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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oxidative modification of low-density lipoproteins (LDL) plays a central role in the initiation and acceleration of atherosclerosis. Iron plays a part in the formation of highly toxic free radicals such as hydroxide and superoxide anions, which can induce lipid peroxidation. We investigated whether serum iron status was associated with circulating oxidized LDL (oxLDL) levels in type 2 diabetic patients, in whom oxidative stress and susceptibility to lipid oxidation were supposedly increased. Serum ferritin levels were significantly correlated with plasma oxLDL concentrations in both male and female patients (p<0.02 and p<0.05, respectively). No correlation was detected between ferritin and LDL-cholesterol (LDL-C) concentrations despite the close correlation between LDL-C and oxLDL concentrations (p<0.0001). Stepwise regression analysis showed that ferritin concentration was an independent positive determinant of oxLDL level, in addition to triglyceride concentration, body mass index and sex. This is the first report to show that serum ferritin is associated with circulating oxLDL levels in patients with type 2 diabetes. Further work is required to establish a causative link between iron excess and the development of diabetic vascular complications.
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PMID:Association between serum ferritin and circulating oxidized low-density lipoprotein levels in patients with type 2 diabetes. 1690 60

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, also known as statins, are the cornerstones of treatment of hyperlipidemia. They are widely used drugs that have well-documented, advantageous effects on cholesterol and atherosclerosis. The pleiotropic activities of statins can lead to newer applications. This review describes some of the available evidence supporting the use of statins for the treatment of acute coronary syndrome, as adjuncts to percutaneous coronary intervention, and for the prevention of sepsis. It also briefly discusses the rationale behind the potential development of statin-eluting stents.
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PMID:Statin therapy: not just used to lower cholesterol? 1735 56

Atherosclerosis and cancer are characterized by uncontrolled cell proliferation and share common risk factors, such as cigarette smoking, dietary habits and ageing. Growth of smooth muscle cells (SMCs) in atherosclerotic plaques may result from DNA damage, caused either by exogenous mutagens or by agents endogenously generated due to oxidative stress and lipid peroxidation (LPO). Hydroxy-2-nonenal (HNE), a major LPO product, binds covalently to cellular DNA to form the exocyclic etheno-DNA-base adducts, 1,N(6)-ethenodeoxyadenine (varepsilondA) and 3,N(4)-ethenodeoxycytosine (varepsilondC). By applying an ultrasensitive (32)P-postlabeling-immunoaffinity method, varepsilondA and varepsilondC were quantified in abdominal aorta SMCs from 13 atherosclerotic patients and 3 non-smoking subjects without atherosclerotic lesions. The levels of etheno-adducts ranged for varepsilondA from 2.3 to 39.6/10(8)dA and for varepsilondC from 10.7 to 157.7/10(8)dC, with a high correlation between varepsilondA and varepsilondC (r=0.84, P=0.0001). Etheno-adduct levels were higher in atherosclerotic smokers than in ex-smokers for both varepsilondA (means 15.2 versus 7.3, P=0.06) and varepsilondC (71.9 versus 51.6, not significant). varepsilondC levels were higher in either ex-smokers (P=0.03) or smokers (P=0.07) than in non-smokers. There was a poor correlation between either varepsilondA or varepsilondC and 8-hydroxy-2'-deoxyguanosine, whereas significant positive correlations were detected with the levels of several postlabeled bulky aromatic DNA adducts. In conclusion, two different types of DNA damage may be involved in atherosclerotic plaque formation and progression: (i) bulky aromatic compounds, to which aorta SMCs are chronically exposed in smokers, can either covalently bind to DNA, induce redox-cycling via quinone intermediates and/or activate local chronic inflammatory processes in the arterial wall; ii) this in turn leads to a self perpetuating generation of reactive oxygen species, LPO-products and increasing DNA-damage, as documented by the presence of high levels of miscoding etheno-DNA adducts in human aorta SMCs.
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PMID:Lipid peroxidation-derived etheno-DNA adducts in human atherosclerotic lesions. 1741 69

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are unequivocally useful for lowering cholesterol levels in patients with dyslipidemias characterized by elevations in total and/or low-density lipoprotein cholesterol. The beneficial effects of statins to lower serum cholesterol translate into significant reductions in cardiovascular morbidity and mortality. In addition to lowering cholesterol levels, statins have other biological effects relevant to cardiovascular homeostasis including anti-inflammatory actions and downregulation of angiotensin type 1 receptor expression that contribute to improvements in endothelial function and arterial compliance. Since endothelial dysfunction and reduced arterial compliance are important pathophysiological determinants of essential hypertension, these actions of statins raise the possibility that statin therapy may be useful for simultaneously treating dyslipidemias and hypertension. However, it has been unclear whether statins are effective in lowering blood pressure. This controversy stems from a variety of methodological limitations including inadequate sample size, confounding effects of antihypertensive drugs, differences in blood pressure measurement techniques, and differences in patient populations. However, based on published results from both small clinical studies and large randomized clinical trials, statins modestly lower blood pressure in patients with high, but not normal, blood pressure, regardless of cholesterol level.
Atherosclerosis 2008 Jan
PMID:Are statins effective for simultaneously treating dyslipidemias and hypertension? 1766 94

Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are in widespread use due to their LDL reducing properties and concomitant improvement of clinical outcome in patients with and without preexisting atherosclerosis. Considerable evidence suggests that immune mediated mechanisms play a dominant role in the beneficial effects of statins. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) have a key role in the prevention of various inflammatory and autoimmune disorders by suppressing immune responses. We tested the hypothesis that statins influence the circulating number and the functional properties of Tregs. We studied the effects of in vivo and in vitro statin treatment of human and murine mononuclear cells on the number of Tregs and the expression level of their master transcription regulator, Foxp3. Atorvastatin, but not mevastatin nor pravastatin, treatment of human peripheral blood mononuclear cells (PBMCs) increased the number of CD4(+)CD25(high) cells, and CD4(+)CD25(+)Foxp3(+) cells. These Tregs, induced by atorvastatin, expressed high levels of Foxp3, which correlated with an increased regulatory potential. Furthermore, co-culture studies revealed that atorvastatin induced CD4(+)CD25(+)Foxp3(+) Tregs were derived from peripheral CD4(+)CD25(-)Foxp3(-) cells. Simvastatin and pravastatin treatment in hyperlipidemic subjects increased the number of Tregs. In C57BL/6 mice however, no effect of statins on Tregs was evident. In conclusion, statins appear to significantly influence the peripheral pool of Tregs in humans. This finding may shed light on the mechanisms governing the plaque stabilizing properties of statins.
Atherosclerosis 2008 Apr
PMID:The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells. 1782 81

Cardiovascular risk factors, particularly low-density lipoproteins (LDL), give rise to atherosclerosis and its complications by triggering a dysfunctional endothelium, inflammation, and a procoagulant vascular surface. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibition by statins leads to a fall in circulating and plaque LDL concentrations and improvement in many cellular dysfunctions, but controlled trials only show partial benefit with regard to myocardial infarction, stroke, and cardiovascular death. Emerging clinical evidence now shows that these risk factors also stimulate the activation (isoprenylation) of small G-binding proteins and, through their effectors (Rho-associated kinase) they can activate many or most of the subcellular and vessel wall pathophysiology of atherosclerosis. Inhibition of Rho-kinase can improve these dysfunctions with no changes in LDL. Similarly, statins can diminish the activation of these small G-binding proteins and their downstream effectors in atherosclerosis. This review compares and contrasts the effects of statins on atherosclerosis that are related to changes in LDL with those effects occurring through these alternate lipid pathways, and suggests that the therapeutic control of these small G-binding proteins and their downstream effectors may significantly add to the partial benefits of using statins in patients with atherosclerotic heart disease.
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PMID:Antiatherosclerotic effects of statins: LDL versus non-LDL effects. 1817 55

The pathogenesis of atherosclerosis involves multiple cellular events, including endothelial cell dysfunction, inflammation, proliferation of vascular smooth muscle cells and matrix alteration that is subsequently characterized by hardening, thickening, loss of elasticity and, finally, a reduction in the vessel's lumen. Leptin, a peptide hormone, is produced by adipocytes, and the majority of obese individuals have high plasma leptin concentrations. Leptin regulates food intake as well as metabolic function. Originally thought to be a satiety factor, leptin is a pleiotropic molecule. In addition to its metabolic effects, leptin regulates the production of several pro- and anti-inflammatory cytokines by activating immune cells. It is associated with increased plasma C-reactive protein concentrations, vascular proliferation, calcification and decreased arterial distensibility. Leptin also increases oxidative stress. Moreover, leptin contributes to increases in blood pressure, and thus, probably plays an important role in the initiation and progression of atherosclerosis. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) lower lipid concentrations and also decrease endothelial apoptosis, inhibit smooth muscle cell proliferation, and lower concentrations of C-reactive protein and proinflammatory cytokines; moreover, it is now known that statins can inhibit leptin release by adipocytes. Therefore, statins have been shown to be beneficial in atherosclerosis. The present review mainly focuses on the various evidence that suggest a potential atherogenic mechanism of leptin, and also briefly addresses the beneficial role of statins in atherosclerosis.
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PMID:Role of leptin in atherogenesis. 1865 Oct 16

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are currently the drug of choice for the clinical management of elevated low-density lipoprotein (LDL) cholesterol. Although statin treatment provides an overall improvement in outcomes, clinical trial data reveal a significant number of cardiac events despite reaching targeted LDL levels. A low serum high-density lipoprotein (HDL) cholesterol level is an independent predictor of cardiovascular risk. Accordingly, there has been interest in determining whether HDL elevation, in addition to LDL lowering, further reduces risk in patients with coronary artery disease. Several commonly prescribed lipid-lowering therapies modestly raise HDL, but their use may be limited by the development of adverse reactions. Emerging data suggest that HDL quality and function may also be significantly reduced by atherosclerosis and other inflammatory diseases. The goal of this review is to discuss the current status of HDL therapeutics, with emphasis on a novel class of agent, the apolipoprotein A-I mimetic peptides, which improve the functional properties of HDL cholesterol.
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PMID:HDL therapy for cardiovascular diseases: the road to HDL mimetics. 1870 82

The accumulation of phosphatidylcholine hydroperoxide (PCOOH), a primary oxidation product of phosphatidylcholine (PC), in blood plasma and tissues has been observed in various pathological conditions, including atherosclerosis. However, the biological roles of PCOOH in these conditions remain unknown. To estimate the atherogenicity of PCOOH, we evaluated the effect of PCOOH on THP-1 monocytic cell adherence to immobilized vascular endothelial cell adhesion molecules. THP-1 cell adhesion to intracellular adhesion molecule-1 (ICAM-1) was dose-dependently increased by addition of PCOOH. Phosphatidylcholine hydroxide (a hydroxyl analog of PCOOH) also induced THP-1 cell adhesion to ICAM-1, whereas nonoxidized PC, sn-2 truncated PCs, and other hydroperoxide compounds did not affect the adhesion. In the PCOOH-treated cells, obvious protruding F-actin-rich membrane structures were formed, and lymphocyte function-associated antigen-1 (LFA-1) was localized to the protruding structures. Cytochalasin D, an actin polymerization inhibitor, suppressed the PCOOH-induced cell adhesion to ICAM-1 and the membrane protrusions. These results indicate that PCOOH evokes LFA-1-mediated cell adhesion to ICAM-1 via actin cytoskeletal organization, and the mechanism may participate in monocyte adherence to the arterial wall in the initiation of atherosclerosis.
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PMID:Phosphatidylcholine hydroperoxide-induced THP-1 cell adhesion to intracellular adhesion molecule-1. 1911 30

The immune system represents a promising novel target for prevention of atherosclerosis. Several pilot vaccines that reduce atherosclerosis in experimental animals have been developed. The aluminum hydroxide adjuvant Alum has been shown to have antiatherogenic properties in itself, suggesting that it may be a suitable adjuvant in possible future atherosclerosis vaccines. To characterize the immune pathways mediating this protection, we treated wild-type C57BL/6 and Apoe(-)(/)(-) mice with Alum or PBS. Analyses of splenocytes isolated from 12-week-old mice demonstrated that Alum increased the presence of CD4(+)CD25(+)FoxP3(+) regulatory T cells and downregulated the expression of T cell activation markers CD28 and ICOS in Apoe(-)(/)(-) mice but not in C57BL/6 wild-type mice. A similar immunosuppressive phenotype was found also in 25-week-old Apoe(-)(/)(-) mice and was associated with reduced atherosclerosis. Alum precipitates recovered from the injection site of Apoe(-)(/)(-) mice contained antigens derived from oxidized LDL. These findings demonstrate that treatment of Apoe(-)(/)(-) mice with Alum results in an increase of regulatory T cells and suggest that these are activated by tolerogenic antigen-presenting cells presenting oxidized LDL antigens. Our findings provide improved mechanistic understanding of the atheroprotective properties of aluminum hydroxide adjuvants but also point to the importance of determining if hypercholesterolemia may compromise the efficacy of Alum-containing vaccines used clinically today.
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PMID:Atheroprotective effects of Alum are associated with capture of oxidized LDL antigens and activation of regulatory T cells. 1947 3


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