 25% coconut oil (Group I), 25% fish oil/coconut oil (1:1) (Group II), or 25% fish oil/coconut oil (3:1) (Group III) for 12 months (n = 8/group). The average serum cholesterol levels were 875 mg/dl for Group I, 463 mg/dl for Group II, and 405 mg/dl for Group III. HDL cholesterol levels were 49 mg/dl for Group I, 29 mg/dl for Group II, and 20 mg/dl for Group III. An average of 79% of the aortic intima was involved with atherosclerosis in Group I, 48% in Group II, and 36% in Group III. The aortas of both fish-oil groups (II or III) contained significantly less cholesterol (total, free, and esterified), as well as less acid lipase, cholesteryl esterase, and ACAT activities when compared to the coconut-oil group (I) (p less than 0.05). Microscopically, the aortic and carotid artery lesions were smaller in cross-sectional area and in thickness, and contained less macrophages in the fish-oil groups (II and III) when compared to the coconut-oil group (I) (p less than 0.05). This protective effect was not consistently enhanced by increasing the proportion of fish oil to 3:1 (Group III) over 1:1 (Group II). The results indicate that fish oil-containing diets reduce serum cholesterol levels and inhibit atherosclerosis even in the face of lowered HDL cholesterol levels when compared to a pure coconut oil/cholesterol diet in rhesus monkeys. Therefore, fish-oil diets exert effective protective control of progression of atherosclerosis during severe atherogenic stimuli. PMID:3675303

  8. Platelets and their chemokines in atherosclerosisclinical applications

    PubMed Central

    von Hundelshausen, Philipp; Schmitt, Martin M. N.

    2014-01-01

    The concept of platelets as important players in the process of atherogenesis has become increasingly accepted due to accumulating experimental and clinical evidence. Despite the progress in understanding the molecular details of atherosclerosis, particularly by using animal models, the inflammatory and thrombotic roles of activated platelet s especially in the human system remain difficult to dissect, as often only the complications of atherosclerosis, i.e., stroke and myocardial infarction are definable but not the plaque burden. Platelet indices including platelet count and mean platelet volume (MPV) and soluble mediators released by activated platelets are associated with atherosclerosis. The chemokine CXCL4 has multiple atherogenic activities, e.g., altering the differentiation of T cells and macrophages by inhibiting neutrophil and monocyte apoptosis and by increasing the uptake of oxLDL and synergizing with CCL5. CCL5 is released and deposited on endothelium by activated platelets thereby triggering atherogenic monocyte recruitment, which can be attenuated by blocking the corresponding chemokine receptor CCR5. Atheroprotective and plaque stabilizing properties are attributed to CXCL12, which plays an important role in regenerative processes by attracting progenitor cells. Its release from luminal attached platelets accelerates endothelial healing after injury. Platelet surface molecules GPIIb/IIIa, GP1b?, P-selectin, JAM-A and the CD40/CD40L dyade are crucially involved in the interaction with endothelial cells, leukocytes and matrix molecules affecting atherogenesis. Beyond the effects on the arterial inflammatory infiltrate, platelets affect cholesterol metabolism by binding, modifying and endocytosing LDL particles via their scavenger receptors and contribute to the formation of lipid laden macrophages. Current medical therapies for the prevention of atherosclerotic therapies enable the elucidation of mechanisms linking platelets to inflammation and atherosclerosis. PMID:25152735

  9. 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

  10. 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

  11. Necrosis of the penis with multiple vessel atherosclerosis.

    PubMed

    Kim, Sung Dae; Huh, Jung Sik; Kim, Young-Joo

    2014-04-01

    Penile necrosis is a very rare complication because of its rich collateral supply. Conservative management is apt to be ineffective; thus penectomy is usually performed. We present a case of penile necrosis and claudication of both legs with multiple atherosclerosis in a type II diabetes mellitus patient who was successfully treated with angioplasty, penoplasty, and additional intracavernous injections of prostaglandin E1. The treatment resulted in relief of the leg pain and healing of the penile ischemic lesions. PMID:24872955

  12. Necrosis of the Penis with Multiple Vessel Atherosclerosis

    PubMed Central

    Kim, Sung Dae; Huh, Jung Sik

    2014-01-01

    Penile necrosis is a very rare complication because of its rich collateral supply. Conservative management is apt to be ineffective; thus penectomy is usually performed. We present a case of penile necrosis and claudication of both legs with multiple atherosclerosis in a type II diabetes mellitus patient who was successfully treated with angioplasty, penoplasty, and additional intracavernous injections of prostaglandin E1. The treatment resulted in relief of the leg pain and healing of the penile ischemic lesions. PMID:24872955

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

    PubMed

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

    2015-08-26

    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

  14. Epicardial adipose excision slows the progression of porcine coronary atherosclerosis

    PubMed Central

    2014-01-01

    Background In humans there is a positive association between epicardial adipose tissue (EAT) volume and coronary atherosclerosis (CAD) burden. We tested the hypothesis that EAT contributes locally to CAD in a pig model. Methods Ossabaw miniature swine (n = 9) were fed an atherogenic diet for 6 months to produce CAD. A 15 mm length by 3–5 mm width coronary EAT (cEAT) resection was performed over the middle segment of the left anterior descending artery (LAD) 15 mm distal to the left main bifurcation. Pigs recovered for 3 months on atherogenic diet. Intravascular ultrasound (IVUS) was performed in the LAD to quantify atheroma immediately after adipectomy and was repeated after recovery before sacrifice. Coronary wall biopsies were stained immunohistochemically for atherosclerosis markers and cytokines and cEAT was assayed for atherosclerosis-related genes by RT-PCR. Total EAT volume was measured by non-contrast CT before each IVUS. Results Circumferential plaque length increased (p < 0.05) in the proximal and distal LAD segments from baseline until sacrifice whereas plaque length in the middle LAD segment underneath the adipectomy site did not increase. T-cadherin, scavenger receptor A and adiponectin were reduced in the intramural middle LAD. Relative to control pigs without CAD, 11β-hydroxysteroid dehydrogenase (11βHSD-1), CCL19, CCL21, prostaglandin D2 synthase, gp91phox [NADPH oxidase], VEGF, VEGFGR1, and angiotensinogen mRNAs were up-regulated in cEAT. EAT volume increased over 3 months. Conclusion In pigs used as their own controls, resection of cEAT decreased the progression of CAD, suggesting that cEAT may exacerbate coronary atherosclerosis. PMID:24387639

  15. EGCG attenuates atherosclerosis through the Jagged-1/Notch pathway.

    PubMed

    Yin, Jianguo; Huang, Fang; Yi, Yuhong; Yin, Liang; Peng, Daoquan

    2016-02-01

    Atherosclerosis is the most common cause of cardiovascular diseases worldwide. Oxidized low-density lipoprotein(ox-LDL) is a particularly important risk factor in the pathogenesis of atherosclerosis. Accumulating evidence has indicated that epigallocatechin-3-gallate(EGCG; a catechin found in the popular beverage, greent tea) protects against ox-LDL-induced atherosclerosis. However, the underlying mechanisms remain unclear. In the present study, ox-LDL(100mg/l) induced damage to, and the apoptosis of human umbilical vein endothelial cells(HUVECs) by reducing endothelial nitric oxide synthase(eNOS) expression and promoting inducible nitric oxide synthase(iNOS) expression; these effects were abrogated by the addition of 50M EGCG. Furthermore, ox-LDL rapidly activated the membrane translocation of p22phox, and altered the protein expression of Jagged-1 and Notch pathway-related proteins [Math1, hairy and enhancer of split(HES)1 and HES5]; these effects were also prevented by pre-treatment with 50M EGCG. In addition, Jagged-1 played a significant role in the EGCG-mediated protection against ox-LDL-induced apoptosis and ox-LDL?diminished cell adhesion in the HUVECs. Finally, EGCG inhibited high-fat diet(HFD)-induced atherosclerosis in apolipoproteinE (ApoE) knockout(ApoE-KO) mice through the Jagged-1/Notch pathway. Taken together, these findings demonstrate that 50M EGCG protects against ox-LDL-induced endothelial dysfunction through the Jagged-1/Notch signaling pathway. Moreover, our data provide insight into the possible molecular mechanisms through which EGCG attenuates ox-LDL?induced vascular endothelial dysfunction. PMID:26648562

  16. Hematopoietic knockdown of PPAR? reduces atherosclerosis in LDLR-/- mice.

    PubMed

    Li, G; Chen, C; Laing, S D; Ballard, C; Biju, K C; Reddick, R L; Clark, R A; Li, S

    2016-01-01

    PPAR? (peroxisome proliferator-activated receptor ?) mediates inflammation in response to lipid accumulation. Systemic administration of a PPAR? agonist can ameliorate atherosclerosis. Paradoxically, genetic deletion of PPAR? in hematopoietic cells led to a reduction of atherosclerosis in murine models, suggesting that downregulation of PPAR? expression in these cells may mitigate atherogenesis. To advance this finding forward to potential clinical translation through hematopoietic stem cell transplantation-based gene therapy, we employed a microRNA (miRNA) approach to knock down PPAR? expression in bone marrow cells followed by transplantation of the cells into LDLR-/- mice. We found that knockdown of PPAR? expression in the hematopoietic system caused a dramatic reduction in aortic atherosclerotic lesions. In macrophages, a key component in atherogenesis, knockdown of PPAR? led to decreased expression of multiple pro-inflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1? and IL-6. Expression of CCR2, a receptor for MCP-1, was also decreased. The downregulation of pro-inflammatory factors is consistent with significant reduction of macrophage presence in the lesions, which may also be attributable to elevation of ABCA1 (ATP-binding cassette, subfamily A, member 1) and depression of adipocyte differentiate-related protein. Furthermore, the abundance of both MCP-1 and matrix metalloproteinase-9 proteins was reduced in plaque areas. Our results demonstrate that miRNA-mediated PPAR? knockdown in hematopoietic cells is able to ameliorate atherosclerosis. PMID:26204499

  17. 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

  18. Protective role for properdin in progression of experimental murine atherosclerosis.

    PubMed

    Steiner, Tanja; Francescut, Lorenza; Byrne, Simon; Hughes, Timothy; Jayanthi, Archana; Guschina, Irina; Harwood, John; Cianflone, Katherine; Stover, Cordula; Francis, Sheila

    2014-01-01

    Genetic, dietary and immune factors contribute to the pathogenesis of atherosclerosis in humans and mice. Complement activation is an integral part of the innate immune defence but also shapes cellular responses and influences directly triglyceride synthesis. Deficiency of Factor B of the alternative pathway (AP) of complement is beneficial in LDLR(-/-) mice fed a high fat diet. The serum glycoprotein properdin is a key positive regulator of the AP but has not been studied in experimental atherosclerosis. Atherosclerosis was assessed after feeding low fat (LFD) or high fat (HFD) Western type diets to newly generated LDLR(-/-) Properdin(KO) (LDLR(-/-)P(KO)) and LDLR-/-PWT mice. Lipids, lymphocytes and monocytes were similar among genotypes, genders and diets. Complement C3, but not C3adesarg, levels were enhanced in LDLR(-/-)P(KO) mice regardless of diet type or gender. Non-esterified fatty acids (NEFA) were decreased in male LDLR(-/-)P(KO) fed a HFD compared with controls. All mice showed significant atherosclerotic burden in aortae and at aortic roots but male LDLR(-/-) mice fed a LFD were affected to the greatest extent by the absence of properdin. The protective effect of properdin expression was overwhelmed in both genders of LDLR(-/-)mice when fed a HFD. We conclude that properdin plays an unexpectedly beneficial role in the development and progression of early atherosclerotic lesions. PMID:24667818

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

    PubMed

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

    2014-12-01

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

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

    PubMed Central

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

    2014-01-01

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

  1. IKK? links vascular inflammation to obesity and atherosclerosis

    PubMed Central

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

    2014-01-01

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

  2. Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis.

    PubMed

    Forbes, Josephine M; Yee, Louis Teo Loon; Thallas, Vicki; Lassila, Markus; Candido, Riccardo; Jandeleit-Dahm, Karin A; Thomas, Merlin C; Burns, Wendy C; Deemer, Elizabeth K; Thorpe, Susan R; Thorpe, Susan M; Cooper, Mark E; Allen, Terri J

    2004-07-01

    Advanced glycation end product (AGE) formation may contribute to the progression of atherosclerosis, particularly in diabetes. The present study explored atherosclerosis in streptozotocin-induced diabetic apolipoprotein E-deficient (apoE-/-) mice that were randomized (n = 20) to receive for 20 weeks no treatment, the AGE cross-link breaker ALT-711, or the inhibitor of AGE formation aminoguanidine (AG). A sixfold increase in plaque area with diabetes was attenuated by 30% with ALT-711 and by 40% in AG-treated mice. Regional distribution of plaque demonstrated no reduction in plaque area or complexity within the aortic arch with treatment, in contrast to the thoracic and abdominal aortas, where significant attenuation was seen. Diabetes-associated accumulation of AGEs in aortas and plasma and decreases in skin collagen solubility were ameliorated by both treatments, in addition to reductions in the vascular receptor for AGE. Collagen-associated reductions in the AGEs carboxymethyllysine and carboxyethyllysine were identified with both treatments. Diabetes was also accompanied by aortic accumulation of total collagen, specifically collagens I, III, and IV, as well as increases in the profibrotic cytokines transforming growth factor-beta and connective tissue growth factor and in cellular alpha-smooth muscle actin. Attenuation of these changes was seen in both treated diabetic groups. ALT-711 and AG demonstrated the ability to reduce vascular AGE accumulation in addition to attenuating atherosclerosis in these diabetic mice. PMID:15220206

  3. Macrophages in vascular inflammation--From atherosclerosis to vasculitis.

    PubMed

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

    2015-05-01

    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

  4. Macrophages in Vascular Inflammation From Atherosclerosis to Vasculitis

    PubMed Central

    Shirai, Tsuyoshi; Hilhorst, Marc; Harrison, David G.; Goronzy, Jrg 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

  5. Obstructive sleep apnea, immuno-inflammation, and atherosclerosis.

    PubMed

    Arnaud, Claire; Dematteis, Maurice; Pepin, Jean-Louis; Baguet, Jean-Philippe; Lvy, Patrick

    2009-06-01

    Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder leading to cardiovascular and metabolic complications. OSA is also a multicomponent disorder, with intermittent hypoxia (IH) as the main trigger for the associated cardiovascular and metabolic alterations. Indeed, recurrent pharyngeal collapses during sleep lead to repetitive sequences of hypoxia-reoxygenation. This IH induces several consequences such as hemodynamic, hormonometabolic, oxidative, and immuno-inflammatory alterations that may interact and aggravate each other, resulting in artery changes, from adaptive to degenerative atherosclerotic remodeling. Atherosclerosis has been found in OSA patients free of other cardiovascular risk factors and is related to the severity of nocturnal hypoxia. Early stages of artery alteration, including functional and structural changes, have been evidenced in both OSA patients and rodents experimentally exposed to IH. Impaired vasoreactivity with endothelial dysfunction and/or increased vasoconstrictive responses due to sympathetic, endothelin, and renin-angiotensin systems have been reported and also contribute to vascular remodeling and inflammation. Oxidative stress, inflammation, and vascular remodeling can be directly triggered by IH, further aggravated by the OSA-associated hormonometabolic alterations, such as insulin resistance, dyslipidemia, and adipokine imbalance. As shown in OSA patients and in the animal model, genetic susceptibility, comorbidities (obesity), and life habits (high fat diet) may aggravate atherosclerosis development or progression. The intimate molecular mechanisms are still largely unknown, and their understanding may contribute to delineate new targets for prevention strategies and/or development of new treatment of OSA-related atherosclerosis, especially in patients at risk for cardiovascular disease. PMID:19404644

  6. Epigenetic pathways in macrophages emerge as novel targets in atherosclerosis.

    PubMed

    Neele, Annette E; Van den Bossche, Jan; Hoeksema, Marten A; de Winther, Menno P J

    2015-09-15

    Atherosclerosis is a lipid-driven chronic inflammatory disorder. Monocytes and macrophages are key immune cells in the development of disease and clinical outcome. It is becoming increasingly clear that epigenetic pathways govern many aspects of monocyte and macrophage differentiation and activation. The dynamic regulation of epigenetic patterns provides opportunities to alter disease-associated epigenetic states. Therefore, pharmaceutical companies have embraced the targeting of epigenetic processes as new approaches for interventions. Particularly histone deacetylase (Hdac) inhibitors and DNA-methyltransferase inhibitors have long received attention and several of them have been approved for clinical use in relation to hematological malignancies. The key focus is still on oncology, but Alzheimer's disease, Huntington's disease and inflammatory disorders are coming in focus as well. These developments raise opportunities for the epigenetic targeting in cardiovascular disease (CVD). In this review we discuss the epigenetic regulation of the inflammatory pathways in relation to atherosclerosis with a specific attention to monocyte- and macrophage-related processes. What are the opportunities for future therapy of atherosclerosis by epigenetic interventions? PMID:26004034

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

    PubMed

    Ketelhuth, Daniel F J; Hansson, Gran 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

  8. 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.

  9. Reversal of atherosis and sclerosis. The two components of atherosclerosis.

    PubMed

    Blankenhorn, D H; Kramsch, D M

    1989-01-01

    In 1904, Marchand recognized the consistent association of fatty degeneration and vessel stiffening and introduced the term "atherosclerosis" to indicate this combination. Current research is focused principally on the lipid component, but there is evidence that both aspects are reversible. Atheromatous lipids add significantly to the volume of lesions and thus contribute to vascular obstruction and end-organ damage. Reversal of atherosis has been observed in all the major species used in atherosclerosis research; rabbits, swine, dogs, chicks, pigeons, and subhuman primates. Direct evidence for reversal in humans is based on angiographic trials and is less extensive. One femoral artery and one coronary artery trial indicate that the lesions can be stabilized. CLAS, the largest angiographic trial to date, indicates that coronary lesion reversal is possible. Clinical effects of sclerosis are more subtle, and there is little evidence that sclerosis alone leads to end-organ damage. However, it should be noted that atherosclerotic lesions producing end-organ damage invariably have a major fibrous component. Sclerotic vessels have reduced systolic expansion and abnormally rapid pulse wave propagation, which can be measured noninvasively. Primate studies indicate that sclerosis is induced by hypercholesterolemic diets and is reversible when these diets are withdrawn. Changes in sclerosis may be another useful indicator of the formation and reversal of lesions and may involve changes in EDRF. Future studies of atherosclerosis reversal should use a combination of measures to evaluate both atherosis and sclerosis. PMID:2642753

  10. 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

  11. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice

    PubMed Central

    Spolitu, Stefano; Milton, Jaclyn; Ghorpade, Devram; Chiasson, Raymond; Kuriakose, George; Perretti, Mauro; Farokzhad, Omid; Tabas, Ira

    2015-01-01

    Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1. The proresolving actions of annexin A1, which are mediated through its receptor N-formyl peptide receptor 2 (FPR2/ALX), can be mimicked by an amino-terminal peptide encompassing amino acids 2–26 (Ac2-26). Collagen IV (Col IV)–targeted nanoparticles (NPs) containing Ac2-26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr−/− mice. When administered to mice with preexisting lesions, Col IV–Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions (which was associated with a decrease in lesional collagenase activity), suppression of oxidative stress, and a decrease in plaque necrosis. In mice lacking FPR2/ALX in myeloid cells, these improvements were not seen. Thus, administration of a resolution-mediating peptide in a targeted NP activates its receptor on myeloid cells to stabilize advanced atherosclerotic lesions. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy. PMID:25695999

  12. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice.

    PubMed

    Fredman, Gabrielle; Kamaly, Nazila; Spolitu, Stefano; Milton, Jaclyn; Ghorpade, Devram; Chiasson, Raymond; Kuriakose, George; Perretti, Mauro; Farokhzad, Omid; Farokzhad, Omid; Tabas, Ira

    2015-02-18

    Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1. The proresolving actions of annexin A1, which are mediated through its receptor N-formyl peptide receptor 2 (FPR2/ALX), can be mimicked by an amino-terminal peptide encompassing amino acids 2-26 (Ac2-26). Collagen IV (Col IV)-targeted nanoparticles (NPs) containing Ac2-26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr(-/-) mice. When administered to mice with preexisting lesions, Col IV-Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions (which was associated with a decrease in lesional collagenase activity), suppression of oxidative stress, and a decrease in plaque necrosis. In mice lacking FPR2/ALX in myeloid cells, these improvements were not seen. Thus, administration of a resolution-mediating peptide in a targeted NP activates its receptor on myeloid cells to stabilize advanced atherosclerotic lesions. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy. PMID:25695999

  13. A comparison of antihypertensive drug effects on the progression of extracranial carotid atherosclerosis. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS).

    PubMed

    Grimm, R H; Flack, J M; Byington, R; Bond, G; Brugger, S

    1990-01-01

    Hypertension is a major risk factor for coronary heart disease (CHD) and is the primary risk factor for stroke. Drug trials lowering blood pressure by pharmacological means have demonstrated impressive reduction in both fatal and nonfatal stroke (33 to 50%) that are virtually identical to the predicted stroke reduction, considering the observed diastolic blood pressure change (5 to 6mm Hg). On the other hand, reduction of CHD risk has been less impressive in these same trials. Although statistically significant, the reduction in CHD risk is roughly one-half (14%) of that predicted (25%) when results from these drug trials are analysed in aggregate. Most trials have used moderate to high dosages of thiazide diuretics or beta-blockers as therapies. Several factors may account for the disappointing results in CHD risk reduction. These drugs may induce metabolic disturbances in lipids, increased glucose tolerance, insulin resistance, or cause inadequate regression of left ventricular hypertrophy, thus attenuating the predicted reduction in CHD risk associated with pharmacological blood pressure lowering. Isradipine is a new dihydropyridine calcium antagonist that is highly effective in lowering blood pressure. Isradipine also has antiatherogenic properties in animal models of atherosclerosis. The effect of isradipine on atherosclerosis in humans is unknown. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) is a 3-year double-blind, randomised trial in over 800 men and women with hypertension, aged 40 years or older. The primary aim of MIDAS is to compare the efficacy of isradipine 2.5 to 5.0mg twice daily vs hydrochlorothiazide 12.5 to 25mg twice daily in retarding the progression of extracranial carotid atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2150640

  14. 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 (? 0.90mm), in non-diabetic participants. Methods Nine hundred-sixty-one (range of age: 1889yrs; 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???0.9mm) 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 consumption in prevention of cardiovascular disease. PMID:24405571

  15. Atherosclerosis, cholesterol, nutrition, and statins--a critical review.

    PubMed

    Gebbers, Jan-Olaf

    2007-01-01

    Atherosclerosis, which causes approximately half of all deaths of adults over age 60 in industrialized nations, is a pandemic among inappropriately nourished and/or physically hypoactive children, adolescents, and adults world wide. Although nowadays statins are widely prescribed to middle age and elderly adults with high blood lipid levels as pharmacological prevention for the late complications of atherosclerosis, from a critical point of view statins seem not to solve the problem, especially when compared with certain natural ingredients of our nutrition like micronutrients as alternative strategy. Statin ingestion is associated with lowering of serum cholesterol and low-density lipoprotein concentrations; some prospective studies have shown statistical associations with subsequent modest reduction of mortality from cardiovascular disease. However, specific biochemical pathways and pharmacological roles of statins in prevention of atherosclerosis, if any, are unknown. Moreover, there have been no systematic cost-benefit analyses of life-style prophylaxis versus statin prophylaxis versus combined life-style plus statin prophylaxis versus neither life-style nor statin prophylaxis for clinically significant complications of cardiovascular diseases in the elderly. Further, in the trials of effectiveness statins were not compared with management of nutrition, which is the most appropriate alternative intervention. Such studies seem to be important, as the ever increasing world population, especially in developing countries, now demand expensive statins, which may be unaffordable for mitigating the pandemic. Studies of this kind are necessary to identify more precisely those patients for whom cardiovascular benefits will outweigh the risks and costs of the statin treatment in comparison with nutritional interventions. Against the background of the current pathogenetic concept of atherogenesis some of its possible risk factors, particularly the roles of cholesterol and homocysteine, and the effects of statins versus nutritional (micronutrients) interventions in prevention and treatment of the disease are discussed. The prevailing opinion that serum cholesterol as a mediator of the disease is increased by eating saturated fats and decreased by eating polyunsaturated fats is being challenged. Evidently, the beneficial effects of statins in atherosclerosis are not mainly due to its cholesterol lowering effect, rather than to its "pleiotropic effects". Other pathogenetic factors in atherosclerosis are involved, like inflammatory and immunologic processes, that can be modulated by statins as well as by other drugs or by the Mediterranean-style nutrition and by micronutrients (folate, B-vitamins). PMID:19675712

  16. 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

  17. 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

  18. MIDAS: hypertension and atherosclerosis. A trial of the effects of antihypertensive drug treatment on atherosclerosis. MIDAS Research Group.

    PubMed

    Borhani, N O; Miller, S T; Brugger, S B; Schnaper, H W; Craven, T E; Bond, M G; Khoury, S; Flack, J

    1992-01-01

    Although clinical trials of the efficacy of antihypertensive treatment have demonstrated impressive reductions in the incidence of stroke, the reduction in coronary artery disease mortality has been less impressive. It may be that the antihypertensive drugs used in these trials induced metabolic disturbances, or produced inadequate regression of left ventricular hypertrophy, thus blunting the reduction in risk of coronary artery disease expected with blood pressure-lowering. Isradipine, a dihydropyridine calcium antagonist known to be an effective antihypertensive agent, has also displayed pronounced antiatherogenic effects in animals. Thus, a reasonable hypothesis could be that isradipine not only reduces the level of blood pressure, but also may have a positive effect on the evolution of atherosclerotic plaque in coronary and carotid arteries, thereby leading to prevention of clinical sequelae of atherosclerosis. On this basis, a 3-year clinical trial is being carried out in the United States--the Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS)--to establish the efficacy of isradipine in inhibiting atherogenesis and retarding the progression of atherosclerosis in carotid arteries of hypertensive patients. The primary end point of the study is intima-media thickness and the extent of atherosclerotic plaque in the carotid arteries, as measured by B-mode ultrasonography. PMID:1376828

  19. 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

  20. 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

  1. 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

  2. Peak inflammation in atherosclerosis, primary biliary cirrhosis and autoimmune arthritis is counter-intuitively associated with regulatory T cell enrichment

    PubMed Central

    Garetto, Stefano; Trovato, Anna Elisa; Lleo, Ana; Sala, Federica; Martini, Elisa; Betz, Alexander G.; Norata, Giuseppe D.; Invernizzi, Pietro; Kallikourdis, Marinos

    2015-01-01

    Regulatory T cells (Treg) influence the development of autoimmunity and their use is increasingly proposed for clinical applications. The well-characterized suppressive potential of Treg frequently leads to the assumption that Treg presence in prevailing numbers is indicative of immunosuppression. We hypothesized that this assumption may be false. We examined models of three different diseases caused by organ-specific autoimmune responses: primary biliary cirrhosis, atherosclerosis and rheumatoid arthritis (RA). We examined indicators of relative abundance of Treg compared to pro-inflammatory T cells, during peak inflammation. In all cases, the results were compatible with a relative enrichment of Treg at the site of inflammation or its most proximal draining lymph node. Conversely, in healthy mice or mice successfully protected from disease via a Treg-mediated mechanism, the data did not suggest that any Treg accumulation was occurring. This counter-intuitive finding may appear to be at odds with the immunosuppressive nature of Treg. Yet extensive previous studies in RA show that an accumulation of Treg occurs at peak inflammation, albeit without resulting in suppression, as the Treg suppressive function is overcome by the cytokine-rich environment. We suggest that this is a ubiquitous feature of autoimmune inflammation. Treg abundance in patient samples is increasingly used as an indicator of a state of immunosuppression. We conclude that this strategy should be revisited as it may potentially be a source of misinterpretation. PMID:25770018

  3. 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

  4. 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 RAW264.7cells 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 kinaseinhibitors, 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

  5. 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.

  6. Ultrasound Biomicroscopic Imaging for Interleukin-1 Receptor AntagonistInhibiting Atherosclerosis and Markers of Inflammation in Atherosclerotic Development in Apolipoprotein-E Knockout Mice

    PubMed Central

    Li, Rong-Juan; Sun, Yan; Wang, Qin; Yang, Jiao; Song, Li; Wang, Zheng; Luo, Xiang-Hong; Su, Rui-Juan

    2015-01-01

    We sought to validate the hypothesis that the development of atherosclerosis can be suppressed by the interleukin-1 receptor antagonist (IL-1Ra) in murine models of atherosclerosis in vivo, noninvasively seen by means of high-resolution ultrasound biomicroscopy, and we studied changes in inflammatory markers such as IL-1 and C-reactive protein (CRP) plasma levels in these models of atherosclerosis. We divided IL-1Ra+/?/apolipoprotein-E (apoE)?/? and IL-1Ra+/+/apoE?/? mice into 2 age groups, used as atherosclerotic models. The control groups were age-matched IL-1Ra+/+/apoE+/+ mice. Plaque thickness was measured in the ascending aorta in short-axis images by means of ultrasound and histology. Plasma levels of IL-1 and CRP were quantified in the 3 murine groups. At 16 weeks, plaque thickness in the ascending aortas of the IL-1Ra+/?/apoE?/? mice was significantly greater than that in the IL-1Ra+/+/apoE?/? mice, on ultrasound and histology (P <0.01). In contrast, at 32 weeks, the differences between these 2 genotypes were not statistically significant. Serum IL-1 levels were lower in the IL-1Ra+/?/apoE?/? mice than in the IL-1Ra+/+/apoE?/? mice at 16 and 32 weeks (P <0.05). At 16 weeks, serum CRP levels in the IL-1Ra+/?/apoE?/? mice were higher than in the IL-1Ra+/+/apoE?/? mice (P <0.01). Our results suggest that ultrasound biomicroscopy enables evaluation of atherosclerotic lesions in vivo, noninvasively and in real-time, in apoE?/? mice. Partial IL-1Ra deficiencies might promote early plaque development in 16-week-old apoE?/? mice. The balance of IL-1 and IL-1Ra might influence atherosclerotic development. Finally, CRP might affect the initiation of atherosclerosis, rather than its progression. PMID:26413013

  7. Ultrasound Biomicroscopic Imaging for Interleukin-1 Receptor Antagonist-Inhibiting Atherosclerosis and Markers of Inflammation in Atherosclerotic Development in Apolipoprotein-E Knockout Mice.

    PubMed

    Li, Rong-Juan; Sun, Yan; Wang, Qin; Yang, Jiao; Yang, Ya; Song, Li; Wang, Zheng; Luo, Xiang-Hong; Su, Rui-Juan

    2015-08-01

    We sought to validate the hypothesis that the development of atherosclerosis can be suppressed by the interleukin-1 receptor antagonist (IL-1Ra) in murine models of atherosclerosis in vivo, noninvasively seen by means of high-resolution ultrasound biomicroscopy, and we studied changes in inflammatory markers such as IL-1 and C-reactive protein (CRP) plasma levels in these models of atherosclerosis. We divided IL-1Ra(+/-)/apolipoprotein-E (apoE)(-/-) and IL-1Ra(+/+)/apoE(-/-) mice into 2 age groups, used as atherosclerotic models. The control groups were age-matched IL-1Ra(+/+)/apoE(+/+) mice. Plaque thickness was measured in the ascending aorta in short-axis images by means of ultrasound and histology. Plasma levels of IL-1 and CRP were quantified in the 3 murine groups. At 16 weeks, plaque thickness in the ascending aortas of the IL-1Ra(+/-)/apoE(-/-) mice was significantly greater than that in the IL-1Ra(+/+)/apoE(-/-) mice, on ultrasound and histology (P <0.01). In contrast, at 32 weeks, the differences between these 2 genotypes were not statistically significant. Serum IL-1 levels were lower in the IL-1Ra(+/-)/apoE(-/-) mice than in the IL-1Ra(+/+)/apoE(-/-) mice at 16 and 32 weeks (P <0.05). At 16 weeks, serum CRP levels in the IL-1Ra(+/-)/apoE(-/-) mice were higher than in the IL-1Ra(+/+)/apoE(-/-) mice (P <0.01). Our results suggest that ultrasound biomicroscopy enables evaluation of atherosclerotic lesions in vivo, noninvasively and in real-time, in apoE(-/-) mice. Partial IL-1Ra deficiencies might promote early plaque development in 16-week-old apoE(-/-) mice. The balance of IL-1 and IL-1Ra might influence atherosclerotic development. Finally, CRP might affect the initiation of atherosclerosis, rather than its progression. PMID:26413013

  8. DISEASE SUPPRESSIVE SOILS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Suppressive soils have been described worldwide for a broad spectrum of plant pathogenic fungi, bacteria and nematodes. Classical approaches employed to identify the microorganisms and mechanisms involved in suppression have changed little during the last four decades. However, when classical approa...

  9. Rotating stall suppression

    NASA Technical Reports Server (NTRS)

    Moore, Franklin K. (Inventor)

    1994-01-01

    Rotating stall in an axial-flow compressor is suppressed by the positioning of a fixed inlet flow divider in the annular inlet flow passage upstream of the compressor. The inlet flow divider is aligned with the flow of fluid through the duct and acts to block or interfere with any rotating wave in the inlet and thereby suppresses rotating stall in the compressor.

  10. The impact of selectins on mortality in stable carotid atherosclerosis.

    PubMed

    Hoke, Matthias; Winter, Max-Paul; Wagner, Oswald; Exner, Markus; Schillinger, Martin; Arnold, Zsuzanna; Mlekusch, Wolfgang; Maurer, Gerald; Koppensteiner, Renate; Minar, Erich; Goliasch, Georg

    2015-08-31

    Cellular adhesion molecules also known as selectins promote recruitment of inflammatory cells into the arterial wall where they interact with lipid particles leading subsequently to plaque formation. The intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1) and the endothelial-leukocyte adhesion molecule 1 (ELAM-1) also known as E-selectin mediate the attachment of leukocytes and have been implicated in the destabilisation of atherosclerotic plaques. Therefore, we hypothesised that plasma selectin levels are associated with adverse clinical outcome. We prospectively studied 855 patients with sonographically confirmed carotid atherosclerosis. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (26?%) died. We detected a significant association between cardiovascular mortality and ICAM-1 (adjusted hazard ratio [HR]: 3.43, 95?% confidence interval [CI] 2.00-5.88, patherosclerosis. These molecules are elevated in states of endothelial activation and might assist to monitor anti-atherosclerotic therapy and select those patients with carotid atherosclerosis, who are at higher risk for cardiovascular events. PMID:25994120

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

    PubMed

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

    2015-11-01

    Atherosclerosis is a chronic inflammatory process that leads to plaque formation in large and medium sized vessels. T helper 1 (Th1) cells constitute the majority of plaque infiltrating pro-atherogenic T cells and are induced via IFN?-dependent activation of T-box (Tbet) and/or IL-12-dependent activation of signal transducer and activator of transcription 4 (STAT4). We thus aimed to define a role for STAT4 in atherosclerosis. STAT4-deficiency resulted in a ?71% reduction (p < 0.001) in plaque burden in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice fed chow diet and significantly attenuated atherosclerosis (?31%, p < 0.01) in western diet fed Stat4(-/-)Apoe(-/-) mice. Surprisingly, reduced atherogenesis in Stat4(-/-)Apoe(-/-) mice was not due to attenuated IFN? production in vivo by Th1 cells, suggesting an at least partially IFN?-independent pro-atherogenic role of STAT4. STAT4 is expressed in T cells, but also detected in macrophages (M?s). Stat4(-/-)Apoe(-/-)in vitro differentiated M1 or M2 M?s had reduced cytokine production compare to Apoe(-/-) M1 and M2 M?s that was accompanied by reduced induction of CD69, I-A(b), and CD86 in response to LPS stimulation. Stat4(-/-)Apoe(-/-) M?s expressed attenuated levels of CCR2 and demonstrated reduced migration toward CCL2 in a transwell assay. Importantly, the percentage of aortic CD11b(+)F4/80(+)Ly6C(hi) M?s was reduced in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice. Thus, this study identifies for the first time a pro-atherogenic role of STAT4 that is at least partially independent of Th1 cell-derived IFN?, and primarily involving the modulation of M? responses. PMID:26386214

  12. Fluorescence spectroscopic detection of virus-induced atherosclerosis

    NASA Astrophysics Data System (ADS)

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

    1994-07-01

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

  13. Hypercysteinemia promotes atherosclerosis by reducing protein S-nitrosylation.

    PubMed

    Chen, Yulong; Liu, Ruihan; Zhang, Guangwei; Yu, Qi; Jia, Min; Zheng, Chao; Wang, Yanli; Xu, Cangbao; Zhang, Yaping; Liu, Enqi

    2015-03-01

    Protein S-nitrosylation plays important role in the regulation of cardiovascular functions in nitric oxide (NO) Pathway. Hypercysteinemia (HHcy) is an independently risk factor for atherosclerosis. We hypothesized that HHcy promotes atherosclerosis by reducing level of vascular protein S-nitrosylation. The aim of present study is to investigate effect of HHcy on vascular protein S-nitrosylation. A total of 45 male apoE-/- mice were randomly divided into three groups. The control group was fed a Western-type diet. The HHcy group was fed a diet containing 4.4% L-methionine, and the HHcy+NONOate group was fed a diet containing 4.4% L-methionine and administrated NONOate (ip). Human umbilical vein endothelial cells were performed for in vitro experiment. Plasma lipids were measured every 4 weeks. After 12 weeks, aortic atherosclerotic lesion areas were detected as well as cellular components. The levels of plasma homocysteine (Hcy) and NO were measured. S-nitrosylation was detected using immunofluorescence, and further confirmed by biotin switch method. We found that compared with the control group, Hcy levels, and atherosclerotic plaque, and content of vascular smooth muscle cells and macrophages in lesions significantly increased, and levels of NO significantly decreased in the HHcy group. However, NONOate reverses this effect. In addition, Hcy significantly reduced protein S-nitrosylation in human umbilical vein endothelial cells. This reduction of protein S-nitrosylation was accompanied by reduced levels of NO. Our results suggested that Hcy promoted atherosclerosis by inhibiting vascular protein S-nitrosylation. PMID:25776509

  14. Splenocytes Seed Bone Marrow of Myeloablated Mice: Implication for Atherosclerosis

    PubMed Central

    Wang, Lai; Yang, Mingjie; Arias, Ana; Song, Lei; Li, Fuqiang; Tian, Fang; Qin, Minghui; Yukht, Ada; Williamson, Ian K.; Shah, Prediman K.; Sharifi, Behrooz G.

    2015-01-01

    Extramedullary hematopoiesis has been shown to contribute to the pathogenesis of a variety of diseases including cardiovascular diseases. In this process, the spleen is seeded with mobilized bone marrow cells that augment its hematopoietic ability. It is unclear whether these immigrant cells that are produced/reprogrammed in spleen are similar or different from those found in the bone marrow. To begin to understand this, we investigated the relative potency of adult splenocytes per se to repopulate bone marrow of lethally-irradiated mice and its functional consequences in atherosclerosis. The splenocytes were harvested from GFP donor mice and transplanted into myeloablated wild type recipient mice without the inclusion of any bone marrow helper cells. We found that adult splenocytes repopulated bone marrow of myeloablated mice and the transplanted cells differentiated into a full repertoire of myeloid cell lineages. The level of monocytes/macrophages in the bone marrow of recipient mice was dependent on the cell origin, i.e., the donor splenocytes gave rise to significantly more monocytes/macrophages than the donor bone marrow cells. This occurred despite a significantly lower number of hematopoietic stem cells being present in the donor splenocytes when compared with donor bone marrow cells. Atherosclerosis studies revealed that donor splenocytes displayed a similar level of atherogenic and atheroprotective activities to those of donor bone marrow cells. Cell culture studies showed that the phenotype of macrophages derived from spleen is different from those of bone marrow. Together, these results demonstrate that splenocytes can seed bone marrow of myeloablated mice and modulate atherosclerosis. In addition, our study shows the potential of splenocytes for therapeutic interventions in inflammatory disease. PMID:26038819

  15. The occurrence of dental caries is associated with atherosclerosis

    PubMed Central

    Glodny, Bernhard; Nasseri, Parinaz; Crismani, Adriano; Schoenherr, Elisabeth; Luger, Anna K.; Bertl, Kristina; Petersen, Johannes

    2013-01-01

    OBJECTIVE: Previous studies have suggested that marginal periodontitis is a risk factor for developing atherosclerosis. The objective of this study was to determine whether caries may also be associated with atherosclerosis. METHODS: The computed tomography data sets of 292 consecutive patients, 137 women and 155 men with a mean age of 54.117.3 years, were analyzed. Caries were quantified based on the number of decayed surfaces of all the teeth, and periodontitis was quantified on the basis of the horizontal bone loss in the jaw. The presence of chronic apical periodontitis (CAP) was assessed, and the aortic atherosclerotic burden was quantified using a calcium scoring method. RESULTS: The patients with <1 caries surfaces/tooth had a lower atherosclerotic burden (0.130.61 mL) than patients with ?1 caries surfaces/tooth. The atherosclerotic burden was greater in patients with a higher number of lesions with pulpal involvement and more teeth with chronic apical periodontitis. In the logistical regression models, age (Wald 49.3), number of caries per tooth (Wald 26.4), periodontitis (Wald 8.6), and male gender (Wald 11) were found to be independent risk factors for atherosclerosis. In the linear regression analyses, age and the number of decayed surfaces per tooth were identified as influencing factors associated with a higher atherosclerotic burden, and the number of restorations per tooth was associated with a lower atherosclerotic burden. CONCLUSION: Dental caries, pulpal caries, and chronic apical periodontitis are associated positively, while restorations are associated inversely, with aortic atherosclerotic burden. Prospective studies are required to confirm these observations and answer the question of possible causality. PMID:23917658

  16. Carotid Atherosclerosis and 10-year Changes in Cognitive Function

    PubMed Central

    Zhong, Wenjun; Cruickshanks, Karen J; Schubert, Carla R; Acher, Charles W; Carlsson, Cynthia M; Klein, Barbara EK; Klein, Ronald; Chappell, Richard J

    2012-01-01

    Background Carotid atherosclerosis has been suggested to be involved in cognitive decline. Methods The Epidemiology of Hearing Loss Study is a longitudinal study of aging among Beaver Dam residents, WI. In 19982000, carotid intima-media thickness (IMT) and plaque were measured by ultrasound; cognitive function was measured by the Mini-Mental State Examination (MMSE). Follow-up examinations were conducted in 20032005 and 20092010. Incidence of cognitive impairment was defined as a MMSE score <24 or reported physician-diagnosed dementia during the follow-up. In the last examination, five additional cognitive tests were added. The associations of carotid atherosclerosis with incident cognitive impairment and cognitive test performance ten years later were evaluated. Results A total of 1651 participants (mean age 66.8 years, 41% men) without cognitive impairment at baseline were included in the incidence analysis. IMT was associated with incidence of cognitive impairment after multiple adjustments (hazard ratio: 1.09, p=0.02 for each 0.1 mm increase in IMT). A total of 1311 participants with atherosclerosis data at baseline had the additional cognitive tests 10 years later. Larger IMT was associated with longer time to complete the Trail-Making Test-part B after multiple adjustments (0.1 mm IMT: 2.3 seconds longer, p=0.02). Plaque was not associated with incident cognitive impairment or cognitive test performance 10 years later. Conclusions In this population-based longitudinal study, carotid IMT was associated with a higher risk of developing cognitive impairment during the 10-year follow-up, and was associated with poorer performance in a test of executive function 10 years later. PMID:22854188

  17. 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

  18. Periodontal Disease-Induced Atherosclerosis and Oxidative Stress.

    PubMed

    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

  19. Sexual dimorphism in rodent models of hypertension and atherosclerosis

    PubMed Central

    Bubb, Kristen J; Khambata, Rayomand S; Ahluwalia, Amrita

    2012-01-01

    Approximately one third of all deaths are attributed to cardiovascular disease (CVD), making it the biggest killer worldwide. Despite a number of therapeutic options available, the burden of CVD morbidity continues to grow indicating the need for continued research to address this unmet need. In this respect, investigation of the mechanisms underlying the protection that premenopausal females enjoy from cardiovascular-related disease and mortality is of interest. In this review, we discuss the essential role that rodent animal models play in enabling this field of research. In particular, we focus our discussion on models of hypertension and atherosclerosis. PMID:22582712

  20. 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

  1. 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

  2. FDG PET/CT Imaging of Carotid Atherosclerosis.

    PubMed

    Ali, Abdelrahman; Tawakol, Ahmed

    2016-02-01

    Atherosclerosis is a complex inflammatory process and an integral component of myocardial infarction and stroke. Atherosclerotic plaques can be detected using ultrasonography, myocardial perfusion imaging, coronary angiography, multidetector computed tomography (CT), and MR imaging. These modalities assess the luminal encroachment of the plaques or the structural features. Imaging plaque biology in concert with plaque structure may provide important insights. PET scanning using (18)F fluorodeoxyglucose. ((18)F FDG-PET) is commonly combined with CT scanning to characterize oncological processes. This review examines the role of (18)F FDG-PET/CT imaging in the characterization of atherosclerotic plaque biology. PMID:26610659

  3. [Determination of the intelligence quotient of pilots with incipient atherosclerosis].

    PubMed

    Krapivnitskaia, T A

    2006-01-01

    Comprehensive examination, including clinical-functional and psychological testing, was given to 189 essentially healthy civil pilots and 235 pilots with atherosclerosis of aorta and trunks without considerable blood flow disturbance. The total of 835 investigations was performed. Distribution into health groups was conducted on clinical diagnosis. Pilots with cardiovascular pathologies were found to have the intelligence quotient significantly lowered. Associated clinical and psychological tests were effective in revealing and dynamic monitoring of incipient diseases, and taking reasoned disposition regarding pilot's fitness for flight duties. PMID:17405281

  4. Fluorescent Molecular Tomography for In Vivo Imaging of Mouse Atherosclerosis.

    PubMed

    Arranz, Alicia; Rudin, Markus; Zaragoza, Carlos; Ripoll, Jorge

    2015-01-01

    Optical imaging technologies such as fluorescence molecular tomography (FMT) are gaining great relevance in cardiovascular research. The main reason is the increased number of available fluorescent agents, especially those termed "activatable probes," which remain quenched under baseline conditions and are fluorescent when a specific enzymatic activity is present. A major characteristic of FMT is the possibility of obtaining quantitative data of fluorescence signal distribution in a noninvasive fashion and using nonionizing radiation, making FMT an invaluable tool for longitudinal studies with biomedical applications. Here, we describe a standard procedure to perform FMT experiments in atherosclerosis mouse models, from the handling of the animals to the reconstruction of the 3D images. PMID:26445804

  5. Studies of atherosclerosis determinants and precursors during childhood and adolescence*

    PubMed Central

    Tell, G. S.; Tuomilehto, J.; Epstein, F. H.; Strasser, T.

    1986-01-01

    At a Meeting of Investigators on Epidemiological Studies of Atherosclerosis Determinants and Precursors, which was held in Geneva on 7-9 November 1983, representatives from 26 countries reviewed the current status of epidemiological studies in this area. Particular interest was shown in the following determinants of cardiovascular disease: blood pressure, blood lipid levels, body weight, pathological studies, and tobacco use. Working papers on each determinant were prepared, and recommendations were made on areas for research, and on the need for prevention programmes and pathological studies. This article summarizes the work of the meeting. PMID:3490929

  6. Recent Advances of Radionuclide-based Molecular Imaging of Atherosclerosis

    PubMed Central

    Kazuma, Soraya M.; Sultan, Deborah; Zhao, Yongfeng; Detering, Lisa; You, Meng; Luehmann, Hannah P.; Abdalla, Dulcineia S.P.; Liu, Yongjian

    2015-01-01

    Atherosclerosis is a systemic disease characterized by the development of multifocal plaque lesions within vessel walls and extending into the vascular lumen. The disease takes decades to develop symptomatic lesions, affording opportunities for accurate detection of plaque progression, analysis of risk factors responsible for clinical events, and planning personalized treatment. Of the available molecular imaging modalities, radionuclide-based imaging strategies have been favored due to their sensitivity, quantitative detection and pathways for translational research. This review summarizes recent advances of radiolabeled small molecules, peptides, antibodies and nanoparticles for atherosclerotic plaque imaging during disease progression. PMID:26369676

  7. Imaging Techniques for Diagnosis of Thoracic Aortic Atherosclerosis

    PubMed Central

    Jansen Klomp, Wouter W.; Brandon Bravo Bruinsma, George J.; van 't Hof, Arnoud W.; Grandjean, Jan. G.; Nierich, Arno P.

    2016-01-01

    The most severe complications after cardiac surgery are neurological complications including stroke which is often caused by emboli merging from atherosclerosis in the ascending aorta to the brain. Information about the thoracic aorta is crucial in reducing the embolization risk for both surgical open and closed chest procedures such as transaortic heart valve implantation. Several techniques are available to screen the ascending aorta, for example, transesophageal echocardiography (TEE), epiaortic ultrasound, TEE A-view method, manual palpation, computed tomography, and magnetic resonance imaging. This paper provides a description of the advantages and disadvantages of these imaging techniques. PMID:26966580

  8. Heterogeneity of plasma low-density lipoproteins and atherosclerosis risk.

    PubMed

    Krauss, R M

    1994-10-01

    Increased levels of IDL and small, dense LDL are associated with the risk of coronary artery disease. Possible mechanisms include increased susceptibility of small, dense LDL to oxidation, and to other pathologic effects, such as increased retention in the arterial wall. Beneficial effects of a low-fat diet and certain lipid-lowering therapies on the levels and properties of small, dense LDL or their precursors may contribute substantially to the reductions in coronary atherosclerosis observed in several lipid-lowering trials. PMID:7858908

  9. Imaging Techniques for Diagnosis of Thoracic Aortic Atherosclerosis.

    PubMed

    Jansen Klomp, Wouter W; Brandon Bravo Bruinsma, George J; van 't Hof, Arnoud W; Grandjean, Jan G; Nierich, Arno P

    2016-01-01

    The most severe complications after cardiac surgery are neurological complications including stroke which is often caused by emboli merging from atherosclerosis in the ascending aorta to the brain. Information about the thoracic aorta is crucial in reducing the embolization risk for both surgical open and closed chest procedures such as transaortic heart valve implantation. Several techniques are available to screen the ascending aorta, for example, transesophageal echocardiography (TEE), epiaortic ultrasound, TEE A-view method, manual palpation, computed tomography, and magnetic resonance imaging. This paper provides a description of the advantages and disadvantages of these imaging techniques. PMID:26966580

  10. Association of Endothelial and Oxidative Stress with Metabolic Syndrome and Subclinical Atherosclerosis: Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Vaidya, Dhananjay; Szklo, Moyses; Cushman, Mary; Holvoet, Paul; Polak, Joseph; Bahrami, Hossein; Jenny, Nancy Swords; Ouyang, Pamela

    2011-01-01

    Objectives A cluster of metabolic abnormalities termed metabolic syndrome (MetS) is associated with vascular endothelial dysfunction and oxidative internal milieu. We examined whether the association of MetS with subclinical atherosclerosis is explained by biomarkers of endothelial damage and oxidative stress. Methods MESA is a population based study of 45-84 year old individuals of four US ethnicities without clinical cardiovascular disease. A random sample of 997 MESA participants had data on the following biomarkers: von Willebrand Factor, soluble intercellular adhesion molecule-1 (sICAM1), CD40 ligand, soluble thrombomodulin, E-selectin, and oxidized LDL (oxLDL). We examined whether the associations of MetS with B-mode ultrasound-defined common and internal carotid intimal medial thickness (IMT) and coronary artery calcium (CAC) measured using computerized tomography were explained by the biomarkers using multiple regression methods. Results MetS was associated with higher levels of each of the biomarkers (p<0.001, CD40L suggestive association p=0.004), with greater IMT (p<0.001), and with greater extent of CAC in those in whom CAC was detectable (p=0.01). The association of MetS with measures of subclinical atherosclerosis remained unchanged after adjustment for the biomarkers. After adjusting for MetS, oxLDL was suggestively associated with greater prevalence of detectable CAC (p=0.005) and thicker internal carotid IMT (p=0.002), while sICAM-1was significantly associated with greater prevalence of detectable CAC (p=0.001). Conclusions The association of MetS with subclinical atherosclerosis was independent of its association with biomarkers of endothelial damage and oxidative stress, suggesting that metabolic abnormalities and oxidative endothelial damage may lead to atherosclerotic disease through distinct mechanisms. PMID:21505504

  11. 75 FR 7482 - Submission for OMB Review; Comment Request; The Atherosclerosis Risk in Communities Study (ARIC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-19

    ... Atherosclerosis Risk in Communities Study (ARIC) Summary: Under the provisions of Section 3507(a)(1)(D) of the... Title: The Atherosclerosis Risk in Communities Study (ARIC). Type of Information Collection Request...: This project involves annual follow-up by telephone of participants in the ARIC study, review of...

  12. 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

  13. 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…

  14. 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

  15. Cholesterol suppresses cellular TGF-? responsiveness: implications in atherogenesis

    PubMed Central

    Chen, Chun-Lin; Liu, I-Hua; Fliesler, Steven J.; Han, Xianlin; Huang, Shuan Shian; Huang, Jung San

    2007-01-01

    Summary Hypercholesterolemia is a major causative factor for atherosclerotic cardiovascular disease. The molecular mechanisms by which cholesterol initiates and facilitates the process of atherosclerosis are not well understood. Here, we demonstrate that cholesterol treatment suppresses or attenuates TGF-? responsiveness in all cell types studied as determined by measuring TGF-?-induced Smad2 phosphorylation and nuclear translocation, TGF-?-induced PAI-1 expression, TGF-?-induced luciferase reporter gene expression and TGF-?-induced growth inhibition. Cholesterol, alone or complexed in lipoproteins (LDL, VLDL), suppresses TGF-? responsiveness by increasing lipid raft and/or caveolae accumulation of TGF-? receptors and facilitating rapid degradation of TGF-? and thus suppressing TGF-?-induced signaling. Conversely, cholesterol-lowering agents (fluvastatin and lovastatin) and cholesterol-depleting agents (?-cyclodextrin and nystatin) enhance TGF-? responsiveness by increasing non-lipid raft microdomain accumulation of TGF-? receptors and facilitating TGF-?-induced signaling. Furthermore, the effects of cholesterol on the cultured cells are also found in the aortic endothelium of ApoE-null mice fed a high-cholesterol diet. These results suggest that high cholesterol contributes to atherogenesis, at least in part, by suppressing TGF-? responsiveness in vascular cells. PMID:17878231

  16. Xanthine oxidoreductase in atherosclerosis pathogenesis: not only oxidative stress.

    PubMed

    Battelli, Maria Giulia; Polito, Letizia; Bolognesi, Andrea

    2014-12-01

    Endothelial xanthine oxidoreductase (XOR) together with NAD(P)H oxidase and nitric oxide (NO) synthase plays a physiologic role in inflammatory signalling, the regulation of NO production and vascular function. The oxidative stress generated by these enzymes may induce endothelial dysfunction, leading to atherosclerosis, cardiovascular diseases and metabolic syndrome. XOR activity creates both oxidant and anti-oxidant products that are implicated in the development of hypertension, smoking vascular injury, dyslipidemia and diabetes, which are the main risk factors of atherosclerosis. In particular, uric acid may have a protective as well as a detrimental role in vascular alterations, thus justifying the multi-directional effects of XOR inhibition. Moreover, XOR products are associated with cell differentiation, leading to adipogenesis and foam cell formation, as well as to the production of monocyte chemoattractant protein-1 from arterial smooth muscle cells, after proliferation and migration. The role of XOR in adipogenesis is also connected with insulin resistance and obesity, two main features of type 2 diabetes. PMID:25463089

  17. 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

  18. BHUx: a patented polyherbal formulation to prevent hyperlipidemia and atherosclerosis.

    PubMed

    Tripathi, Yamini B

    2009-01-01

    Since hyperlipidemia, inflammation and obesity are closely related to atherosclerosis, therefore management of these factors together would be beneficial for overall treatment approach for atherosclerosis. Although, Indian system of medicine, especially Ayurveda has several medicinal plants with proven beneficial claims towards these pathological conditions, but most of them lack enough experimental data. BHUx is a novel polyherbal formulation, consisting of 5 medicinal plants namely Termenalia arjuna, Strychnox nux vomica, Boswellia serrata, Commiphora mukul, and Semecarpus anacardium, which have history of clinical use as single or in other combinations, but these plant fractions were never tried collectively in this ratio as in BHUx, which has been found to be effective on all the etiological factors, together. In this paper, antioxidant, anti-inflammatory, hypo-lipidemic, anti-proliferative properties of BHUx have been studied on several experimental models based on chemical tests, cell culture, in vitro models, and in vivo experiments with normal and transgenic animals. A separate pre-clinical toxicity study has also been carried out to prove its safety margin in therapeutic doses. Further, clinical trail of BHUx is under way, before it comes to market for public use as functional food to maintain healthy heart. This article also review some patent related to the field. PMID:19149746

  19. Aortic smooth muscle cell proteoglycan synthesis in relation to atherosclerosis

    SciTech Connect

    Edwards, I.J.

    1989-01-01

    Proteoglycans (PG) are implicated in atherogenesis by their effects on tissue permeability and cell proliferation and their interaction with plasma low density lipoproteins. Using the pigeon model in which an atherosclerosis-susceptible (WC) and -resistant (SR) breed can be compared, PG synthesis by cultured aortic smooth muscle cells was examined by the use of ({sup 35}S)-sodium sulfate and ({sup 3}H)-serine or ({sup 3}H)-glucosamine as labeling precursors. In both SR and WC cells, the majority of newly synthesized PG were secreted into the media. Chondroitin sulfate (CS) PG and dermatan sulfate (DS) PG were the major PG produced. Total PG production was consistently lower in WC compared to SR cultures due in part to reduce PG synthesis but also to degradation of newly synthesized PG. Since increased DS-PG accompanines atherosclerosis progression, experiments were designed to test the hypothesis that macrophages modulate smooth muscle cell metabolism to cause increase DS-PG production. Cultured WC aortic smooth muscle cells were exposed to the media of cholesteryl ester-loaded pigeon peritoneal macrophages or a macrophage cell line P388D1 and the production of PG examined. Increasing concentration of conditioned media from both types of macrophages caused increased incorporation of {sup 35}S-sulfate into secreted PG, but no change in cell-associated PG. Lipopolysaccharide activation of P388D1 cells enhanced the effect.

  20. Zebrafish models of dyslipidemia: Relevance to atherosclerosis and angiogenesis

    PubMed Central

    Fang, Longhou; Liu, Chao; Miller, Yury I.

    2013-01-01

    Lipid and lipoprotein metabolism in zebrafish and in humans are remarkably similar. Zebrafish express all major nuclear receptors, lipid transporters, apolipoproteins and enzymes involved in lipoprotein metabolism. Unlike mice, zebrafish express cetp and the Cetp activity is detected in zebrafish plasma. Feeding zebrafish a high cholesterol diet, without any genetic intervention, results in significant hypercholesterolemia and robust lipoprotein oxidation, making zebrafish an attractive animal model to study mechanisms relevant to early development of human atherosclerosis. These studies are facilitated by the optical transparency of zebrafish larvae and the availability of transgenic zebrafish expressing fluorescent proteins in endothelial cells and macrophages. Thus, vascular processes can be monitored in live animals. In this review article we discuss recent advances in using dyslipidemic zebrafish in atherosclerosis-related studies. We also summarize recent work connecting lipid metabolism with regulation of angiogenesis, the work that considerably benefited from using the zebrafish model. These studies uncovered the role of aibp, abca1, abcg1, mtp, apoB and apoC2 in regulation of angiogenesis in zebrafish and paved the way for future studies in mammals, which may suggest new therapeutic approaches to modulation of excessive or diminished angiogenesis contributing to the pathogenesis of human disease. PMID:24095954

  1. 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

  2. Effects of niacin on atherosclerosis and vascular function

    PubMed Central

    Ruparelia, Neil; Digby, Janet E; Choudhury, Robin P

    2011-01-01

    Purpose of Review Niacin has been used for over fifty years in the management of atherosclerosis and is associated with improved patient outcomes. The routine use of niacin has been superseded in recent years with the advent of newer lipid-modulating interventions. Recently however, there has been a renewed interest in its use due to the appreciation of its many beneficial effects on atherosclerosis and endothelial function both ‘lipid-targeted’ and ‘pleiotropic’. This review will consider the effects of niacin in the setting of clinical trials and will critically evaluate proposed mechanisms of action. Recent Findings The identification of the GPR109A receptor has promoted a greater insight into niacin’s mechanism of action, with demonstrated beneficial effects on endothelial function and inflammation, in addition to its lipid modulation role. Summary Whether niacin itself is used routinely in the future will depend on the outcomes of two large outcome trials (AIM-HIGH and HPS2-THRIVE). In the future however, with even better understanding of niacin pharmacology, new drugs may be able to be engineered to capture aspects of niacin that capitalise on the benefits more specifically and also more selectively, to avoid troublesome side effects. PMID:21045681

  3. Radionuclide imaging of experimental atherosclerosis with nonspecific polyclonal immunoglobulin G

    SciTech Connect

    Fischman, A.J.; Rubin, R.H.; Khaw, B.A.; Kramer, P.B.; Wilkinson, R.; Ahmad, M.; Needelman, M.; Locke, E.; Nossiff, N.D.; Strauss, H.W.

    1989-06-01

    The utility of nonspecific polyclonal IgG for external imaging of experimental atherosclerosis was tested in a series of rabbits after balloon catheter deendothelialization of the abdominal aorta. Following injection of /sup 111/In-IgG, /sup 111/In-Fc, or /sup 111/In-Fab serial images were recorded. In addition, several animals received /sup 125/I-low density lipoproteins (/sup 125/I-LDL), or /sup 125/I human serum albumin (/sup 125/I-HSA) as positive and negative controls. Forty-eight hours after injection of the radiolabeled proteins, the aortas were removed, divided into abdominal and thoracic regions, counted, and autoradiographed. The images acquired after injection of /sup 111/In-IgG and /sup 111/In-Fc, showed clear focal accumulation of radioactivity in the healing abdominal aorta. In contrast, the images obtained after injection of /sup 111/In-Fab did not show focal radionuclide accumulation. For /sup 111/In-IgG and /sup 111/In-Fc there were three to six times as many counts in the abdominal as in the thoracic aorta, while for /sup 111/In-Fab and /sup 125/I HSA, the abdominal and thoracic counts were nearly equal. The results suggest that radiolabeled IgG and Fc can be used to image experimental atherosclerosis.

  4. Conjugated linoleic acid modulation of risk factors associated with atherosclerosis

    PubMed Central

    Nakamura, Yukiko K; Flintoff-Dye, Nichole; Omaye, Stanley T

    2008-01-01

    Conjugated linoleic acid (CLA) has been the subject of extensive investigation regarding its possible benefits on a variety of human diseases. In some animal studies, CLA has been shown to have a beneficial effect on sclerotic lesions associated with atherosclerosis, be a possible anti-carcinogen, increase feed efficiency, and act as a lean body mass supplement. However, the results have been inconsistent, and the effects of CLA on atherogenesis appear to be dose-, isomer-, tissue-, and species-specific. Similarly, CLA trials in humans have resulted in conflicting findings. Both the human and animal study results may be attributed to contrasting doses of CLA, isomers, the coexistence of other dietary fatty acids, length of study, and inter-and/or intra-species diversities. Recent research advances have suggested the importance of CLA isomers in modulating gene expression involved in oxidative damage, fatty acid metabolism, immune/inflammatory responses, and ultimately atherosclerosis. Although the possible mechanisms of action of CLA have been suggested, they have yet to be determined. PMID:18718021

  5. Accelerated atherosclerosis with apolipoprotein(a) and oxidized low-density lipoprotein deposition in acute rejection of transplanted kidney: analogous to atherosclerosis.

    PubMed

    Shimoyamada, Hiroaki; Fan, Jianglin; Watanabe, Teruo; Nagata, Michio

    2002-01-01

    Atherosclerosis is a chronic inflammatory process affecting mainly elastic and muscular arteries. Although small arteries and arterioles are usually spared, atherosclerosis can occur in these small vasculatures for a very short period. Here we report a case of atherosclerosis-like lesions that occurred in a transplanted kidney showing acute accelerated rejection in a 43-year-old man. Histologically, biopsy specimens at 14 and 28 days and nephrectomy material at 52 days post-transplantation showed atherosclerosis-like lesions in various-sized arteries. The lesions were characterized by the intimal infiltration of inflammatory cells, including foamy macrophages and a variable number of T-lymphocytes, with smooth muscle cell proliferation. Immunohistochemistry disclosed that the foam cells expressing CD68 contained oxidized LDL. In addition, apolipoprotein(a) (Lp(a)), another major atherogenic lipoprotein, was found in the intimal smooth muscle layer, suggesting that Lp(a) induced smooth muscle cell proliferation in the rejected kidney as a mechanism of atherosclerosis. This case shows that immunoinflammatory reactions during a relatively short period can mimic the chronic atherosclerotic process even in small arteries and arterioles. Furthermore, the deposition of atherogenic lipoproteins, Lp(a) and oxidized LDL in lesions of rejected tissue present an analogy between vascular rejection in transplanted kidney and atherosclerosis. PMID:12464130

  6. Differentially expressed genes in aortic smooth muscle cells from atherosclerosis-susceptible and atherosclerosis-resistant pigeons.

    PubMed

    Anderson, J L; Taylor, R L; Smith, E C; Thomas, W K; Smith, S C

    2012-06-01

    Susceptibility to spontaneous atherosclerosis in the White Carneau (WC-As) pigeon shows autosomal recessive inheritance. Aortic smooth muscle cells (SMC) cultured from susceptible WC-As and resistant Show Racer (SR-Ar) pigeons exhibit developmental and degenerative features corresponding to the respective SMC at atherosclerosis-prone sites in vivo. We used representational difference analysis to identify differentially expressed genes between WC-As and SR-Ar aortic SMC. Total RNA was extracted from cultured primary SMC of each breed, converted to double-stranded cDNA, followed by direct comparison in reciprocal representational difference analysis experiments. Difference products were cloned, sequenced, and identified by BLAST against the chicken genome. Six putative biochemical pathways were distinctly different between breeds with genes involved in energy metabolism and contractility exhibiting the most striking disparity. Genes associated with glycolysis and a synthetic SMC phenotype were expressed in WC-As cells. In contrast, SR-Ar cells expressed genes indicative of oxidative phosphorylation and a contractile SMC phenotype. In WC-As cells, the alternatives of insufficient ATP production limiting contractile function or the lack of functional contractile elements downregulating ATP synthesis cannot be distinguished due to the compressed in vitro versus in vivo developmental time frame. However, the genetic potential for effectively coupling energy production to muscle contraction present in the resistant SR-Ar was lacking in the susceptible WC-As. PMID:22582288

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

    PubMed

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

    2015-01-01

    In workers employed in the aluminum industry, the main harmful production factor is exposure to fluoride salts, which can cause chronic fluoride intoxication. For the assessment of the impact of chronic fluoride intoxication on the development of atherosclerosis, we conducted a comprehensive survey of 87 aluminum-metal makers with chronic fluoride intoxication and 43 aluminum-metal makers without occupational diseases, mean age--52.1 ± 0.4 years. There were considered the presence and severity of atherosclerosis of brachiocephalic arteries, and the arteries of the lower extremities in the studied group, there was evaluated the effect of other risk factors for atherosclerosis (smoking, presence of hypertension, diabetes, dyslipidemia). With the use of Doppler ultrasound of the arteries it was revealed that in metallurgists with chronic fluoride intoxication atherosclerosis was detected in 73.6% versus 55.8% in persons of the comparison group. The performed analysis of the prevalence of main risk factors for atherosclerosis showed that in metal makers with chronic fluoride intoxication in combination with atherosclerosis hypertension is more common (in 54.7%) than in metallurgists with chronic fluoride intoxication without atherosclerosis--only 26.1%. According to the frequency of occurrence of smoking, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia, there were no significant differences between the metallurgists with chronic fluoride intoxication, with and without atherosclerosis, and the control group, the increase in LDL cholesterol occurs significantly more often in metal-makers with chronic fluoride intoxication in combination with atherosclerosis if compared to workers without occupational diseases. Thus, chronic fluoride intoxication acts as a risk factor in the development of atherosclerosis: atherosclerosis in metal-makers with chronic fluoride intoxication occurs more frequently than in workers who do not have professional pathology. Hypertension and elevated levels of LDL cholesterol were established to increase the relative risk of developing atherosclerosis in metallurgists with chronic fluoride intoxication. At that there are no significant differences in the prevalence of common risk factors for atherosclerosis (smoking, diabetes, hypercholesterolemia, hypertriglyceridemia). PMID:26625626

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

    SciTech Connect

    Son, Dong Ju; Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA ; Kim, Soo Yeon; Han, Seong Su; Kim, Chan Woo; Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA; Department of Bioinspired Science, Ehwa Womans University, Seoul ; Kumar, Sandeep; Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA ; Park, Byeoung Soo; Lee, Sung Eun; Yun, Yeo Pyo; Jo, Hanjoong; Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA; Department of Bioinspired Science, Ehwa Womans University, Seoul ; 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.

  9. 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 injury may be prevented by reducing diet fat content. Our study indicates that vascular injury of high-fat diet induced rhesus monkey is similar to that of human in position and progression. PMID:25602196

  10. Ambient Air Pollution and the Progression of Atherosclerosis in Adults

    PubMed Central

    Knzli, Nino; Jerrett, Michael; Garcia-Esteban, Raquel; Basagaa, Xavier; Beckermann, Bernardo; Gilliland, Frank; Medina, Merce; Peters, John; Hodis, Howard N.; Mack, Wendy J.

    2010-01-01

    Background Cross-sectional studies suggest an association between exposure to ambient air pollution and atherosclerosis. We investigated the association between outdoor air quality and progression of subclinical atherosclerosis (common carotid artery intima-media thickness, CIMT). Methodology/Principal Findings We examined data from five double-blind randomized trials that assessed effects of various treatments on the change in CIMT. The trials were conducted in the Los Angeles area. Spatial models and land-use data were used to estimate the home outdoor mean concentration of particulate matter up to 2.5 micrometer in diameter (PM2.5), and to classify residence by proximity to traffic-related pollution (within 100 m of highways). PM2.5 and traffic proximity were positively associated with CIMT progression. Adjusted coefficients were larger than crude associations, not sensitive to modelling specifications, and statistically significant for highway proximity while of borderline significance for PM2.5 (P?=?0.08). Annual CIMT progression among those living within 100 m of a highway was accelerated (5.5 micrometers/yr [95%CI: 0.1310.79; p?=?0.04]) or more than twice the population mean progression. For PM2.5, coefficients were positive as well, reaching statistical significance in the socially disadvantaged; in subjects reporting lipid lowering treatment at baseline; among participants receiving on-trial treatments; and among the pool of four out of the five trials. Conclusion Consistent with cross-sectional findings and animal studies, this is the first study to report an association between exposure to air pollution and the progression of atherosclerosis indicated with CIMT change in humans. Ostensibly, our results suggest that air pollution may contribute to the acceleration of cardiovascular disease development the main causes of morbidity and mortality in many countries. However, the heterogeneity of the volunteering populations across the five trials, the limited sample size within trials and other relevant subgroups, and the fact that some key findings reached statistical significance in subgroups rather than the sample precludes generalizations to the general population. PMID:20161713

  11. Atherosclerosis - do we know enough already to prevent it?

    PubMed

    Aluganti Narasimhulu, Chandrakala; Fernandez-Ruiz, Irene; Selvarajan, Krithika; Jiang, Xeuting; Sengupta, Bhaswati; Riad, Aladdin; Parthasarathy, Sampath

    2016-04-01

    In this review, we have briefly summarized the characteristics of lipids and lipoproteins and the atherosclerotic process. The development of atherosclerosis is a continuous process that involves numerous cellular and acellular processes that influence the behavior of each other. These include oxidative stress, lipoprotein modifications, macrophage polarization, macrophage lipid accumulation, generation of pro- and anti-inflammatory components, calcification, cellular growth and proliferation, and plaque rupture. The precise role(s) of many of these are unknown. Understanding the events at each particular stage might shed more light onto the process as a whole and could potentially reveal targets for intervention. Therapeutic modalities that work at one stage may have little to no influence on other stages of the disease. PMID:26974701

  12. 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

  13. Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?

    PubMed

    Paynter, Nina P; Ridker, Paul M; Chasman, Daniel I

    2016-02-19

    In this review, we lay out 3 areas currently being evaluated for incorporation of genetic information into clinical practice related to atherosclerosis. The first, familial hypercholesterolemia, is the clearest case for utility of genetic testing in diagnosis and potentially guiding treatment. Already in use for confirmatory testing of familial hypercholesterolemia and for cascade screening of relatives, genetic testing is likely to expand to help establish diagnoses and facilitate research related to most effective therapies, including new agents, such as PCSK9 inhibitors. The second area, adding genetic information to cardiovascular risk prediction for primary prevention, is not currently recommended. Although identification of additional variants may add substantially to prediction in the future, combining known variants has not yet demonstrated sufficient improvement in prediction for incorporation into commonly used risk scores. The third area, pharmacogenetics, has utility for some therapies today. Future utility for pharmacogenetics will wax or wane depending on the nature of available drugs and therapeutic strategies. PMID:26892961

  14. HDL functionality and crystal-based sterile inflammation in atherosclerosis.

    PubMed

    Eren, Esin; Ellidag, Hamit Yasar; Aydin, Ozgur; Yilmaz, Necat

    2015-01-15

    Change is inevitable. In early evolution, due to the limited availability of resources, the sole purpose of living organisms was to survive long enough to transmit their genes to the next generation. During their short lifetime, organisms used pathogen-associated and damage-associated molecular pattern pathways as an inflammatory response against pathogens (exogenous factors) and tissue damage (endogenous factors), respectively. Despite advances in human lifespan, it appears that an increasing number of diseases such as atherosclerosis are associated with inflammation. Excessive glucose, lipid and protein intake leads to the formation of endogenous crystals, i.e., cholesterol, which can induce a sterile inflammatory immune response that manifests as a vicious cycle. In this review, we evaluate the possible relationship between crystal-based sterile inflammatory response and HDL functionality. PMID:25278350

  15. Mechanisms of Premature Atherosclerosis in Rheumatoid Arthritis and Lupus

    PubMed Central

    Kahlenberg, J. Michelle; Kaplan, Mariana J.

    2014-01-01

    Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), the two most common systemic autoimmune disorders, have both unique and overlapping manifestations. One feature they share is a significantly enhanced risk of atherosclerotic cardiovascular (CV) disease that significantly contributes to morbidity and mortality. The primary mechanisms that drive CV damage in these diseases remain to be fully characterized, but recent discoveries indicate that distinct inflammatory pathways and immune dysregulation characteristic of RA and SLE likely play prominent roles. This review focuses on analyzing the major mechanisms and pathways potentially implicated in the acceleration of atherothrombosis [**AU: Should this be atherosclerosis for consistency?**] and CV risk in SLE and RA, as well as in the identification of putative preventive strategies that may mitigate vascular complications in systemic autoimmunity. PMID:23020882

  16. Dynamic Aspects of Macrophage Polarization during Atherosclerosis Progression and Regression

    PubMed Central

    Peled, Michael; Fisher, Edward A.

    2014-01-01

    It is well recognized that macrophages in many contexts in vitro and in vivo display a spectrum of inflammatory features and functional properties. A convenient system to group together different subsets of macrophages has been the M1 (inflammatory)/M2 (anti-inflammatory) classification. In addition to other sites of inflammation, it is now established that atherosclerotic plaques contain both M1 and M2 macrophages. We review results made possible by a number of recent mouse models of atherosclerotic regression that, taken with other literature, have shown the M1/M2 balance in plaques to be dynamic, with M1 predominating in disease progression and M2 in regression. The regulation of the macrophage phenotype in plaques and the functional consequences of the M1 and M2 states in atherosclerosis will also be discussed. PMID:25429291

  17. 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

  18. 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

  19. Immunohistochemical study of intimal microvessels in coronary atherosclerosis.

    PubMed Central

    Zhang, Y.; Cliff, W. J.; Schoefl, G. I.; Higgins, G.

    1993-01-01

    Two hundred ninety-nine human coronary artery paraffin-embedded tissue blocks were examined for intimal microvessel invasion by probing for factor VIII-associated antigen with indirect immunofluorescence and high resolution confocal microscopy. The results obtained confirm that intimal microvessels originate in the adventitia and show that the richness of intimal microvessels is strongly positively correlated with intimal thickness and negatively correlated with relative lumen size. A number of plasma constituents were examined in serial sections. Comparison of immunofluorescence distribution patterns of these components with intimal microvessel distribution patterns reveals that intimal microvessels leak plasma albumin into artery walls, exude fibrinogen, and are associated with the build-up of plasma cells within atherosclerotic lesions. Therefore, intimal microvessels are demonstrated to play important roles in the development of atherosclerosis. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:7686341

  20. Genetics of Leukocyte Telomere Length and its Role in Atherosclerosis

    PubMed Central

    Aviv, Abraham

    2011-01-01

    Humans display a large inter-individual variation in leukocyte telomere length (LTL), which is influenced by heredity, sex, race/ethnicity, paternal age at conception and environmental exposures. LTL dynamics (birth LTL and its age-dependent attrition thereafter) mirror telomere dynamics in hematopoietic stem cells (HSCs). LTL at birth is evidently a major determinant of LTL throughout the human lifespan, such that individuals endowed with short (or long) LTL at birth probably have short (or long) LTL later in life. Therefore, the associations of short LTL with atherosclerosis and with diminished survival in the elderly may relate to short birth LTL, accelerated age-dependent LTL attrition, or both. The mechanisms underlying these associations are still not well understood, but they stem in part from genetic factors in control of telomere maintenance and the rate of HSC replication. PMID:21600224

  1. Chlorogenic Acid Protects against Atherosclerosis in ApoE?/? Mice and Promotes Cholesterol Efflux from RAW264.7 Macrophages

    PubMed Central

    Wu, Chongming; Luan, Hong; Zhang, Xue; Wang, Shuai; Zhang, Xiaopo; Sun, Xiaobo; Guo, Peng

    2014-01-01

    Chlorogenic acid (CGA) is one of the most abundant polyphenols in the human diet and is suggested to be a potential antiatherosclerotic agent due to its proposed hypolipidemic, anti-inflammatory and antioxidative properties. The aim of this study was to evaluate the effect of CGA on atherosclerosis development in ApoE?/? mice and its potential mechanism. ApoE?/? mice were fed a cholesterol-rich diet without (control) or with CGA (200 and 400 mg/kg) or atorvastatin (4 mg/kg) for 12 weeks. During the study plasma lipid and inflammatory parameters were determined. Treatment with CGA (400 mg/kg) reduced atherosclerotic lesion area and vascular dilatation in the aortic root, comparable to atorvastatin. CGA (400 mg/kg) also significantly decreased plasma levels of total cholesterol, triglycerides and low-density lipoprotein-cholesterol as well as inflammatory markers. Supplementation with CGA or CGA metabolites-containing serum suppressed oxidized low-density lipoprotein (oxLDL)-induced lipid accumulation and stimulated cholesterol efflux from RAW264.7 cells. CGA significantly increased the mRNA levels of PPAR?, LXR?, ABCA1 and ABCG1 as well as the transcriptional activity of PPAR?. Cholesterol efflux assay showed that three major metabolites, caffeic, ferulic and gallic acids, significantly stimulated cholesterol efflux from RAW264.7 cells. These results suggest that CGA potently reduces atherosclerosis development in ApoE?/? mice and promotes cholesterol efflux from RAW264.7 macrophages. Caffeic, ferulic and gallic acids may be the potential active compounds accounting for the in vivo effect of CGA. PMID:25187964

  2. Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration.

    PubMed

    Wang, Qingjie; Huo, Leijun; He, Jinlong; Ding, Wenshuang; Su, Hang; Tian, Dongping; Welch, Carrie; Hammock, Bruce D; Ai, Ding; Zhu, Yi

    2015-12-01

    Epoxyeicosatrienoic acids (EETs) have beneficial effects on cardiovascular disease. Soluble epoxide hydrolase (sEH) metabolizes EETs to less active diols, thus diminishing their biological activity. sEH inhibitors can suppress the progression of atherosclerotic lesions in animal models. However, the regulation of sEH in vascular smooth muscle cells (VSMCs) and role of sEH in patients with atherosclerosis have not been evaluated. We hypothesize that sEH in VSMCs plays a pivotal role in atherosclerosis and injury-induced neointima formation. In this study, sEH expression in human autopsy atherosclerotic plaque was determined by immunohistochemistry. In cultured rat and human VSMCs, the phenotypic switching marker and sEH expression induced by platelet-derived growth factor-BB (PDGF-BB) were examined by Western blot analysis. Carotid-artery balloon injury was performed after adenovirus-mediated overexpression of sEH or oral administration of a potent sEH inhibitor in Sprague-Dawley rats. sEH was highly expressed in VSMCs of the intima and media within human atherosclerotic plaque. In vitro, PDGF-BB upregulated the expression in VSMCs after transcription and promoted cell proliferation and migration; the latter effect could be largely attenuated by an sEH inhibitor. Adenovirus-mediated overexpression of sEH could mimic the effect of PDGF-BB and induce VSMC proliferation and migration. In vivo, the sEH inhibitor led to a significant decrease in injury-induced neointima formation in a rat carotid-artery injury model. These data establish the effect of sEH expression on atherosclerotic progression and vascular remodeling after injury, thus identifying a novel integrative role for sEH in VSMC phenotypic modulation and migration. Blocking sEH activity may be a potential therapeutic approach for ameliorating vascular occlusive disease. PMID:26453326

  3. Biodegradable synthetic high-density lipoprotein nanoparticles for atherosclerosis

    PubMed Central

    Marrache, Sean; Dhar, Shanta

    2013-01-01

    Atherosclerosis remains one of the most common causes of death in the United States and throughout the world because of the lack of early detection. Macrophage apoptosis is a major contributor to the instability of atherosclerotic lesions. Development of an apoptosis targeted high-density lipoprotein (HDL)-mimicking nanoparticle (NP) to carry contrast agents for early detection of vulnerable plaques and the initiation of preventative therapies that exploit the vascular protective effects of HDL can be attractive for atherosclerosis. Here, we report the construction of a synthetic, biodegradable HDL-NP platform for detection of vulnerable plaques by targeting the collapse of mitochondrial membrane potential that occurs during apoptosis. This HDL mimic contains a core of biodegradable poly(lactic-co-glycolic acid), cholesteryl oleate, and a phospholipid bilayer coat that is decorated with triphenylphosphonium (TPP) cations for detection of mitochondrial membrane potential collapse. The lipid layer provides the surface for adsorption of apolipoprotein (apo) A-I mimetic 4F peptide, and the core contains diagnostically active quantum dots (QDs) for optical imaging. In vitro uptake, detection of apoptosis, and cholesterol binding studies indicated promising detection ability and therapeutic potential of TPP-HDL-apoA-I-QD NPs. In vitro studies indicated the potential of these NPs in reverse cholesterol transport. In vivo biodistribution and pharmacokinetics indicated favorable tissue distribution, controlled pharmacokinetic parameters, and significant triglyceride reduction for i.v.-injected TPP-HDL-apoA-I-QD NPs in rats. These HDL NPs demonstrate excellent biocompatibility, stability, nontoxic, and nonimmunogenic properties, which prove to be promising for future translation in early plaque diagnosis and might find applications to prevent vulnerable plaque progression. PMID:23671083

  4. Biodegradable synthetic high-density lipoprotein nanoparticles for atherosclerosis.

    PubMed

    Marrache, Sean; Dhar, Shanta

    2013-06-01

    Atherosclerosis remains one of the most common causes of death in the United States and throughout the world because of the lack of early detection. Macrophage apoptosis is a major contributor to the instability of atherosclerotic lesions. Development of an apoptosis targeted high-density lipoprotein (HDL)-mimicking nanoparticle (NP) to carry contrast agents for early detection of vulnerable plaques and the initiation of preventative therapies that exploit the vascular protective effects of HDL can be attractive for atherosclerosis. Here, we report the construction of a synthetic, biodegradable HDL-NP platform for detection of vulnerable plaques by targeting the collapse of mitochondrial membrane potential that occurs during apoptosis. This HDL mimic contains a core of biodegradable poly(lactic-co-glycolic acid), cholesteryl oleate, and a phospholipid bilayer coat that is decorated with triphenylphosphonium (TPP) cations for detection of mitochondrial membrane potential collapse. The lipid layer provides the surface for adsorption of apolipoprotein (apo) A-I mimetic 4F peptide, and the core contains diagnostically active quantum dots (QDs) for optical imaging. In vitro uptake, detection of apoptosis, and cholesterol binding studies indicated promising detection ability and therapeutic potential of TPP-HDL-apoA-I-QD NPs. In vitro studies indicated the potential of these NPs in reverse cholesterol transport. In vivo biodistribution and pharmacokinetics indicated favorable tissue distribution, controlled pharmacokinetic parameters, and significant triglyceride reduction for i.v.-injected TPP-HDL-apoA-I-QD NPs in rats. These HDL NPs demonstrate excellent biocompatibility, stability, nontoxic, and nonimmunogenic properties, which prove to be promising for future translation in early plaque diagnosis and might find applications to prevent vulnerable plaque progression. PMID:23671083

  5. Peculiarities of spectroscopic information of whole blood in atherosclerosis

    NASA Astrophysics Data System (ADS)

    Khairullina, Alphiya Y.; Oleinik, Tatiana V.; Yusupova, Lira B.; Prigoun, Natalia

    1995-01-01

    The coefficient of diffuse reflection and light transmission measurements in an optically thick layer of blood at atherosclerosis conditions under multiple scattering of light in the visual and nearest IR-spectra region (590 -900 nm) were measured for calculation of the absorption coefficients of the material of particles and surrounding medium K((lambda) ) and parameter Q (the latter parameter was defined by the sizes of erythrocytes and aggregates and by refraction coefficient of red cells relative to plasma at atherosclerosis). For the main quantitative spectroscopy of particles the K1((lambda) ) for known value of K((lambda) ) and the parameter Q determinations it is necessary to have the knowledge of relative volume part H occupied by particles. In the case of a high concentration of particles H >= 0.2 as it takes place in the blood the parameters Q and K((lambda) ) are in dependence of H (H - is hematocrit ration for the case of whole blood). It should be noted that spectroscopy of multiple scattering light can give some information out of main absorption bands with the higher accuracy and higher light scattering. The latter value provides the opportunity of determination of faint absorption bands which couldn't be achieved by other methods. The method proposed is characterized by absence of probe preparations, approach to in viva conditions, expressivity, and high informativity of each experiment. A many-fold investigation of the blood of healthy men in the spectral region 650 - 810 nm shows the electron spectrum of absorption of molecular hemoglobin hem is the most optically active blood spectra component K((lambda) ). The broadening of spectral investigations, as in short wave or long wave areas of the spectrum, by the use of multiple scattering methods for calculations of K((lambda) ) and Q((lambda) ) enlarges the number of chromophores studied.

  6. Pattern recognition of magnetic resonance images with application to atherosclerosis

    SciTech Connect

    Carman, C.S.

    1989-01-01

    Magnetic resonance imaging provides excellent soft tissue contrast enabling the non-invasive visualization of soft tissue diseases. The quantification of tissues visible in MR images would significantly increase the diagnostic information available. While tissue selection methods exist for CT images, those same methods do not work with MR images. This dissertation focuses on the application of image processing and pattern recognition techniques to MR images for the identification and quantification of soft tissues, atherosclerosis in particular. Atherosclerosis is a chronic disease of human arteries responsible for significant mortality and medical expense. Current diagnostic methods are invasive and carry significant risk. Supervised pattern recognition methods were investigated for tissue identification in MR images. The classifiers were trained A Fisher linear classifier successfully identified the tissues of interest from MR images of excised arteries, performing better than a minimum distance to the means classifier. Quantitative measures of the disease state were computed from the results and 3-D displays were generated of the diseased anatomy. For tissue in vivo, adequate histology can be difficult to collect, increasing the difficulty of training the classifiers and making the results less accurate. Cluster analysis was used in this dissertation to generate the training information. A new cluster analysis method was developed. ISODATA was modified to use hierarchical stopping rules. The new method was tested in a Monte Carlo study and with real world data sets. Comparisons were made with published methods using the same data. An information theoretic criterion, the CAIC, was found to be an excellent criteria for hierarchical stopping rules.

  7. Egg Consumption and Carotid Atherosclerosis in the Northern Manhattan Study

    PubMed Central

    Goldberg, Sharon; Gardener, Hannah; Tiozzo, Eduard; Kuen, Cheung Ying; Elkind, Mitchell SV; Sacco, Ralph L.; Rundek, Tatjana

    2014-01-01

    Background The evidence supporting recommendations to limit intake of cholesterol rich foods is inconclusive. We aimed to examine the association between egg consumption and carotid atherosclerosis phenotypes, and the association with clinical vascular events in a prospective, urban, multi-ethnic population. Methods and Results The Northern Manhattan Study is a population based cohort to determine stroke incidence, risk factors and prognosis. A sub-cohort of 1,429 NOMAS participants with both carotid ultrasounds and comprehensive dietary information was evaluated (mean±SD age of participants 65.80±8.80, 40% male, 18% white, 20% black, 60% Hispanic). The association between egg consumption and carotid intima media thickness (cIMT) was assessed with linear regression. Logistic and quantile regression was used to examine the association between egg consumption and carotid plaque presence, thickness, and area. The relation between egg consumption and clinical vascular events (N=2669) was examined with Cox models. The mean total cIMT was 0.91±0.08 mm and 58% had carotid plaque present. Increasing egg consumption was inversely associated with cIMT, plaque presence, thickness, and area, in models adjusted for demographics, vascular risk factors and diet. For every additional egg consumed per week, the risk of plaque decreased by 11% (95% CI 3%-18%). No association was detected between egg consumption and risk of clinical vascular outcomes, over a mean follow up of 11 years and after adjustment for covariates. Conclusions Frequency of egg consumption in the low to moderate range was inversely related to several markers of carotid atherosclerosis. No association with clinical vascular events, including stroke, was detected. Our findings do not support current vascular health guidelines suggesting the extreme limitation or avoidance of egg consumption due to its cholesterol content. PMID:24887016

  8. Soluble TWEAK independently predicts atherosclerosis in renal transplant patients

    PubMed Central

    2013-01-01

    Background Cardiovascular risk is increased in the early stages of chronic kidney disease (CKD) and also found to be ongoing in renal transplant (Rtx) patients. As a sign of atherosclerosis, increased carotid intima-media thickness (CIMT) has been widely accepted as a strong predictor of cardiovascular disease (CVD) and mortality in CKD patients. A novel markers, soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and neutrophil-to-lymphocyte ratio (NLR) were introduced as potential markers in inflammatory disorders including CKD. The role of Rtx in terms of atherogenesis is still unclear. We aimed to investigate the relationship between sTWEAK, NLR and CIMT in Rtx patients without overt CVD and to compare these results with those obtained from healthy subjects. Methods Cross-sectional analysis in which CIMT measurements, NLR and serum TWEAK levels were assessed in 70 Rtx patients (29 females; mean age, 40.6 ± 12.4 years) and 25 healthy subjects (13 females, mean age; 37.4±8.8 years). Results sTWEAK levels were significantly decreased (p=0.01) and hs-CRP, NLR and CIMT levels of Rtx patients were significantly increased compared to healthy subjects (p<0.0001, p=0.001, p<0.0001, respectively). sTWEAK was also found to be decreased when eGFR was decreased (p=0.04 between all groups). CIMT was positively correlated with sTWEAK and NLR in Rtx patients (r=0.81, p<0.0001 and r=0.33, p=0.006, respectively). sTWEAK was also positively correlated with NLR (r=0.37, p=0.002). In the multivariate analysis only sTWEAK was found to be an independent variable of increased CIMT. Conclusion sTWEAK might have a role in the pathogenesis of ongoing atherosclerosis in Rtx patients. PMID:23849432

  9. The assessment of cardiac autonomic functions in adolescents with a family history of premature atherosclerosis

    PubMed Central

    Dursun, Huseyin; Kilicaslan, Baris; Aydin, Mehmet

    2014-01-01

    OBJECTIVES: Subclinical atherosclerosis has been recently detected in adolescents with a family history of premature atherosclerosis. However, no studies in the literature have assessed the cardiac autonomic functions of these adolescents. The aim of this study was to evaluate the cardiac autonomic functions of adolescents with a family history of premature atherosclerosis compared with those of age- and gender-matched adolescents without a family history of atherosclerosis. METHOD: We evaluated the cardiac autonomic functions of 36 adolescents with a family history of premature atherosclerosis (Group 1) and compared them with those of 31 age- and gender-matched adolescents whose parents did not have premature atherosclerosis (Group 2). Twenty-four-hour time domain (standard deviation of all normal sinus RR intervals [SDNN], standard deviation of the mean of normal RR intervals in each 5-minute segment [SDANN], root-mean-square differences in successive RR intervals) and frequency domain (very low frequency, low frequency, high frequency, low frequency/high frequency) parameters of heart rate variability were used for the evaluation of cardiac autonomic functions. RESULTS: There were no differences in the time and frequency domain parameters of heart rate variability between the two groups. Heart rate was negatively correlated with SDNN (r = -0.278, p = 0.035), while age was significantly correlated with root-mean-square differences in successive RR intervals, high frequency, low frequency and low frequency/high frequency (r = -0.264, -0.370, 0.265 and 0.374, respectively; p<0.05 for all). CONCLUSION: We found that the cardiac autonomic functions of adolescents with a family history of premature atherosclerosis were not different compared with those of adolescents without a positive family history of premature atherosclerosis. It appears that subclinical atherosclerosis does not reach a critical value such that it can alter cardiac autonomic functions in adolescence. PMID:25627994

  10. Sulforaphane attenuates the development of atherosclerosis and improves endothelial dysfunction in hypercholesterolemic rabbits.

    PubMed

    Shehatou, George Sg; 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-?B) 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-?B 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-?B-mediated inflammation. PMID:26490346

  11. 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

  12. New aspects on the metabolic role of intestinal microbiota in the development of atherosclerosis.

    PubMed

    Drosos, Ioannis; Tavridou, Anna; Kolios, George

    2015-04-01

    Gut microbiota remains a very interesting, yet largely unexplored ecosystem inside the human organism. The importance of this ecosystem for the physiology and the pathophysiology of the organism is being slowly unraveled. Recent studies reveal a connection between intestinal microbiota and atherosclerosis development. It seems that alterations in the function and composition of this bacterial population lead through complex mechanisms to a high risk for atherosclerosis. Although these mechanisms remain largely unknown, published studies show that microbiota can lead to atherosclerosis either by augmenting known risk factors or via other, more "direct" mechanisms. This review article summarizes the available literature regarding this matter. PMID:25676802

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

    SciTech Connect

    Hsieh, Yi-Chen; Lien, Li-Ming; School of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Neurology, Shin Kong WHS Memorial Hospital, Taipei, Taiwan ; Chung, Wen-Ting; Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan ; Hsieh, Fang-I; Hsieh, Pei-Fan; Wu, Meei-Maan; Graduate Institute of Basic Medicine, College of Medicine, Fu-Jen Catholic University, Taipei, Taiwan ; 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} A case-control study was conducted to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. {yields} Arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate atherosclerosis risk in individuals with high levels of arsenic in well water.

  14. Explosion suppression system

    DOEpatents

    Sapko, Michael J. (Finleyville, PA); Cortese, Robert A. (Pittsburgh, PA)

    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.

  15. Association of SERPINA9 gene variants with carotid artery atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study

    PubMed Central

    Tang, Weihong; Morrison, Alanna; Wasserman, Bruce A; Folsom, Aaron R; Sun, Wei; Campbell, Stephen; Kao, W H Linda; Boerwinkle, Eric

    2013-01-01

    The SNP rs11628722 in the SERPINA9 gene was previously associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Centerin, the protein encoded by SERPINA9, is involved in maturation and maintenance of nave B cells, which play a role in atherogenesis. We investigated whether 21 tag SNPs in the SERPINA9 gene are associated with features of carotid artery atherosclerotic plaque measured by magnetic resonance imaging (MRI). Carotid MRI data were obtained from 1,282 European Americans and 341 African Americans of the ARIC Carotid MRI study, which recruited participants from ARIC by a stratified sampling plan that over-sampled participants with carotid intima-media thickening. Five MRI measures, focused on carotid wall volume, wall thickness, and lipid core, were analyzed. Genetic associations between the MRI measurements and each of the 21 SNPs were analyzed in linear regression models with adjustment for sample weights and traditional risk factors. Rs11628722 was tested a priori. In African Americans, rs11628722 was significantly associated with carotid wall volume (p < 0.05). Among the other 20 SNPs, adjusted for multiple testing, rs4905204, which encodes an Ala to Val amino acid change, was significantly associated with maximum wall thickness (p < 0.000625) and suggestively associated with total wall volume (p < 0.0026) in European Americans. In conclusion, SNPs in the SERPINA9 gene showed race-specific associations with characteristics of carotid atherosclerotic plaques. Replications in other populations are needed to validate findings of this study and to establish the SERPINA9 gene as a candidate in the etiology of carotid atherosclerosis. PMID:24319541

  16. Understanding the Role of B cells in Atherosclerosis: Potential Clinical Implications

    PubMed Central

    Morris-Rosenfeld, Samuel; Lipinski, Michael J.; McNamara, Coleen A.

    2015-01-01

    Atherosclerosis is a progressive inflammatory disease of the medium to large arteries that is the largest contributor to cardiovascular disease (CVD). B cell subsets have been shown in animal models of atherosclerosis to have both atherogenic and atheroprotective properties. In this review we highlight the research that developed our understanding of the role of B cells in atherosclerosis both in humans and mice. From this we discuss the potential clinical impact B cells could have both as diagnostic biomarkers and as targets for immunotherapy. Finally, we recognize the inherent difficulty in translating findings from animal models into humans given the differences in both cardivascular disease and the immune system between mice and humans, making the case for greater efforts at addressing the role of B cells in humans atherosclerosis. PMID:24308836

  17. 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

  18. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis.

    PubMed

    Warnatsch, Annika; Ioannou, Marianna; Wang, Qian; Papayannopoulos, Venizelos

    2015-07-17

    Secretion of the cytokine interleukin-1? (IL-1?) by macrophages, a major driver of pathogenesis in atherosclerosis, requires two steps: Priming signals promote transcription of immature IL-1?, and then endogenous "danger" signals activate innate immune signaling complexes called inflammasomes to process IL-1? for secretion. Although cholesterol crystals are known to act as danger signals in atherosclerosis, what primes IL-1? transcription remains elusive. Using a murine model of atherosclerosis, we found that cholesterol crystals acted both as priming and danger signals for IL-1? production. Cholesterol crystals triggered neutrophils to release neutrophil extracellular traps (NETs). NETs primed macrophages for cytokine release, activating T helper 17 (TH17) cells that amplify immune cell recruitment in atherosclerotic plaques. Therefore, danger signals may drive sterile inflammation, such as that seen in atherosclerosis, through their interactions with neutrophils. PMID:26185250

  19. 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

  20. 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

  1. The renal artery ostium flow diverter: structure and potential role in atherosclerosis

    PubMed Central

    Neufeld, Edward B.; Yu, Zu-Xi; Springer, Danielle; Yu, Qing; Balaban, Robert S.

    2010-01-01

    Initiation of renal atherosclerosis occurs primarily at the caudal region of the renal artery ostium. To date, no mechanism for initiation of atherosclerosis at this site has been substantiated. Herein, we identify a renal artery flow diverter on the caudal wall of the renal artery ostium that directs flow into the renal artery and selectively retains LDL, an initial step in atherosclerosis. High resolution ultrasound revealed the generation of flow eddies by the caudal diverter in vivo, consistent with a role in directing aortic flow to the renal artery. Two photon excitation en face microscopy of the diverter revealed a substantial reduction in the elastic lamina exposing potential retention sites for LDL. Fluorescent LDL was selectively retained by the renal artery diverter, consistent with its molecular structure. We propose that the rigid macromolecular structure of the renal artery ostium diverter is required for its vascular function and contributes to the initiation of renal atherosclerosis by the retention of LDL. PMID:20149375

  2. An in vivo test of the hypothesis that glucose in myeloid cells stimulates inflammation and atherosclerosis

    PubMed Central

    Nishizawa, Tomohiro; Kanter, Jenny E.; Kramer, Farah; Barnhart, Shelley; Shen, Xia; Vivekanandan-Giri, Anuradha; Wall, Valerie Z.; Kowitz, Jason; Devaraj, Sridevi; OBrien, Kevin D.; Pennathur, Subramaniam; Tang, Jingjing; Miyaoka, Robert S.; Raines, Elaine W.; Bornfeldt, Karin E.

    2014-01-01

    SUMMARY Inflammatory activation of myeloid cells is accompanied by increased glycolysis, which is required for the surge in cytokine production. Although in vitro studies suggest that increased macrophage glucose metabolism is sufficient for cytokine induction, the pro-inflammatory effects of increased myeloid cell glucose flux in vivo and the impact on atherosclerosis, a major complication of diabetes, are unknown. We therefore tested the hypothesis that increased glucose uptake in myeloid cells stimulates cytokine production and atherosclerosis. Overexpression of the glucose transporter GLUT1 in myeloid cells caused increased glycolysis and flux through the pentose phosphate pathway, but did not induce cytokines. Moreover, myeloid cell-specific overexpression of GLUT1 in LDL receptor-deficient mice was ineffective in promoting atherosclerosis. Thus, increased glucose flux is insufficient for inflammatory myeloid cell activation and atherogenesis. If glucose promotes atherosclerosis by increasing cellular glucose flux, myeloid cells do not appear to be the key targets. PMID:24726364

  3. Oxidative stress in atherosclerosis: the role of microRNAs in arterial remodeling.

    PubMed

    Zampetaki, Anna; Dudek, Katarzyna; Mayr, Manuel

    2013-09-01

    Atherosclerosis is the underlying condition in most cardiovascular diseases. Among the highly specific cellular and molecular responses, endothelial dysfunction plays a key role in disease initiation and progression. These events coincide with the occurrence of oxidative stress. Increased reactive oxygen species production and oxidization of low-density lipoprotein are detected throughout atherosclerosis progression. MicroRNAs (miRNAs) have emerged as important regulators of gene expression that posttranscriptionally modify cellular responses and function. Accumulating studies indicate an integrated miRNA network in the molecular mechanisms that control cellular homeostasis, vascular inflammation, and metabolism. Experimental models of atherosclerosis highlight a direct link between altered miRNA expression profiles and the pathophysiology of the disease and identify putative miRNA candidates for the development of novel therapeutic strategies. In this review, we provide an overview of the role of miRNA regulatory networks in oxidative stress in atherosclerosis and arterial remodeling and discuss their potential therapeutic implications. PMID:23797034

  4. 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

  5. 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-?, integrin ?2, 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

  6. Relation between Birth Weight, Growth, and Subclinical Atherosclerosis in Adulthood

    PubMed Central

    Valente, Maria Helena; Gomes, Filumena Maria da Silva; Benseñor, Isabela Judith Martins; Brentani, Alexandra Valéria Maria; Escobar, Ana Maria de Ulhôa; Grisi, Sandra J. F. E.

    2015-01-01

    Background and Objectives. Adverse conditions in the prenatal environment and in the first years of life are independently associated with increased risk for cardiovascular disease. This paper aims to study the relation between birthweight, growth in the first year of life, and subclinical atherosclerosis in adults. Methods. 88 adults aged between 20 and 31 were submitted to sociodemographic qualities, anthropometric data, blood pressure measurements, metabolic profile, and evaluation of subclinical atherosclerosis. Results. Birthweight <2,500 grams (g) was negatively correlated with (a) increased waist-to-hip ratio (WHR), according to regression coefficient (RC) equal to −0.323, 95% CI [−0.571, −0.075] P < 0.05; (b) diastolic blood pressure (RC = −4.744, 95% CI [−9.017, −0.470] P < 0.05); (c) low HDL-cholesterol (RC = −0.272, 95% CI [−0.516, −0.029] P < 0.05); (d) frequency of intima-media thickness (IMT) of left carotid >75th percentile (RC = −0.242, 95% CI [−0.476, −0.008] P < 0.05). Birthweight >3,500 g was associated with (a) BMI >25.0 kg/m2, (RC = 0.317, 95% CI [0.782, 0.557] P < 0.05); (b) increased waist circumference (RC = 0.284, 95% CI [0.054, 0.513] P < 0.05); (c) elevated WHR (RC = 0.280, 95% CI [0.054, 0.505] P < 0.05); (d) minimum subcutaneous adipose tissue (SAT) (RC = 4.354, 95% CI [0.821, 7.888] P < 0.05); (e) maximum SAT (RC = 7.095, 95% CI [0.608, 13.583] P < 0.05); (f) right lobe of the liver side (RC = 6.896, 95% CI [1.946, 11.847] P < 0.001); (g) frequency's right lobe of the liver >75th percentile (RC = 0.361, 95% CI [0.169, 0.552] P < 0.001). Weight gain in the first year of life was inversely correlated with (a) mean IMT of left carotid (RC = −0.046, 95% CI [−0.086, −0.006] P < 0.05; (b) frequency IMT of left carotid >75th percentile (RC = −0.253, 95% CI [−0.487, −0.018] P < 0.05); (c) mean IMT (RC = −0.038, 95% CI [0.073, −0.002] P < 0.05); (d) the frequency of the mean IMT >75th percentile (RC = −0.241, 95% CI [−0.442, −0.041] P < 0.05). Conclusions. Adults birthweight <2,500 g and >3,500 g and with insufficient weight gain in the first year of life have showed different metabolic phenotypes, but all of them were related to subclinical atherosclerosis. PMID:25648854

  7. 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

  8. The role of endothelial mechanosensitive genes in atherosclerosis andomics approaches.

    PubMed

    Simmons, Rachel D; Kumar, Sandeep; Jo, Hanjoong

    2016-02-01

    Atherosclerosis is the leading cause of morbidity and mortality in the U.S., and is a multifactorial disease that preferentially occurs in regions of the arterial tree exposed to disturbed blood flow. The detailed mechanisms by which d-flow induces atherosclerosis involve changes in the expression of genes, epigenetic patterns, and metabolites of multiple vascular cells, especially endothelial cells. This review presents an overview of endothelial mechanobiology and its relation to the pathogenesis of atherosclerosis with special reference to the anatomy of the artery and the underlying fluid mechanics, followed by a discussion of a variety of experimental models to study the role of fluid mechanics and atherosclerosis. Various invitro and invivo models to study the role of flow in endothelial biology and pathobiology are discussed in this review. Furthermore, strategies used for the global profiling of the genome, transcriptome, miR-nome, DNA methylome, and metabolome, as they are important to define the biological and pathophysiological mechanisms of atherosclerosis. These "omics" approaches, especially those which derive data based on a single animal model, provide unprecedented opportunities to not only better understand the pathophysiology of atherosclerosis development in a holistic and integrative manner, but also to identify novel molecular and diagnostic targets. PMID:26686737

  9. A perspective for atherosclerosis vaccination: is there a place for plant-based vaccines?

    PubMed

    Salazar-Gonzlez, Jorge Alberto; Rosales-Mendoza, Sergio

    2013-02-27

    Alternatives to pharmacological treatments for atherosclerosis are highly desirable in terms of cost and compliance. During the last two decades several vaccination strategies have been reported as an effort to develop immunotherapeutic treatments. This approach consists on eliciting immune responses able to modulate either the atherosclerosis-associated inflammatory processes or the activity of some physiological mechanisms that are up-regulated under this pathologic condition. In particular, the apolipoprotein B100 (ApoB100) and the cholesterilester transferase protein (CETP) have been targeted in these strategies. It is considered that recent progress in the development of experimental models of oral vaccines against atherosclerosis has opened a new avenue in the field: as plant-based vaccines are considered a viable platform for vaccine production and delivery at low costs, they could serve as an oral-delivered therapeutic approach for atherosclerosis in an economical and patient-friendly manner. The rationale of the design, development and evaluation of possible plant-based vaccines against atherosclerosis is discussed in this review. We identify within this approach a significant trend that will positively impact the field of atherosclerosis vaccination. PMID:23313656

  10. Computer densitometry for angiographic assessment of arterial cholesterol content and gross pathology in human atherosclerosis.

    PubMed

    Crawford, D W; Brooks, S H; Selzer, R H; Barndt, R; Beckenbach, E S; Blankenhorn, D H

    1977-02-01

    Sequential change studies in human atherosclerosis are desirable in disease regression trials but are now limited by dependence on the occurrence of epidemiologic end-points. Prior radiographic studies have pertained to advanced obstructive atherosclerosis. This is a study of measures applied by computer-generated densitometry of angiograms to assess early to advanced nonobstructive atherosclerosis. Measures are based on pathologic and angiographic appearance of all stages of atherosclerosis and include image edge roughness, local width, and local contrast density changes. Femoral angiograms were made in 21 cadavers under simulated clinical conditions, with a pressurized radiopaque casting material. Full-size color photographs were made of 10 cm. segments of opened artery, with matching cast and arterial specimens analyzed for cholesterol content. Four graders, on two occasions, sequenced the photographs in increasing order of disease on the basis of the International Atherosclerosis Grading scheme. The correlation between the two sessions was 0.93. Thirteen computer indices correlated significantly with visual grade and cholesterol and were allowed to compete in a step-wise regression for best indices of prediction. Computer index correlation coefficient for visual grade prediction was 0.86, and for cholesterol content, 0.84. Computer densitometry measurement appears useful in the evaluation of all stages of atherosclerosis as recorded angiographically and obviates the necessity for exacting visual comparisons of large numbers of films. PMID:833474

  11. 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

  12. Lp-PLA2 InhibitionThe Atherosclerosis Panacea?

    PubMed Central

    Karakas, Mahir; Koenig, Wolfgang

    2010-01-01

    Based on the complex pathophysiology of atherosclerosis, a large number of biomarkers that relate to lipids, inflammation, immunity, thrombosis and hemostasis, have been investigated experimentally, in epidemiologic studies and in clinical trials. Interest focuses on their potential role to aid in risk stratification, as possible surrogate markers of atherosclerosis, and potential targets for therapy. More recently, one lipid associated biomarker, lipoprotein-associated phospholipase A2 (Lp-PLA2), has gained considerable interest. In addition to a plausible pathophysiological role by generating pro-inflammatory and pro-atherogenic compounds from oxidized LDL in the vessel wall, there is a large, fairly consistent epidemiological database indicating that increased levels of Lp-PLA2 mass or activity are associated with increased risk for cardiovascular outcomes; such data further suggest that it might improve risk stratification. In addition, clinical studies indicate that increased Lp-PLA2 levels are associated with endothelial dysfunction. Moreover, it may also serve as an interesting therapeutic target, since a specific inhibitor of the enzyme is available with promising animal data and initial positive data in humans. Recent experimental data from a hyperlipidemic diabetic pig model strongly suggest that increased Lp-PLA2 in the vessel wall is associated with a more vulnerable plaque phenotype which can be modulated by inhibiting Lp-PLA2 activity. A biomarker study in more than 1,000 patients with CHD over three months has demonstrated a positive effect on various inflammatory molecules. In addition, an imaging study using IVUS based modalities (greyscale, virtual histology, and palpography) together with a panel of biomarkers (IBIS-2) has been done in more than 300 patients with CHD treated over 12 months and results indicate that the progression of the necrotic core of the plaque can be retarded. Inhibition of the pro-atherogenic and pro-inflammatory effects of Lp-PLA2 may therefore contribute to decrease the residual risk in high risk patients already on polypharmacotherapy. This hypothesis is now being tested in two large phase 3 clinical trials. Thus, Lp-PLA2 indeed may represent a biomarker and a promising target for intervention.

  13. 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid, an active principle of kimchi, inhibits development of atherosclerosis in rabbits.

    PubMed

    Kim, Hyun Ju; Lee, Jin Su; Chung, Hae Young; Song, Su Hee; Suh, Hongsuk; Noh, Jung Sook; Song, Yeong Ok

    2007-12-12

    The effects of 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA) originating from Korean cabbage kimchi were investigated, showing an antioxidant effect on the prevention of atherosclerosis in hypercholesterolemic rabbits. Twenty-one 3-month-old rabbits were fed an atherogenic diet containing 0.5% (w/w) cholesterol and 10% (w/w) coconut oil, whereas another two groups were given an atherogenic diet with intravenous injection of either HDMPPA or simvastatin (0.33 mg/kg/day) for 4 weeks. HDMPPA inhibited the oxidative modification of low-density lipoprotein (IC 50 = 1.4 microg/mL) and increased 2,2'-diphenyl-1-picrylhydrazyl radical scavenging activity (IC 50 = 0.78 microg/mL) in a dose-dependent manner. In hypercholesterolemic rabbits, the thickness of intima of aorta of the HDMPPA group was significantly reduced (control versus HDMPPA, 42%; simvastatin, 38%) without a plasma cholesterol-lowering effect. Thiobarbituric acid reactive substance formation in the plasma of the HDMPPA group was significantly decreased compared to that of the control group. Furthermore, the generation of vascular reactive oxygen species in HDMPPA group was suppressed as the cyclooxygenase-2 protein level decreased. These findings suggest that HDMPPA prevents the development of aortic atherosclerosis in high-cholesterol-fed rabbits. The antiatherosclerotic effect of HDMPPA may be due to an antioxidative effect at a low dose without cholesterol-lowering effects. PMID:18004805

  14. Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-?B and STAT Signaling Pathways in Diabetic Mice.

    PubMed

    Lazaro, Iolanda; Oguiza, Ainhoa; Recio, Carlota; Mallavia, Beat; Madrigal-Matute, Julio; Blanco, Julia; Egido, Jesus; Martin-Ventura, Jose-Luis; Gomez-Guerrero, Carmen

    2015-10-01

    Heat shock proteins (HSPs) are induced by cellular stress and function as molecular chaperones that regulate protein folding. Diabetes impairs the function/expression of many HSPs, including HSP70 and HSP90, key regulators of pathological mechanisms involved in diabetes complications. Therefore, we investigated whether pharmacological HSP90 inhibition ameliorates diabetes-associated renal damage and atheroprogression in a mouse model of combined hyperglycemia and hyperlipidemia (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Treatment of diabetic mice with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG, 2 and 4 mg/kg, 10 weeks) improved renal function, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leukocyte infiltration, and fibrosis), and expression of proinflammatory and profibrotic genes. Furthermore, DMAG significantly reduced atherosclerotic lesions and induced a more stable plaque phenotype, characterized by lower content of lipids, leukocytes, and inflammatory markers, and increased collagen and smooth muscle cell content. Mechanistically, the renoprotective and antiatherosclerotic effects of DMAG are mediated by the induction of protective HSP70 along with inactivation of nuclear factor-?B (NF-?B) and signal transducers and activators of transcription (STAT) and target gene expression, both in diabetic mice and in cultured cells under hyperglycemic and proinflammatory conditions. In conclusion, HSP90 inhibition by DMAG restrains the progression of renal and vascular damage in experimental diabetes, with potential implications for the prevention of diabetes complications. PMID:26116697

  15. Pressure suppression containment system

    DOEpatents

    Gluntz, Douglas M. (San Jose, CA); Townsend, Harold E. (San Jose, CA)

    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.

  16. 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.

  17. Adipose Tissue in Metabolic Syndrome: Onset and Progression of Atherosclerosis.

    PubMed

    Luna-Luna, María; Medina-Urrutia, Aida; Vargas-Alarcón, Gilberto; Coss-Rovirosa, Fernanda; Vargas-Barrón, Jesús; Pérez-Méndez, Óscar

    2015-07-01

    Metabolic syndrome (MetS) should be considered a clinical entity when its different symptoms share a common etiology: obesity/insulin resistance as a result of a multi-organ dysfunction. The main interest in treating MetS as a clinical entity is that the addition of its components drastically increases the risk of atherosclerosis. In MetS, the adipose tissue plays a central role along with an unbalanced gut microbiome, which has become relevant in recent years. Once visceral adipose tissue (VAT) increases, dyslipidemia and endothelial dysfunction follow as additive risk factors. However, when the nonalcoholic fatty liver is present, risk of a cardiovascular event is highly augmented. Epicardial adipose tissue (EAT) seems to increase simultaneously with the VAT. In this context, the former may play a more important role in the development of the atherosclerotic plaque than the latter. Hence, EAT may act as a paracrine tissue vis-à-vis the coronary arteries favoring the local inflammation and the atheroma calcification. PMID:26009250

  18. Intracranial atherosclerosis as a contributing factor to Alzheimer's disease dementia

    PubMed Central

    Roher, Alex E.; Tyas, Suzanne L.; Maarouf, Chera L.; Daugs, Ian D.; Kokjohn, Tyler A.; Emmerling, Mark R.; Garami, Zsolt; Belohlavek, Marek; Sabbagh, Marwan N.; Sue, Lucia I.; Beach, Thomas G.

    2010-01-01

    Background A substantial body of evidence amassed from epidemiologic, correlative and experimental studies strongly associates atherosclerotic vascular disease (AVD) with Alzheimer's disease (AD). Depending on the precise interrelationship between AVD and AD, systematic application of interventions to maintain vascular health and function as a component of standard AD therapy offers the prospect of mitigating what is presently the inexorable course of dementia. To assess this hypothesis it is vital to rigorously establish the measures of AVD that are most strongly associated with an AD diagnosis. Methods A precise neuropathological diagnosis was established for all subjects using a battery of genetic, clinical, and histological methods. The severity of atherosclerosis in the circle of Willis (CW) was quantified by direct digitized measurement of arterial occlusion in postmortem specimens and compared between AD and non-demented control (NDC) groups by calculating a corresponding index of occlusion. Results Atherosclerotic occlusion of the CW arteries was more extensive in the AD group than the NDC group. Statistically significant differences were also observed between control and AD groups with regard to Braak stage, total plaque score, total NFT score, total white matter rarefaction score, brain weight, MMSE scores and apolipoprotein E allelic frequencies. Conclusions Our results, combined with a consideration of the multifaceted impacts of impaired cerebral circulation, suggest an immediate need for prospective clinical trials to assess the efficacy of AD prevention using anti-atherosclerotic agents. PMID:21388893

  19. 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

  20. Celastrol Prevents Atherosclerosis via Inhibiting LOX-1 and Oxidative Stress

    PubMed Central

    Gu, Yue; Meng, Guoliang; Xie, Liping; Wang, Jing; Xiao, Yujiao; Shan, Liyang; Zhou, Suming; Wei, Lei; Ferro, Albert; Ji, Yong

    2013-01-01

    Celastrol is a triterpenoid compound extracted from the Chinese herb Tripterygium wilfordii Hook F. Previous research has revealed its anti-oxidant, anti-inflammatory, anti-cancer and immunosuppressive properties. Here, we investigated whether celastrol inhibits oxidized low-density lipoprotein (oxLDL) induced oxidative stress in RAW 264.7 cells. In addition, the effect of celastrol on atherosclerosis in vivo was assessed in apolipoprotein E knockout (apoE?/?) mouse fed a high-fat/high-cholesterol diet (HFC). We found that celastrol significantly attenuated oxLDL-induced excessive expression of lectin-like oxidized low density lipoprotein receptor-1(LOX-1) and generation of reactive oxygen species (ROS) in cultured RAW264.7 macrophages. Celastrol also decreased I?B phosphorylation and degradation and reduced production of inducible nitric oxide synthase (iNOS), nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor (TNF)-? and IL-6. Celastrol reduced atherosclerotic plaque size in apoE?/? mice. The expression of LOX-1 within the atherosclerotic lesions and generation of superoxide in mouse aorta were also significantly reduced by celastrol while the lipid profile was not improved. In conclusion, our results show that celastrol inhibits atherosclerotic plaque developing in apoE?/? mice via inhibiting LOX-1 and oxidative stress. PMID:23799016

  1. 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

  2. Aortic Atherosclerosis: A Common Source of Cerebral Emboli, Often Overlooked!

    PubMed

    Ismail, Imtiaz; Agarwal, Anushree; Aggarwal, Saurabh; Al-Khafaji, Nawfal; Gupta, Navdeep; Badi, Hani; Chopra, Aashish; Khosla, Sandeep; Arora, Rohit

    2016-01-01

    Aortic atherosclerotic plaques are usually seen in males older than 55 years who are known to have risk factors of atherosclerosis. Recent large series of consecutive stroke patients reported that the prevalence of aortic atheromatous plaques in patients with stroke is about 21%-27%, which is in the same magnitude when compared with the prevalence of carotid disease (10%-13%) and atrial fibrillation (18%-30%). Atheromatous plaques are composed of a lipid pool, a fibrous cap, smooth muscle cells, and mononuclear cell infiltration with calcification. Aortic plaques can cause embolization to brain, extremities, or visceral organs. Atheroembolization can occur spontaneously or as a result of manipulation during cardiac or vascular surgery. Only few cases of cerebral embolization from an aortic plaque in the absence of any manipulation have been described. Although few atherosclerotic plaques can be visualized on the aortogram, transesophageal echocardiogram remains a preferred modality for diagnosis in such cases. We present a case of cerebral embolism arising from a mobile noncalcified complex aortic arch plaque diagnosed on a transesophageal echocardiogram and review the literature on its diagnosis, clinical implications, and management. PMID:25569596

  3. 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

  4. Paradoxical roles of perivascular adipose tissue in atherosclerosis and hypertension.

    PubMed

    Chang, Lin; Milton, Hamblin; Eitzman, Daniel T; Chen, Y Eugene

    2013-01-01

    Perivascular adipose tissue (PVAT) is the fat tissue surrounding most of the vasculature and it has long been considered solely as vessel-supporting connective tissue. There are 2 major types of adipose tissue widely distributed throughout the body: white (WAT) and brown (BAT). PVAT is similar to BAT in rodents, but it was believed that only WAT existed in adult humans and BAT was present only in infants. However, the presence of functional BAT in adult humans is now accepted. The main function of BAT is to generate heat, and it is essential for adaptive thermogenesis and energy expenditure, whereas the main function of WAT is to store lipids. Besides the different functions of WAT and BAT, growing evidence suggests that different depots of adipose tissue have different functions. Similar to other fat depots, PVAT produces various adipokines, growth factors and inhibitors that affect functions of adjacent layers of the vasculature. Pathophysiological conditions such as obesity, vascular injury, aging and infection could cause PVAT dysfunction, leading to vascular endothelial and smooth muscle cell dysfunctions. In this review, we discuss the function and dysfunction of PVAT on atherosclerosis and hypertension. PMID:23207957

  5. 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

  6. 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

  7. Vascular health late after Kawasaki disease: implications for accelerated atherosclerosis

    PubMed Central

    2014-01-01

    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

  8. PET Imaging of the Human Nicotinic Cholinergic Pathway in Atherosclerosis.

    PubMed

    Bauwens, Matthias; Mottaghy, Felix M; Bucerius, Jan

    2015-08-01

    During the past years, non-neuronal vascular nicotinic acetylcholine receptors (nAChRs) increasingly have gained interest in cardiovascular research, as they are known to mediate the deleterious effects of nicotine and nitrosamines, components of tobacco smoke, on the vasculature. Because smoking is a major risk factor for the development of atherosclerosis, it is obvious that understanding the pathophysiologic role of nAChRs in the atherosclerotic disease process, as well as in the development of new diagnostic and therapeutic nAChR-related options, has become more important. Accordingly, we briefly summarize the pathophysiologic role of vascular nAChRs in the atherosclerotic disease process. We also provide an overview of currently available nAChR positron emission tomography (PET) tracers and their performance in the noninvasive imaging of vascular nAChRs, as well as potential nAChR PET tracers that might be an option for vascular nAChR PET imaging in the future. PMID:26183620

  9. Nuclear microscopy investigations into the role of iron in atherosclerosis

    NASA Astrophysics Data System (ADS)

    Makjanic, Jagoda; Ponraj, D.; Tan, B. K. H.; Watt, F.

    1999-10-01

    Using nuclear microscopy we have investigated elemental distributions and concentrations in aortic arch tissue sections from three groups of rabbits: (a) rabbits on normal diet (normal group), (b) rabbits on a high-cholesterol diet (control group), and (c) rabbits on a high-cholesterol diet and depleted in iron by weekly bleeding (test group). Rabbits in each group were sacrificed at 4-week time intervals, at 4, 8, 12 and 16 weeks. As early as 4 weeks, the aortic arches of control rabbits showed signs of fatty streaks and lesions, with a 2-fold average increase of iron concentration in the artery wall of cholesterol fed rabbits compared to the normal group. At 12 and 16 weeks the control group exhibited well-developed atherosclerotic lesions with an accompanying 3-fold increase in iron. The test group showed a significant reduction of lesion formation compared to the controls, and only after 12 weeks was an increase in iron concentration in the aortic arch observed. These findings show that controlled blood letting results in reduced uptake of iron by the artery wall and delayed atherosclerotic lesion formation. This correlation strongly suggests that iron has an important role in the aetiology of atherosclerosis.

  10. Secondhand Smoke and Periodontal Disease: Atherosclerosis Risk in Communities Study

    PubMed Central

    Slade, Gary D.; Beck, James D.; gstsdttir, 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 5374 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

  11. Increased prostacyclin and thromboxane A sub 2 biosynthesis in atherosclerosis

    SciTech Connect

    Mehta, J.L.; Lawson, D.; Mehta, P.; Saldeen, T. )

    1988-06-01

    It has been proposed that atherosclerotic arteries produce less prostacyclin (PGI{sub 2}) than nonatherosclerotic arteries do, thereby predisposing arteries to vasospasm and thrombosis in vivo. The authors reexamined this concept by measuring spontaneous as well as arachidonate-induced PGI{sub 2} biosynthesis in aortic segments from nonatherosclerotic and cholesterol-fed atherosclerotic New Zealand White rabbits. Thromboxane A{sub 2} (TXA{sub 2}) generation was also measured. Formation of PGI{sub 2}, as well as TXA{sub 2}, as measured by radioimmunoassay (RIA) of their metabolites, was increased in atherosclerotic aortic segments relative to nonatherosclerotic segments at 0, 5, 10, 15 and 30 min of incubation with arachidonate. Pretreatment of arterial segments with indomethacin inhibited PGI{sub 2} as well as TXA{sub 2} formation, whereas pretreatment with the selective TXA{sub 2} inhibitor OKY-046 inhibited only TXA{sub 2} release, thus confirming the identity of icosanoids. To confirm the RIA data, aortic segments were incubated with ({sup 14}C)arachidonate prior to stimulation with unlabeled arachidonate. The uptake of arachidonate was similar, but the release of incorporated ({sup 14}C)arachidonate was significantly greater in atherosclerotic segments than in nonatherosclertic ones. Thus, synthesis of PGI{sub 2} as well as TXA{sub 2} is increased in atherosclerosis, and this alteration in arachidonate metabolism is related to increased release of arachidonate.

  12. Transforming growth factor-? and atherosclerosis: interwoven atherogenic and atheroprotective aspects.

    PubMed

    Toma, Ian; McCaffrey, Timothy A

    2012-01-01

    Age-related progression of cardiovascular disease is by far the largest health problem in the US and involves vascular damage, progressive vascular fibrosis and the accumulation of lipid-rich atherosclerotic lesions. Advanced lesions can restrict flow to key organs and can trigger occlusive thrombosis resulting in a stroke or myocardial infarction. Transforming growth factor-beta (TGF-?) is a major orchestrator of the fibroproliferative response to tissue damage. In the early stages of repair, TGF-? is released from platelets and activated from matrix reservoirs; it then stimulates the chemotaxis of repair cells, modulates immunity and inflammation and induces matrix production. At later stages, it negatively regulates fibrosis through its strong antiproliferative and apoptotic effects on fibrotic cells. In advanced lesions, TGF-? might be important in arterial calcification, commonly referred to as "hardening of the arteries". Because TGF-? can signal through multiple pathways, namely the SMADs, a MAPK pathway and the Rho/ROCK pathways, selective defects in TGF-? signaling can disrupt otherwise coordinated pathways of tissue regeneration. TGF-? is known to control cell proliferation, cell migration, matrix synthesis, wound contraction, calcification and the immune response, all being major components of the atherosclerotic process. However, many of the effects of TGF-? are essential to normal tissue repair and thus, TGF-? is often thought to be "atheroprotective". The present review attempts to parse systematically the known effects of TGF-? on both the major risk factors for atherosclerosis and to isolate the role of TGF-? in the many component pathways involved in atherogenesis. PMID:21626289

  13. Grading atherosclerosis in aorta and coronary arteries obtained at autopsy

    PubMed Central

    Kagan, Aubrey; Uemura, Kazuo

    1962-01-01

    Many attempts have been made to grade atherosclerosis as found in autopsy material, but the repeatability of the methods used has seldom been tested. Most of the methods used are rough; and, where comparisons are to be made between the data obtained by different observers on different material, it is essential to know whether the differences found are due to the crudity of the method or in fact represent a real difference in the material studied. This paper describes an attempt to obtain comparable data by presenting specially prepared specimens to 14 pathologists from five laboratories in Europe and the Americas. For the purposes of the study, agreed definitions, techniques and criteria were adopted. Intra-observer, intra-laboratory and inter-laboratory disagreement was measured using both transverse- and longitudinal-section procedures. The longitudinally sectioned specimens were examined unstained and subsequently stained for lipid. The results indicate that the longitudinal-section procedure is likely to be useful in discriminating between groups of specimens, provided that certain procedural rules are observed. PMID:14030099

  14. Nanocrystals, a new tool to study lipoprotein metabolism and atherosclerosis.

    PubMed

    Heeren, Joerg; Bruns, Oliver

    2012-02-01

    Nanotechnology deals with structures with a maximum size of 100 nanometers and is applied in various scientific disciplines. The basis for this is its potential to create many new materials such as nanoparticles which are suitable for a vast range of applications in electronics or energy production but also in biomedicine. Nanoparticles have exceptional physical properties useful for different applications ranging from material sciences to biomedical imaging. In life sciences nanoparticles provide a novel tool to study metabolic processes such as the metabolism of lipoproteins or to noninvasively detect diseases in a very early stage. Major hallmarks of early atherosclerotic lesion formation are endothelial dysfunction and accumulation of large amounts of lipoprotein-derived cholesterol esters in macrophages within the vessel wall. Since conventional methods such as plasma marker analyses are not specific and sensitive enough to reliably assess the risk of cardiovascular events at an early stage, nanoparticles-based imaging technologies might provide a valuable tool for the non-invasive assessment of atherosclerotic lesions in the future. In this review, we will give an overview on the characteristics of modern nanoparticles and will emphasize the current studies utilizing nanoparticles for the visualization of both lipoprotein metabolism and atherosclerosis. PMID:21470118

  15. Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis?

    PubMed

    Kunnen, Sandra; Van Eck, Miranda

    2012-09-01

    Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme that catalyzes the esterification of free cholesterol in plasma lipoproteins and plays a critical role in high-density lipoprotein (HDL) metabolism. Deficiency leads to accumulation of nascent pre?-HDL due to impaired maturation of HDL particles, whereas enhanced expression is associated with the formation of large, apoE-rich HDL(1) particles. In addition to its function in HDL metabolism, LCAT was believed to be an important driving force behind macrophage reverse cholesterol transport (RCT) and, therefore, has been a subject of great interest in cardiovascular research since its discovery in 1962. Although half a century has passed, the importance of LCAT for atheroprotection is still under intense debate. This review provides a comprehensive overview of the insights that have been gained in the past 50 years on the biochemistry of LCAT, the role of LCAT in lipoprotein metabolism and the pathogenesis of atherosclerosis in animal models, and its impact on cardiovascular disease in humans. PMID:22566575

  16. Controlled Attentional Suppression.

    PubMed

    Carlisle, Nancy; Nitka, Aleksander

    2015-01-01

    When participants are given a cue about the color of distractors in an upcoming array, they are faster to find a target then when no distractor cue is given (Arita, Carlisle, & Woodman, 2012). While the benefit of this cue is not as large as the benefit for a cue that indicates the color of the target, it indicates participants can engage in active suppression of a specific color features. However, other evidence suggests that participants may first need to attend to the distractor color in order to suppress it, a 'search and destroy' mechanism (Moher & Egeth, 2012). In this study, we used the N2pc ERP component to evaluate the conflicting proposals from these two explanations. We used an array that contained 6 items of one color in the left visual hemifield, and 6 items of another color in the right visual hemifield. Participants were provided with a neutral cue (color will not appear in array), a negative cue (color will be distractor), or a positive cue (color will be target). The active suppression hypothesis predicts the cued distractors will be avoided in the negative cue condition, leading to an N2pc toward target features. The search and destroy hypothesis predicts the cued distractors will first be attended, leading to an N2pc toward the cued distractors. We found no evidence of an N2pc toward the cued distractors, in contrast to the prediction of the search and destroy hypothesis. Both the positive and negative cues led to N2pcs toward the target color. The latency of the N2pc response was much faster for the positive cue condition, leading to an interaction of early vs. late window and cue type. Overall, these results show that in some conditions participants can actively avoid a cued distractor feature, suggesting the possibility of active attentional suppression. Meeting abstract presented at VSS 2015. PMID:26325918

  17. 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.

  18. Nonsense suppression in archaea

    PubMed Central

    Bhattacharya, Arpita; Khrer, Caroline; Mandal, Debabrata; RajBhandary, Uttam L.

    2015-01-01

    Bacterial strains carrying nonsense suppressor tRNA genes played a crucial role in early work on bacterial and bacterial viral genetics. In eukaryotes as well, suppressor tRNAs have played important roles in the genetic analysis of yeast and worms. Surprisingly, little is known about genetic suppression in archaea, and there has been no characterization of suppressor tRNAs or identification of nonsense mutations in any of the archaeal genes. Here, we show, using the ?-gal gene as a reporter, that amber, ochre, and opal suppressors derived from the serine and tyrosine tRNAs of the archaeon Haloferax volcanii are active in suppression of their corresponding stop codons. Using a promoter for tRNA expression regulated by tryptophan, we also show inducible and regulatable suppression of all three stop codons in H. volcanii. Additionally, transformation of a ?pyrE2 H. volcanii strain with plasmids carrying the genes for a pyrE2 amber mutant and the serine amber suppressor tRNA yielded transformants that grow on agar plates lacking uracil. Thus, an auxotrophic amber mutation in the pyrE2 gene can be complemented by expression of the amber suppressor tRNA. These results pave the way for generating archaeal strains carrying inducible suppressor tRNA genes on the chromosome and their use in archaeal and archaeviral genetics. We also provide possible explanations for why suppressor tRNAs have not been identified in archaea. PMID:25918386

  19. Denervation suppresses gastric tumorigenesis

    PubMed Central

    Kodama, Yosuke; Muthupalani, Sureshkumar; Westphalen, Christoph B.; Andersen, Gran T.; Flatberg, Arnar; Johannessen, Helene; Friedman, Richard A.; Renz, Bernhard W.; Sandvik, Arne K.; Beisvag, Vidar; Tomita, Hiroyuki; Hara, Akira; Quante, Michael; Li, Zhishan; Gershon, Michael D.; Kaneko, Kazuhiro; Fox, James G.; Wang, Timothy C.; Chen, Duan

    2015-01-01

    The nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. We provide evidence that proper innervation is critical at all stages of gastric tumorigenesis. In three separate mouse models of gastric cancer, surgical or pharmacological denervation of the stomach (bilateral or unilateral truncal vagotomy, or local injection of botulinum toxin type A) markedly reduced tumor incidence and progression, but only in the denervated portion of the stomach. Vagotomy or botulinum toxin type A treatment also enhanced the therapeutic effects of systemic chemotherapy and prolonged survival. Denervation-induced suppression of tumorigenesis was associated with inhibition of Wnt signaling and suppression of stem cell expansion. In gastric organoid cultures, neurons stimulated growth in a Wnt-mediated fashion through cholinergic signaling. Furthermore, pharmacological inhibition or genetic knockout of the muscarinic acetylcholine M3 receptor suppressed gastric tumorigenesis. In gastric cancer patients, tumor stage correlated with neural density and activated Wnt signaling, whereas vagotomy reduced the risk of gastric cancer. Together, our findings suggest that vagal innervation contributes to gastric tumorigenesis via M3 receptormediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer. PMID:25143365

  20. 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

  1. Impact of Hydroxychloroquine on Atherosclerosis and Vascular Stiffness in the Presence of Chronic Kidney Disease

    PubMed Central

    Shukla, Ashutosh M.; Bose, Chhanda; Karaduta, Oleg K.; Apostolov, Eugene O.; Kaushal, Gur P.; Fahmi, Tariq; Segal, Mark S.; Shah, Sudhir V.

    2015-01-01

    Cardiovascular disease is the largest cause of morbidity and mortality among patients with chronic kidney disease (CKD) and end-stage kidney disease, with nearly half of all deaths attributed to cardiovascular disease. Hydroxychloroquine (HCQ), an anti-inflammatory drug, has been shown to have multiple pleiotropic actions relevant to atherosclerosis. We conducted a proof-of-efficacy study to evaluate the effects of hydroxychloroquine in an animal model of atherosclerosis in ApoE knockout mice with and without chronic kidney disease. Forty male, 6-week-old mice were divided into four groups in a 2 x 2 design: sham placebo group; sham treatment group; CKD placebo group; and CKD treatment group. CKD was induced by a two-step surgical procedure. All mice received a high-fat diet through the study duration and were sacrificed after 16 weeks of therapy. Mice were monitored with ante-mortem ultrasonic echography (AUE) for atherosclerosis and vascular stiffness and with post-mortem histology studies for atherosclerosis. Therapy with HCQ significantly reduced the severity of atherosclerosis in CKD mice and sham treated mice. HCQ reduced the area of aortic atherosclerosis on en face examination by approximately 60% in HCQ treated groups compared to the non-treated groups. Additionally, therapy with HCQ resulted in significant reduction in vascular endothelial dysfunction with improvement in vascular elasticity and flow patterns and better-preserved vascular wall thickness across multiple vascular beds. More importantly, we found that presence of CKD had no mitigating effect on HCQ’s anti-atherosclerotic and vasculoprotective effects. These beneficial effects were not due to any significant effect of HCQ on inflammation, renal function, or lipid profile at the end of 16 weeks of therapy. This study, which demonstrates structural and functional protection against atherosclerosis by HCQ, provides a rationale to evaluate its use in CKD patients. Further studies are needed to define the exact mechanisms through which HCQ confers these benefits. PMID:26414017

  2. T‐Helper Type 1 Bias in Healthy People Is Associated With Cytomegalovirus Serology and Atherosclerosis: The Multi‐Ethnic Study of Atherosclerosis

    PubMed Central

    Tracy, Russell P.; Doyle, Margaret F.; Olson, Nels C.; Huber, Sally A.; Jenny, Nancy S.; Sallam, Reem; Psaty, Bruce M.; Kronmal, Richard A.

    2013-01-01

    Background Although T‐helper type 1 (Th1) cells are considered important in atherosclerosis, the relationships between Th1 and Th2 cells and atherosclerosis have not been examined in population‐based studies. Methods and Results We measured Th cells as a percentage of lymphocytes by flow cytometry using CD4 staining (%CD4) in 917 participants of the Multi‐Ethnic Study of Atherosclerosis. We also measured interferon gamma–positive and interleukin‐4‐positive CD4+ cells, representing Th1 and Th2 subpopulations (%Th1 and %Th2), respectively. We found that %CD4 was 1.5% lower per 10 years of age (P<0.0001). Whites had higher %CD4 and lower %Th1 and %Th2 values than other race/ethnic groups. Body mass index (BMI) and blood pressure were associated with %CD4, but no traditional cardiovascular disease (CVD) risk factors were associated with %Th1 or %Th2. In multivariable models, the major independent variable associated with %Th1 was cytomegalovirus (CMV) antibody titer, with minor contributions from age, sex, seasonality, and interleukin‐6. In models with coronary artery calcification level as the outcome, significant independent variables included age, sex, smoking status, and %Th1 (β=0.25; P≤0.01). Both %Th1 and %Th2 were associated with common carotid intimal media thickness (β=0.02 and −0.02, respectively; both P<0.05), as were age, sex, race/ethnicity, blood pressure, and BMI. Conclusions Th1 bias is associated with subclinical atherosclerosis in a multiethnic population. The main Th1 correlate was CMV infectious burden. These findings are consistent with a role of Th1 cells in atherosclerosis and suggest the importance of prospective studies of T‐helper cell biasing in CVD. PMID:23688675

  3. A harbor background suppression approach

    NASA Astrophysics Data System (ADS)

    Gong, Xun; Shi, Wen-Jun

    2015-12-01

    In order to resolve false segmentation and false tracking problems caused by the influence of complex harbor background during IR moving target detection, a harbor background suppression approach is presented. Firstly, Sky-sea line region can be obtained by Otsu segmentation, which is applied to split images obtained through wavelet transform. Secondly, harbor background suppression point in sequential images can be located by multilevel filter. Finally, harbor background suppression can be realized according to those background suppression points. The proposed approach is validated by using actual IR in complex harbor background to realize background suppression. Experiment results indicate the feasibility and effectiveness of the proposed method.

  4. Special characteristics of atherosclerosis in chronic renal failure.

    PubMed

    Amann, K; Tyralla, K; Gross, M L; Eifert, T; Adamczak, M; Ritz, E

    2003-07-01

    Cardiovascular complications are a major clinical problem in patients with chronic kidney disease and end stage renal failure. Death from cardiac causes accounts for 40%-50% of all deaths in these patients and is thus up to 20 times more common in uremic patients than in the general population. Cardiovascular pathology in patients with renal failure is complex, but accelerated atherosclerosis has repeatedly been discussed as one major cause. The prevalence of coronary atheroma in uremic patients is approximately 30% by autopsy and coronary angiography studies. Not only is the prevalence of atherosclerotic lesions very high, but also the case fatality rate of myocardial infarction. Recently, excess mortality in uremic patients having had a myocardial infarct was noted; the one year mortality was 55.4% and 62.3% in uremic patients with and without diabetes, respectively, compared to about 10-15% in non-uremic patients. This study goes beyond the well-known notion that urea is associated with more severe atherosclerosis and shows that, in addition, the adaptation to coronary perfusion deficits is inappropriate. Recent clinical and autoptical studies in pre-dialysis and dialysis cohorts have documented increased intima and media thickness which appear early in the course of renal disease; Vascular wall thickening in renal failure seems to be modified at least in part by parathyroidhormone (PTH) and endothelin-1 (ET-1) which are both elevated in patients with renal failure. In experimental renal failure a direct effect of high phosphorus diet in arterial wall thickening was also documented. In addition to thickening of the vascular wall marked structural alterations were noted in renal failure i.e. a decrease in elastic fibre content and an increase in extracellular matrix. Furthermore, increased calcification of coronary atherosclerotic plaques and of the media of the aorta and some peripheral arteries has been documented in patients with renal failure. Factors contributing to this increased calcification process may be deposition of abundant circulating calcium, microinflammation, oxidative stress, de novo expression of bone morphogenous proteins and lack of inhibitors of calcifcation. These changes in vascular wall composition may alter vessel elasticity and thus contribute to impaired vessel function in renal failure. It is obvious from the above mentioned facts that cardiovascular disease in the renal patient is certainly multifaetorial in origin. There are, however, important issues to adress in the future, like (I) the characterization of vascular morphology in the different vascular beds, (II) the pathomechanisms of vascular and plaque calcification as well as the potential beneficial effect of rigorous control of non-classical risk factors (i.e. high P or Ca x P, inflammation, oxidative stress, etc.), (III) an additive or supraadditive effect of various classical and non-classical risk factors and (IV) the role of diabetes mellitus in modifying these vascular alterations. PMID:12940530

  5. Next generation fire suppressants

    NASA Technical Reports Server (NTRS)

    Brown, Jerry A.

    1995-01-01

    Spectrex, Inc., located in Cedar Grove, NJ is a manufacturer of fire detection and suppression equipment. Spectrex is one of the original pioneers in high speed fire detection and suppression systems for combat vehicles. Spectrex has installed fire suppressions systems in thousands of combat vehicles and ships throughout the world. Additionally, they manufacture flame explosion detectors, ship damage control systems, and optical gas and vapor detectors. The culmination of several years of research and development has recently produced an innovative electro-optical continuous monitoring systems called SharpEye 20/20I IR(sup 3) and SAFEYE that provide fast and reliable gas, vapor, aerosol, flame, and explosion detection. SharpEye 20/20I IR(sup 3) is a self-contained triple spectrum flame detector which scans for oscillating IR radiation (1 to 10 Hz) in the spectral bands ranging from 4.0 to 5.0 microns and uses programmed algorithms to check the ratio and correlation of data received by the three sensors to make the system highly immune to false alarms. It is extremely sensitive as it can detect a 1 x 1 square foot gasoline pan fire at 200 feet in less than 3 seconds. The sensitivity is user programmable, offering 4 ranges of detection. SAFEYE is comprised of a selected number of multispectral ban microprocessors controlled detectors which are in communication with one or more radiation sources that is projected along a 600 feet optical path. The signals from the selected narrow bands are processed and analyzed by highly sophisticated algorithms. It is ideal for high risk, remote, large areas such as petroleum and chemical manufacturing sites, waste dumps, aircraft cargo bays, and ship compartments. The SAFEYE will perform direct readings of the presence or rate of rise of concentrations of gases, vapors, or aerosols at the range of parts per million and provide alarms at various set points at different levels of concentrations.

  6. Novel agents to manage dyslipidemias and impact atherosclerosis.

    PubMed

    Nachimuthu, S; Raggi, P

    2006-09-01

    Strong epidemiological evidence linked elevated levels of low-density lipoprotein cholesterol (LDL-C) to risk of atherosclerotic heart disease. As a consequence, LDL-C lowering has been the main goal of therapy to reduce cardiovascular risk for the past few decades and hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have become some of the most commonly prescribed drugs. In spite of the proven efficacy of these drugs, statins reduce cardiovascular events by only 30-40%. Epidemiological analyses clearly indicate that a significant portion of risk is linked to other particles such as low high-density lipoprotein cholesterol (HDL-C), high triglycerides and others. Furthermore, several quantitative coronary angiography studies showing regression of atherosclerosis and reduction in subsequent events utilized a combination of drugs effective on LDL-C as well as other lipoproteins. Hence, several new drugs are being investigated that affect more than the traditional LDL-C pathways. In this article, we review lipoprotein-modifying agents that have either been recently released, or are still in various phases of development. They include agents that reduce LDL-C levels by mechanisms other than HMG-CoA inhibition (such as cholesterol absorption inhibitors, Acyl-CoA cholesterol acyl transferase inhibitors, sterol-regulating binding protein cleavage activating protein ligands, microsomal triglyceride transfer protein inhibitors, LDL-C receptor activators and farnesoid X receptor antagonists) and agents that raise HDL-C cholesterol or improve cholesterol efflux (such as cholesterol ester transfer protein inhibitors, retinoid X receptor selective agonists, specific peroxisome proliferator-activated receptor (PPAR) agonists and estrogen like compounds). PMID:17017903

  7. Fluorescence spectroscopic detection of early injury-induced atherosclerosis</