Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to cholesterol lowering, 3-hydroxy-3-nethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors limit inflammatory changes associated with atherosclerosis. There is also support for their use as inhibitors of progression in chronic renal disease, irrespective of cause. In this study, their capacity to limit acute renal inflammation was evaluated. For this purpose, mice were treated with Simvastatin either prior to, at the time of, or shortly after induction of nephrotoxic nephritis. The severity of disease was determined by evaluation of blood urea nitrogen (BUN), proteinuria, and renal histologic changes. The reversibility of benefit was evaluated by the administration of mevalonic acid along with nephrotoxic serum (NTS) and Simvastatin The severity of the acute nephritis, including proteinuria, elevated BUN, and histologic changes, was ameliorated in a dose-dependent manner, when Simvastatin was administered either prior to NTS injection or at the time of NTS injection. By contrast, Simvastatin did not alter the course of established nephritis. Coadministration of mevalonic acid, the immediate substrate following HMG-CoA reductase, abolished Simvastatin's renoprotective effect, indicating that the benefit is, at least in part, due to interference with HMG-CoA reductase and biosynthetic substrates downstream from the enzyme. These findings provide the rationale for the evaluation of the efficacy of HMG-CoA reductase inhibitors in patients with recurrent forms of renal inflammation, to limit the severity of acute exacerbations of disease, prevent renal scarring and slow the rate of progression.
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PMID:Simvastatin protection against acute immune-mediated glomerulonephritis in mice. 1640 85

We investigated the pleiotropic effects of a calcium antagonist (amlodipine) on early atherosclerosis development in the presence and absence of an HMG-CoA-reductase inhibitor (atorvastatin) in apolipoprotein E*3-Leiden/human C-reactive protein (E3L/CRP) transgenic mice. Male E3L/CRP transgenic mice were fed a cholesterol-containing diet either with or without amlodipine and/or atorvastatin. After 31 weeks, atherosclerosis in the aortic root area was quantified. Treatment with amlodipine did not significantly lower blood pressure, but resulted in a 43% reduction (P < 0.03) of lesion area as compared with the untreated group. Treatment with atorvastatin resulted in an 80% reduction of lesion area as compared with the untreated group (P < 0.001). Combined treatment with amlodipine and atorvastatin decreased the lesion area by 93%, significantly more than either treatment alone (P < 0.008). Plasma C-reactive protein levels were mildly elevated, on average 10 +/- 6 mg/L, and did not differ between groups, neither on baseline nor during treatment. Treatment with amlodipine, independently of blood pressure lowering, reduced atherosclerosis development in E3L/CRP mice. Atorvastatin had a strong anti-atherosclerotic effect, whereas co-treatment with amlodipine enhanced this effect significantly. Plasma C-reactive protein levels were not affected by any of the three treatments.
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PMID:Anti-atherosclerotic effect of amlodipine, alone and in combination with atorvastatin, in APOE*3-Leiden/hCRP transgenic mice. 1642 91

Endothelial dysfunction complicates hypertension and is a precursor of atherosclerosis. It is characterized by a reduction in the bioavailability of vasodilators, particularly nitric oxide (NO), and an increase in the activity of vasoconstrictors, including angiotensin (Ang) II and reactive oxygen species (ROS). To the extent that cardiovascular disease is characterized by an imbalance between NO, Ang II, and ROS in the endothelium, modulating the activity of these vasoactive substances has important implications for both the treatment of hypertension and the prevention of atherosclerosis and end organ damage. Accumulating experimental and clinical data suggest that a multitherapy antihypertensive regimen that includes inhibitors of the renin-angiotensin system and calcium channel antagonists may further reduce cardiovascular risk via greater improvements in endothelial function, in addition to the well-documented blood pressure lowering effects. Experimental studies in small and large coronary arteries and in aorta indicate that the calcium channel blocker, amlodipine, stimulates NO generation. These drug-specific actions beyond blood pressure lowering may exert cardio- and vasculoprotective effects by preventing the maladaptive changes that accompany hypertension, namely endothelial dysfunction, upregulation of proinflammatory molecules, vascular smooth muscle cell (VSMC) growth and migration, and increased extracellular matrix deposition, mechanisms that lead to atherosclerotic cardiovascular disease. These effects compliment those of other classes of antihypertensive agents and also 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), which have also been demonstrated to ameliorate the damaging consequences of endothelial dysfunction and thus reduce the incidence of cardiovascular events.
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PMID:Calcium channel blockers, endothelial dysfunction, and combination therapy. 1664 Jan 72

Recent studies have suggested that the periodontal disease, chronic sub-clinical inflammation, is associated with atherosclerosis, although "cause or effect" relationship is still unclear. The aim of this study was to assess the association between the degree of periodontal infection and lipid profiles in diabetic subjects. Additionally, the association of such sub-clinical inflammation with HMG-CoA reductase gene expression was evaluated. One hundred and thirty-one non-obese relatively well-controlled Japanese type 2 diabetic patients were enrolled for the study. Although no significant association was observed between serum triglycerides, HLD-cholesterol and antibody titer to Porphyromonas gingivalis (Pg), the most predominant periodontal pathogen in adults, LDL-cholesterol was significantly associated with antibody titer to Pg. Concomitantly, the same works out to be true for total cholesterol. To understand the possible mechanisms underlying this association, we evaluated 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase gene expression in cultured HepG2 cells stimulated by either bacterial lipopolysaccharide (LPS) or inflammatory cytokines. Although Pg and E. coli LPS had no effect on HMG-CoA reductase gene expression, both tumor necrosis factor-alpha and interleukin-6 (IL-6), especially IL-6 at low concentration, markedly up-regulated HMG-CoA reductase gene expression. It can be concluded that Pg infection is associated with increased LDL-cholesterol in diabetic subjects, which may be accompanied by increased cholesterol synthesis by inflammatory cytokines.
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PMID:Periodontal infection and dyslipidemia in type 2 diabetics: association with increased HMG-CoA reductase expression. 1694 Dec 80

Oxidative modification of low-density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis. In this study, we investigated the effects of antioxidants including probucol, vitamin E, and fluvastatin, an HMG-CoA (hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor with antioxidative property, on plasma levels of oxidized LDL (OxLDL) during the progression of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. OxLDL were measured as ligand for lectin-like OxLDL receptor-1 (LOX-1). LOX-1-ligand was higher in WHHL rabbits than in control rabbits as early as 2 months of age and was sustained throughout the experimental period. Supplementation of probucol (1%) and vitamin E (0.5%) to the diet reduced LOX-1-ligand but had little effect on total cholesterol (T-CHO). Fluvastatin (0.03%) significantly reduced both LOX-1-ligand and T-CHO. The extent of reduction in T-CHO was less prominent than in the case of LOX-1-ligand. All of the agents reduced the atherosclerotic lesion area and lipid contents of aortic arches. These parallel results indicate that oxidatively modified LDL elevated in the early stages of atherogenesis is of functional importance in the progression of the disease and can be suppressed by antioxidant treatment. Furthermore, fluvastatin may reduce the evolution of atherosclerosis, not only by lowering plasma cholesterol but also by reducing oxidative modification of LDL.
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PMID:Antioxidants suppress plasma levels of lectinlike oxidized low-density lipoprotein receptor-ligands and reduce atherosclerosis in watanabe heritable hyperlipidemic rabbits. 1708 97

Hypercholesterolemia is a major risk factor for atherosclerosis. HMG-CoA Reductase inhibitors (statins), which block hepatic synthesis of cholesterol, are the mainstay of therapy of hypercholesterolemia. Recent trials have demonstrated the importance of maintaining very low LDL-cholesterol levels in high-risk patients. Such low levels are sometimes hard to reach with statin monotherapy. Another source of cholesterol is intestinal absorption of dietary cholesterol and bile salts. Recent studies have elucidated the mechanism of intestinal cholesterol absorption. Ezetimibe, a specific inhibitor of cholesterol absorption can be used as an add-on therapy to statins in order to achieve treatment goals.
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PMID:[Cholesterol absorption as a target for the treatment of hypercholesterolemia]. 1718 57

Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Statins act by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in endogenous cholesterol biosynthesis, which catalyzes the reduction of HMG-CoA to mevalonic acid. Inhibition of this enzyme has proven to be effective for lowering plasma total cholesterol, low-density lipoprotein-cholesterol, and triglyceride levels in humans and can therefore be useful to treat atherosclerotic and dyslipidemic disorders. However, the clinical benefits of statins appear to extend beyond their lipid-lowering effects. Besides reducing cholesterol biosynthesis, inhibition of mevalonate by statins also leads to a reduction in the synthesis of important intermediates, such as the isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These intermediates are involved in the posttranslational prenylation of several proteins (e.g., Ras, Rho, Rac) that modulate a variety of cellular processes including cellular signaling, differentiation, and proliferation. Given the central role of these isoprenylated proteins in endothelial function, atherosclerotic plaque stability, platelet activity, coagulation, oxidation, and inflammatory and immunologic responses, it could be anticipated that these compounds may exert multiple beneficial effects in a broad spectrum of disorders including cardiovascular disease, osteoporosis, Alzheimer's disease and related vascular dementia, viral and bacterial infection, etc. This article summarizes these cholesterol-lowering-independent effects of statins, termed "pleiotropic effects", and the underlying mechanisms, as well as the preclinical experimental approaches that would be useful to evaluate the effects of statins.
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PMID:Pleiotropic effects of statins and related pharmacological experimental approaches. 1747 99

Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Statins act by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in endogenous cholesterol biosynthesis, which catalyzes the reduction of HMG-CoA to mevalonic acid. Inhibition of this enzyme has proven to be effective for lowering plasma total cholesterol, low-density lipoprotein-cholesterol, and triglyceride levels in humans and can therefore be useful to treat atherosclerotic and dyslipidemic disorders. However, the clinical benefits of statins appear to extend beyond their lipid-lowering effects. Besides reducing cholesterol biosynthesis, inhibition of mevalonate by statins also leads to a reduction in the synthesis of important intermediates, such as the isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These intermediates are involved in the posttranslational prenylation of several proteins (e.g., Ras, Rho, Rac) that modulate a variety of cellular processes including cellular signaling, differentiation, and proliferation. Given the central role of these isoprenylated proteins in endothelial function, atherosclerotic plaque stability, platelet activity, coagulation, oxidation, and inflammatory and immunologic responses, it could be anticipated that these compounds may exert multiple beneficial effects in a broad spectrum of disorders including cardiovascular disease, osteoporosis, Alzheimer's disease and related vascular dementia, viral and bacterial infection, etc. This article summarizes these cholesterol-lowering-independent effects of statins, termed "pleiotropic effects," and the underlying mechanisms, as well as the preclinical experimental approaches that would be useful to evaluate the effects of statins.
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PMID:Pleiotropic effects of statins and related pharmacological experimental approaches. 1720 Jul 29

Numerous reports on the molecular mechanism of atherogenesis indicate an increase in oxidative stress, formation of advanced glycoxidation end products (AGEs), chronic inflammation, and activated cellular response particularly in diabetic patients. To elucidate the initiating and early accelerating events this review will focus on the molecular causes of the induction of these stress factors, their interactions, and their contribution to atherogenesis. Metabolic factors such as elevated free fatty acids, high glucose levels or AGEs induce reactive oxygen species (ROS) in vascular cells leading to ongoing AGE formation and to gene induction of proinflammatory cytokines. Vice versa, numerous cytokines found elevated in obesity and diabetes may also induce oxidative stress thus a circulus vitious may be initiated and accelerated. Increased production of ROS, mainly from mitochondria and NAD(P)H oxidase, stimulates signaling cascades including protein kinase C and mitogen-activated protein kinase pathway leading to nuclear translocation of transcription factors such as nuclear factor-kappaB (NF-kappaB), activator protein 1, and specificity protein 1. Subsequently, the expression of numerous genes including cytokines is rapidly induced, which, in turn, may act on vascular cells promoting the deleterious effects. From animal models of accelerated atherosclerosis a causal role of NAD(P)H oxidase and the AGE/RAGE/NF-kappaB axis to atherogenesis is suggested. Because all factors involved form a highly interwoven network of interactions, the blockade of ROS or AGE formation at different sites may interrupt the vicious cycle. Promising candidate agents are, currently on trial. Most important to clinical practice, a number of drugs commonly used in the treatment of diabetes, hypertension, or cardiovascular disease, such as angiotensin-converting enzyme inhibitors, AT(1) receptor blockers, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins), and thiazolidindiones have shown promising 'preventive' intracellular antioxidant activity in addition to their primary pharmacological actions.
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PMID:Oxidative stress, AGE, and atherosclerosis. 1765 6

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, exert various beneficial effects independent of serum cholesterol reduction; among others is antioxidative action. Human promyelocytic cells (HL-60) were used to examine the effect of the statin rosuvastatin on reactive oxygen species-induced DNA damage, formation of oxidative stress and expression of glutathione metabolising enzymes. Rosuvastatin from 10nM significantly reduced DNA damage induced by phorbol 12-myristate 13-acetate (PMA) or by hydrogen peroxide, as assessed by the comet assay. PMA-provoked formation of reactive oxygen species, measured by flow cytometric measurement, was also prevented by rosuvastatin. Pre-incubation of cells with rosuvastatin revealed a protective effect of the statin even after its removal from the incubation medium. Total glutathione in cells treated with PMA, with and without co-incubation with rosuvastatin, was increased significantly in cells incubated with rosuvastatin alone. The quantification of the mRNA and activity of glutathione synthesizing enzymes by PCR showed a significant upregulation of gamma-glutamylcysteine synthetase. In conclusion, rosuvastatin exerts antioxidative effects, which are also capable of preventing DNA damage. These effects seem to be independent of HMG-CoA reductase inhibition and involve the induction of the expression of antioxidant defense enzymes.
Atherosclerosis 2008 Aug
PMID:Rosuvastatin protects against oxidative stress and DNA damage in vitro via upregulation of glutathione synthesis. 1815 58


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