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

Hypercholesterolemia and increased concentrations of an apolipoprotein E (apoE)-containing HDL subclass, high density lipoprotein1 (HDL1) have been observed in streptozocin-alloxan diabetic dogs consuming normal amounts of dietary cholesterol. The aim of this study was to characterize the response of HDL1 and its targeting ligand, apoE, to insulin and HMG-CoA reductase inhibitor treatment in pancreatectomized diabetic dogs. Following induction of diabetes, plasma total cholesterol, HDL1, and apoE concentrations were all increased. Urinary mevalonate excretion, an index of cholesterol synthesis in humans, was 6-fold that of nondiabetic controls. Lipoprotein fractionation by Pevikon block electrophoresis and gel filtration chromatography showed that the increased cholesterol and apoE were associated with alpha 2-migrating particles corresponding to HDL1. Insulin treatment, resulting in near normal fasting blood glucose concentrations in the group as a whole (average 5.1 mM, 92 mg/dl), led to variable reductions in apoE, total plasma cholesterol, and HDL1. Uncorrected dyslipidemia during intensified insulin treatment appeared to be related to failure to achieve euglycemia. Despite unremitting hyperglycemia, treatment with lovastatin resulted in pronounced decreases in plasma cholesterol, HDL1 and apoE to concentrations below those observed in nondiabetic animals. Mevalonate excretion also fell, but remained twice normal. Thus neither modality corrected all of the abnormalities in canine diabetic dyslipidemia. Since apoE-containing HDL1 may mediate cholesterol traffic between the periphery and the liver (reverse cholesterol transport), the present observations suggest that increased cholesterol synthesis is accompanied by parallel abnormalities in cholesterol flux through the reverse transport pathway in the canine model.
Atherosclerosis 1990 Sep
PMID:Plasma apolipoprotein E, high density lipoprotein1 (HDL1) and urinary mevalonate excretion in pancreatectomized diabetic dogs: effects of insulin and lovastatin. 224 16

Atherosclerosis is a complex multifactorial process resulting from an excessive inflammatory/fibroproliferative response to various forms of injurious stimuli to the arterial wall. The potential interactions of cells, cytokines, and growth-regulatory molecules among the different cells in the atherosclerotic lesion present numerous opportunities for modulating lesion formation and progression. Smooth muscle cell (SMC) migration and proliferation, together with lipid deposition, are now recognized as the major phenomena occurring within the arterial wall, and thus these phenomena serve as targets for pharmacologic intervention in the process of atherogenesis. Migration and proliferation of SMC are key events in atherosclerosis--and in restenosis after angioplasty. An understanding of the factors that induce such events is important for the prevention and treatment of these diseases. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell proliferation; hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, this group provided in vitro and in vivo evidence of decreases in SMC proliferation by fluvastatin and simvastatin, but not pravastatin, independent of their cholesterol-lowering properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70-90% decrease) was completely prevented by the addition of mevalonate, and partially prevented (70-80%) by farnesol or geranylgeraniol. This confirms the specific role of isoprenoid metabolites--most probably geranylgerylated protein(s)--in regulating cell migration and proliferation. The inhibitory effect of fluvastatin and simvastatin on cholesterol esterification induced by acetyl low density lipoprotein in macrophages was also prevented by the addition of geranylgeraniol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pathogenesis of atherosclerosis and the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. 760 91

Hypercholesterolemia may contribute to the pathogenesis of atherosclerosis associated with chronic renal failure (CRF). The mechanism underlying CRF-induced hypercholesterolemia, however, is still unknown. Mevalonate is the direct product of the rate-limiting step in cholesterol synthesis which is catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A reductase. We studied the changes in mevalonate metabolism in a mouse model of CRF in which serum total cholesterol levels are directly correlated with the degree of severity of the disease as measured by serum urea levels. The results of these experiments indicated that in CRF mice, the urine mevalonate levels were significantly lower, while serum mevalonate and total cholesterol levels were significantly higher than in normal mice. We believe that by restricting the normal urinary excretion of mevalonate CRF results in more of this precursor being available for direct cholesterol synthesis. In addition, an increase in circulating mevalonate may upregulate the shunt pathway of mevalonate metabolism in the liver and peripheral tissues, thus providing increased levels of the substrates acetoacetate and acetyl coenzyme A for cholesterol synthesis.
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PMID:Possible role of mevalonate in the hypercholesterolemia seen in experimental chronic renal failure. 772 97

HMG-CoA reductase inhibitors simvastatin, fluvastatin and fluvastatin enantiomers (0.1 to 5 microM) were utilized to block both mevalonate formation and cholesterol esterification in mouse peritoneal macrophages in the presence of a large excess of cholesterol supplied by acetylated LDL. Supplementation of cultures with mevalonate fully reversed, in a dose-dependent manner, the inhibitory effect of the drugs on cholesterol esterification. Mevalonate alone, in the range of the tested concentrations, did not affect cholesterol esterification in the absence of the HMG-CoA reductase inhibitors, indicating that its effect was linked to the restoration of the endogenous pool depleted by the pharmacological block of HMG-CoA reductase. The inhibitory effect of fluvastatin was also prevented by the non-sterol mevalonate isoprenoid derivative geranylgeraniol. Evaluation of fluvastatin enantiomers demonstrated the stereospecificity of drug action with most of the effect associated to the antipode with the highest inhibitory activity of HMG-CoA reductase. We conclude that mevalonate or a mevalonate product(s), possibly a non-sterol derivative(s), are required in cholesterol esterification induced by acetylated LDL in macrophages.
Atherosclerosis 1993 Dec
PMID:Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages. 814 43

With the increasing knowledge on the pathogenesis of atherosclerosis, it appears that the prevention of cardiovascular disease in the future will involve, besides risk factor correction, direct pharmacological control of processes occurring in the arterial wall. Among them, a pivotal role is played by smooth muscle cell migration and proliferation that, together with lipid deposition, are prominent features of atherogenesis and restenosis after angioplasty. Mevalonate and other intermediates (isoprenoids) of cholesterol synthesis are essential for cell growth, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently we provided evidence that fluvastatin, simvastatin, lovastatin, but not pravastatin, dose-dependently decrease smooth muscle cell migration and proliferation, independently of their hypocholesterolemic properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70-90% decrease) was completely prevented by the addition of mevalonate and partially (80%) by farnesol and geranylgeraniol, confirming the specific role of isoprenoid metabolites--probably through prenylated proteins--in regulating these cellular events. The present results provide evidence that HMG-CoA reductase inhibitors interfere directly with processes involved in atherogenesis--beyond their effects on plasma lipids--partially through local inhibition of isoprenoid biosynthesis.
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PMID:[The pharmacology of the statins: the evidence of a direct antiatherosclerotic action]. 856 63

With the increasing knowledge of the pathogenesis of atherosclerosis, it appears that in the future the prevention of cardiovascular disease will involve not only risk factor correction, but also direct pharmacological control of processes occurring in the arterial wall. Among these, a pivotal role is played by smooth muscle cell (SMC) migration and proliferation, which, together with lipid deposition, are prominent features of atherogenesis and restenosis after angioplasty. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell growth, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, we provided in vitro and in vivo evidence that fluvastatin, simvastatin and lovastatin, but not pravastatin, decrease SMC migration and proliferation dose dependently, independently of their hypocholesterolemic properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70-90% decrease) was prevented completely by the addition of mevalonate, and partially prevented by farnesol and geranylgeraniol (80%), confirming the specific role of isoprenoid metabolites in regulating these cellular events, probably through prenylated protein(s). The in vivo antiproliferative activity of fluvastatin on neointimal hyperplasia in normocholesterolemic rabbits was also prevented fully by the local delivery of mevalonate, by means of an Alzet pump. Fluvastatin and simvastatin also inhibited cholesterol esterification and deposition induced by acetylated LDL in cultured macrophages. This effect was fully prevented by the addition of mevalonate or geranylgeraniol. Taken together, these results suggest that, beyond their effects on plasma lipids, HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect on the arterial wall, probably through local inhibition of isoprenoid biosynthesis.
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PMID:Non-lipid-related effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. 890 71

Statins are most potent lipid-lowering drugs. The mechanisms of their action is specific inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) activity. HMG-CoA reductase catalyses the reduction of HMG-CoA o mevalonate and is rate-limiting step in cholesterol biosynthesis pathway. Mevalonate is considered to be not only an important intermediate of cholesterol synthesis, but also the source of isoprenoids which play important role in DNA replication and cell growth. It was shown that statins inhibit the proliferation and migration of vascular smooth muscle cell--key events in atherogenesis. HMG-CoA reductase inhibitors lower the reactivity of arterial wall to vasoconstrictor agents, decrease the concentration of lipoprotein [a]--an independent risk factor of atherosclerosis, inhibit the generation of free radicals and lipid peroxidation, decrease the number of macrophages in atherosclerotic lesion and finally, equilibrate the clotting-fibrynolysis processes of attennuating platelets function, reducing the tissue factor synthesis and decreasing the concentration of plasminogen activator inhibitors. Statins are presently considered by NCEP to be the drugs of first choice for treatment of hypercholesterolemia.
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PMID:[Anti-atherosclerotic actions of HMG-CoA reductase inhibitors]. 950 89

A decrease in serum cholesterol is one of the most beneficial effects in anti-atherogenesis. Nitric oxide is also an anti-atherogenic substance, inducing vasodilation and inhibits proliferation of smooth muscle cells (SMC). Therefore, we examined sodium nitroprusside (SNP)-induced apoptosis of vascular SMC with respect to cholesterol metabolism. Cultured vascular SMC from bovine carotid arteries and rat aorta were used. Apoptosis was determined by propidium iodide assay. Treatment of the SMC with SNP(100 micromol/l-1 mmol/l ) for 6 h induced a little nuclear fragmentation. SNP (1 mmol/l ) elicited apoptosis in 4.4+/-2.2% of cells. Pretreatment of SMC with simvastatin (1 microg/ml, 2 days), a hydroxymethylglutaryl Coenzyme A (HMG CoA) reductase inhibitor, synergistically enhanced SNP-induced apoptosis (% apoptosis =15. 9+/-3.3%). Either mevalonate (100 micromol/l) or geranylgeraniol (30 micromol/l) recovered the simvastatin (1 microg/ml)-enhanced SMC apoptosis induced by SNP. Neither squalene (10 mmol/l) nor farnesol (30 micromol/l) had a recovery effect on the simvastatin-enhanced SMC apoptosis induced by SNP. Pretreatment with simvastatin (1 microg/ml) reduced total cholesterol content in SMC. Mevalonate (100 micromol/l) restored a decrease in total cholesterol content. However, incubation with LDL deficient serum did not enhance SNP-induced apoptosis of SMC, although treatment with LDL deficient serum decreased the total cholesterol content in SMC. These data suggested that decrease in HMG CoA reductase metabolites, especially geranylgeraniol might enhance the SNP-induced apoptosis of SMC, and that, apoptosis was not involved in a decrease in cholesterol of SMC.
Atherosclerosis 2000 Feb
PMID:Simvastatin enhanced sodium nitroprusside-induced apoptosis of smooth muscle cells. An involvement of geranylgeraniol. 1065 67

The fibrinolytic inhibitor plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of atherothrombosis and is produced by macrophages that infiltrate the atherosclerotic vessel wall. Because statins are effective in reducing atherosclerosis, we investigated if they modulate the synthesis of PAI-1 in human monocytes/macrophages. To this end, we studied the effect of atorvastatin in different models of monocyte/macrophage differentiation, such as differentiated human promyelocytic cell line HL-60 and human peripheral blood monocyte-derived macrophages. HL-60 cells were differentiated along monocyte lineage by phorbol myristate acetate (PMA) or a mixture of transforming growth factor-beta type 1 (TGF-beta1)/1alpha,25-dihydroxyvitamin D3 (D3). In these conditions, PAI-1 synthesis was strongly induced and atorvastatin upregulated this synthesis, especially during TGF-beta1/D3-induced differentiation. Recombinant human tumor necrosis factor-alpha (TNF-alpha) strongly upregulated PAI-1 synthesis in PMA- or TGF-beta1/D3-differentiated cells, and the potentiating effect of atorvastatin was of the same order as in the absence of TNF-alpha. Mevalonate reversed the enhancing effect of atorvastatin. In mature human monocyte-derived macrophages, atorvastatin, alone or in combination with TNF-alpha, TGF-beta1, or PMA, did not exert any significant effect on PAI-1 synthesis. Basal production of urokinase (uPA), which was below detection limits in HL-60 cells and very low in human monocyte-derived macrophages, was not altered by atorvastatin. These results show that atorvastatin upregulates PAI-1 synthesis during the early stages of monocyte/macrophage differentiation, but has no effect on PAI-1 and uPA synthesis in mature human monocyte-derived macrophages. Atorvastatin did not significantly interact with the upregulating action of TNF-alpha on PAI-1 synthesis during differentiation.
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PMID:Effect of atorvastatin on plasminogen activator inhibitor type-1 synthesis in human monocytes/macrophages. 1139 73

Reactive oxygen species formation by phagocytes and subsequent modifications of vascular wall are involved in the early step of human atherogenesis. This study looked for the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors on NADPH oxidase-dependent superoxide anion production in THP-1 cells, a monocyte-derived cell line, and on the translocation of p21 Rac 2 and p67. A 30-min incubation with simvastatin (50 micro M ) inhibited phorbol 12-myristate 13-acetate-induced superoxide anion production by monocytes (32%) and a maximum inhibition was obtained at 3 h of incubation (69.5%). In addition, after 3 h of incubation a dose-dependent inhibition was obtained in the range 10-50 micro M of simvastatin with a median inhibitory concentration of 36 +/- 2.3 micro M Mevalonic acid (100 and 300 micro M ) and geranylgeraniol (100 micro M ) totally prevented the simvastatin-induced inhibitory effect of superoxide production by monocytes whereas farnesyl PP (100 micro M ) partially prevented (50%) this effect. In addition, simvastatin inhibited the translocation of p21 rac 2 and p67, suggesting that geranylgeranylation is required for NADPH oxidase activation. In another set of experiments, the rank order of potency of different statins on NADPH oxidase was determined (pravastatin < cerivastatin < lovastatin < fluvastatin < simvastatin). In conclusion, inhibition of superoxide formation by HMG CoA reductase inhibitors is highly suitable to prevent or limit the oxidative stress involved in the atherosclerosis process.
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PMID:Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are able to reduce superoxide anion production by NADPH oxidase in THP-1-derived monocytes. 1235 24


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