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

This article has focused on the influence of NO. on vascular homeostasis. Vascular tone, however, is also influenced by other vasoactive factors released by the endothelium, including the endothelial-derived hyperpolarizing factors, prostacyclin, and vasoconstrictor factors. There is also abundant evidence that these factors are altered by pathophysiologic states, although the mechanisms responsible are not as well understood as they seem to be for the NO. system. There is now evidence that several endothelial-derived hyperpolarizing factors may exist. One is almost certainly the cytochrome p450 metabolite of arachidonic acid, epoxyeicosatrienoic acid (EET) [92], whereas another is likely H2O2, which stimulates potassium channel opening in a fashion similar to the EET [93]. EET has anti-inflammatory properties, whereas H2O2 may potentially enhance inflammation and promote vascular hypertrophy. Thus, two factors released by the endothelium with similar acute effects on the vascular smooth muscle may have very different long-term consequences in terms of protecting against or promoting vascular disease. During the past two decades, physicians have gained a substantial understanding of the L-arginine/eNOS/NO. pathway and how this modulates vascular reactivity. Further, physicians now are aware that this process is altered by many risk factors for atherosclerosis and have begun to understand how these disorders alter NO. production and bioavailability. These abnormalities are likely multifactorial and physicians are beginning to understand how they can be corrected. An exciting aspect of endothelial function is that it has prognostic significance above and beyond the traditional risk factors for atherosclerosis. Several studies now have shown that individuals with intact endothelial function in either the forearm or the coronary circulation have a low incidence of events during follow-up periods, whereas those individuals with abnormal endothelial function have a high incidence of major cardiovascular events [94-96]. Because of the complexity of abnormalities that underlie endothelial dysfunction, there are various therapeutic targets that may have to be addressed to improve endothelial function and ultimately improve prognosis in these individuals.
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PMID:Endothelial control of vasomotion and nitric oxide production. 1462 46

Of the 60,000 patients receiving heart transplants between 1982 and 2001, approximately 12,000 are currently alive. The high incidence of hyperlipidemia and coronary disease (also known as accelerated graft atherosclerosis, or AGA) in these patients warrants early prophylaxis soon after transplantation with 3-hydroxy-3-methylglutaryl (HMG) Co-A reductase inhibitors (statins). Immunosuppressive agents such as prednisone, cyclosporine, mycophenylate mofetil, and sirolimus are associated with hyperlipidemia. Statins, in addition to lowering cholesterol levels, also benefit cardiac transplant recipients via effects on the immune system and endothelial function. Recent data have demonstrated that statins decrease AGA and mortality rates. Furthermore, greater benefits are seen when statins are started early. The 2 statins shown to decrease mortality in patients after cardiac transplantation are pravastatin and simvastatin, which differ in their metabolism (pravastatin is the only statin with non-cytochrome metabolism) and lipophilicity (pravastatin is less lipophilic). Although the benefit of simvastatin has been shown to extend to 8 years after transplantation, increased adverse effects in other studies with higher doses of simvastatin have resulted in new prescribing recommendations, which state that the dose of simvastatin should probably not exceed 10 mg with cyclosporine or gemfibrozil and 20 mg with amiodarone or verapamil. The evidence for potential benefits, interactions, and adverse effects of other potential lipid-lowering drugs for this patient population, such as fibrates, niacin, fish oil, cholestyramine, and ezetimibe, are also discussed. A summary algorithm is proposed, including approaches to patients with statin-associated musculoskeletal symptoms and patients with inadequate results after initial statin therapy.
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PMID:Treatment of hyperlipidemia in cardiac transplant recipients. 1530 89

Endothelium-derived nitric oxide (NO) is critically involved in the regulation of a wide variety of vascular functions. It had been hypothesized that a deficiency of vascular NO might be involved in the accelerated atherosclerosis and dramatic cardiovascular mortality observed in patients with chronic renal failure. At present it is difficult to measure authentic NO in vivo. An alternative is to study NO by its effect on vascular tone by using the forearm blood flow technique. In this way, studies demonstrated an unimpaired availability of NO under baseline conditions but a profound reduction of agonist-induced endothelium-dependent vasodilatation in uremic patients. Further investigation showed that the latter phenomenon is mainly attributable to a reduced availability of vascular NO upon agonist stimulation, while the NO-independent mechanism(s) appear(s) to be intact in this setting. Explanations for this finding include an uncoupling of NO synthase induced by cofactor deficiency, and/or a reduced NO availability caused by high levels of oxidative stress. Recent data suggest only a minor role for cytochrome-P450 2C9-dependent pathways in this context. Future studies have to show which mechanisms are most relevant, and whether they are sensitive to therapeutic intervention.
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PMID:Nitric oxide in chronic renal failure. 1584 8

Atherogenesis is a complex pathogenetic process involving a variety of structural and functional deficits within the arterial wall that culminate in the formation of fibrous atherosclerotic plaques. Cigarette smoking is potentially the most remediable contributor to cardiovascular mortality and morbidity. Among the 4000 plus chemicals present in tobacco and tobacco smoke, polycyclic aromatic hydrocarbons (PAHs) have been firmly implicated in the etiology of atherosclerosis in experimental model systems. However, the molecular mechanisms responsible for PAH-induced vascular injury are not well understood. In this review, we have focused on the mechanisms of bioactivation of PAHs in the vas-culature, and the possible role(s) of cytochrome P4501A and 1B enzymes in the formation of PAH-DNA adducts within the vessel wall, a phenomenon that may contribute to the development of atherosclerotic plaques in humans.
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PMID:Bioactivation of polycyclic aromatic hydrocarbon carcinogens within the vascular wall: implications for human atherogenesis. 1639 87

This article aims to give an overview on the characterization, properties and regulation of enzymes, particularly the cytochrome (CYP) P450 enzymes, in the formation of bile acids from cholesterol. Bile acids are biologically active molecules that promote absorption of dietary lipids in the intestine and stimulate biliary excretion of cholesterol. Bile acids and oxysterols, formed from cholesterol, act as ligands to nuclear receptors regulating the expression of important genes in cholesterol homeostasis. Thus, the bioactivation of cholesterol into bile acids is crucial for regulation of cholesterol homeostasis. The primary human bile acids, cholic acid and chenodeoxycholic acid, are formed from cholesterol via several pathways involving many different enzymes. Many of these enzymes are cytochrome P450 (CYP) enzymes, introducing a hydroxyl group in the molecule. The "classic" pathway of bile acid formation starts with a 7alpha-hydroxylation of cholesterol by CYP7A1 in the liver. The "acidic" pathway starts with a hepatic or extrahepatic 27-hydroxylation by CYP27A1. There also exist some quantitatively minor pathways which may be of importance under certain conditions. Formation of cholic acid requires insertion of a 12alpha-hydroxyl group performed by CYP8B1. Oxysterols are precursors to bile acids, participate in cholesterol transport and are known to affect the expression of several genes in cholesterol homeostasis. Enzymes with capacity to form and metabolize oxysterols are present in liver and extrahepatic tissues. The enzymes, nuclear receptors and transcription factors involved in bile acid biosynthesis are potential pharmaceutical targets for the development of new drugs to control hypercholesterolemia and to prevent atherosclerosis and other diseases related to disturbed cholesterol homeostasis. The review will also discuss some inborn errors of bile acid biosynthesis and the recently acquired knowledge on the genetic defects underlying these diseases.
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PMID:Enzymes in the conversion of cholesterol into bile acids. 1734 71

Silymarin is widely used in supportive therapy of liver diseases. It has been shown lately that silymarin has beneficial effects on some risk factors of atherosclerosis owing to its hypolipidemic properties. PPARalpha plays a key role in lipid metabolism and homeostasis as its target genes are involved in catabolism of fatty acids by beta-oxidation (e.g. acyl-CoA oxidase) and by omega-oxidation (e.g. cytochrome P4504A). Here we studied the possibility that hypolipidemic effects of silymarin may be mediated by PPARalpha. Rats fed with a high-cholesterol diet with either silymarin or fenofibrate (as a positive control both for PPARalpha expression as well as for lipid determination) were used. The effects of silymarin on expression of PPARalpha both at the mRNA (including selected target genes) as well as the protein level were determined. In parallel, the levels of cholesterol and triacylglycerols were determined. Our results confirmed the hypolipidemic effects of silymarin and demonstrated that these effects are probably not mediated by PPARalpha because of unchanged mRNA levels of PPARalpha target genes. Furthermore, this work shows for the first time that cholesterol itself inhibits expression of CYP4A mRNA.
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PMID:Hypolipidemic effects of silymarin are not mediated by the peroxisome proliferator-activated receptor alpha. 1762 Feb 19

The tobacco industry markets potentially reduced exposure products (PREPs) as less harmful or addictive alternatives to conventional cigarettes. This study compared the effects of mainstream smoke from Quest, Eclipse, and 2R4F reference cigarettes on the development of atherosclerosis in apolipoprotein E-deficient (apoE -/-) mice. Mice were exposed to smoke from four cigarette types for 12 weeks beginning at age of 12 weeks, and in a separate study for 8 weeks, beginning at age of 8 weeks. In both studies, mice exposed to smoke from high-nicotine, high-tar Quest 1, and 2R4F cigarettes developed greater areas of lipid-rich aortic lesions than did non-smoking controls. Exposure to smoke from the lower-nicotine products, Eclipse, and Quest 3, was associated with smaller lesion areas, but animals exposed to smoke from all of the tested types of cigarette had larger lesions than did control animals not exposed to smoke. Urinary levels of isoprostane F2 alpha VI, increased proportionally to cigarette nicotine yield, whereas induction of pulmonary cytochrome P4501A1 was proportional to tar yield. Lesion area was associated with both nicotine and tar yields, although in multiple regression analysis only nicotine was a significant predictor of lesion area. Smoke exposure did not alter systolic blood pressure (SBP), heart rate (HR), blood cholesterol, or leukocyte count. Taken together, these observations suggest that smoking may accelerate atherosclerosis by increasing oxidative stress mediated at least in part via the actions of nicotine.
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PMID:Potentially reduced exposure cigarettes accelerate atherosclerosis: evidence for the role of nicotine. 1790 62

Pentaerythritol tetranitrate (PETN) treatment reduces progression of atherosclerosis and endothelial dysfunction and decreases oxidation of low-density lipoprotein (LDL) in rabbits. These effects are associated with decreased vascular superoxide production, but the underlying molecular mechanisms remain unknown. Previous studies demonstrated that endogenous nitric oxide could regulate the expression of extracellular superoxide dismutase (ecSOD) in conductance vessels in vivo. We investigated the effect of PETN and overexpression of endothelial nitric oxide synthase (eNOS(++)) on the expression and activity of ecSOD. C57BL/6 mice were randomized to receive placebo or increasing doses of PETN for 4 weeks and eNOS(++) mice with a several fold higher endothelial-specific eNOS expression were generated. The expression of ecSOD was determined in the lung and aortic tissue by real-time PCR and Western blot. The ecSOD activity was measured using inhibition of cytochrome C reduction. There was no effect of PETN treatment or eNOS overexpression on ecSOD mRNA in the lung tissue, whereas ecSOD protein expression increased from 2.5-fold to 3.6-fold (P < 0.05) by 6 mg PETN/kg body weight (BW)/day and 60 mg PETN/kg BW/day, respectively. A similar increase was found in aortic homogenates. eNOS(++) lung cytosols showed an increase of ecSOD protein level of 142 +/- 10.5% as compared with transgene-negative littermates (P < 0.05), which was abolished by N(omega)-nitro-L-arginine treatment. In each animal group, the increase of ecSOD expression was paralleled by an increase of ecSOD activity. Increased expression and activity of microvascular ecSOD are likely induced by increased bioavailability of vascular nitric oxide. Up-regulation of vascular ecSOD may contribute to the reported antioxidative and anti-atherosclerotic effects of PETN.
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PMID:Pharmacological induction of vascular extracellular superoxide dismutase expression in vivo. 1932 Jul 75

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants implicated in the development of pro-inflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. PCB exposure of endothelial cells results in increased cellular oxidative stress, activation of stress and inflammatory pathways leading to increased expression of cytokines and adhesion molecules and ultimately cell death, all of which can lead to development of atherosclerosis. To date no studies have been performed to examine the direct effects of PCB exposure on the vasculature relaxant response which if impaired may predispose individuals to hypertension, an additional risk factor for atherosclerosis. Overactivation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) following oxidative/nitrosative stress in endothelial cells and subsequent depletion of NADPH has been identified as a central mediator of cellular dysfunction. The aim therefore was to investigate whether 2,2',4,6,6'-pentachlorobiphenyl (PCB 104) directly causes endothelial cell dysfunction via increased oxidative stress and subsequent overactivation of PARP. Exposure of ex vivo rat aortic rings to PCB 104 impaired the acetylcholine-mediated relaxant response, an effect that was dependent on both concentration and exposure time. In vitro exposure of mouse endothelial cells to PCB 104 resulted in increased cellular oxidative stress through activation of the cytochrome p450 enzyme CYP1A1 with subsequent overactivation of PARP and NADPH depletion. Pharmacological inhibition of CYP1A1 or PARP protected against the PCB 104-mediated endothelial cell dysfunction. In conclusion, the environmental contaminants, PCBs, can activate PARP directly impairing endothelial cell function that may predispose exposed individuals to development of hypertension and cardiovascular disease.
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PMID:PCB-induced endothelial cell dysfunction: role of poly(ADP-ribose) polymerase. 1954 8

Luteolin, a naturally occurring polyphenol flavonoid, has demonstrated some beneficial modulation toward the endothelium. This study aims to investigate the effects of luteolin on lysophosphatidylcholine (LPC)-induced apoptosis, a key event in the pathogenesis of atherosclerosis, in endothelial cells. Luteolin reduced not only LPC-induced cell death but also lactate dehydrogenase (LDH) leakage. Luteolin inhibition of LPC-induced apoptosis in endothelial cells demonstrated its protection against the cytotoxicity of LPC. LPC-induced apoptosis is characterized by a calcium-dependent mitochondrial pathway, involving calcium influx, activation of calpains, cytochrome C release and caspases activation. Luteolin reduced calcium influx. It also inhibited calpains activation and prevented the release of cytochrome C from mitochondrion. The inhibition of cytochrome C release by luteolin blocked the activation of caspase-3 and thus prevented subsequent endothelial cell apoptosis. These results suggested that luteolin inhibits LPC-induced apoptosis in endothelial cells through the blockage of the calcium-dependent mitochondrial pathway.
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PMID:Luteolin inhibits lysophosphatidylcholine-induced apoptosis in endothelial cells by a calcium/mitocondrion/caspases-dependent pathway. 1983 Jun 54


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