Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interstitial fibrosis is recognised as the best histological predictor of progressive renal disease. Myofibroblasts contribute to this process through several functions including hyperproliferation, collagen and collagenase synthesis and reorganisation of extracellular matrix. Recent limited in vitro studies suggest that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors may reduce renal injury not only through their lipid-lowering effects but also by antagonising myofibroblast function. This study therefore examined the effects of lovastatin on the above interstitial myofibroblast behaviours in vitro. Primary cultures of rat renal cortical myofibroblasts were grown by explantation and characterised by immunohistochemistry. Dose response effects of lovastatin (0, 15, 30 microM) in DMEM and 10% FCS were examined on myofibroblast kinetics, total collagen synthesis, collagen I lattice contraction and actin filament rearrangement. Lovastatin decreased myofibroblast proliferation and growth. Likewise, collagen I lattice contraction and actin filament rearrangement were partially inhibited when lovastatin was added at 30 microM. In addition, lovastatin decreased both collagen and collagenase synthesis. Our results suggest that myofibroblast function may be downregulated by lovastatin in vitro. Although a decrease in myofibroblast activity may offer potential benefit in the prevention of progressive scarring, further studies will be necessary to determine the relative importance of these functions.
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PMID:Lovastatin downregulates renal myofibroblast function in vitro. 1213 76

Angiogenesis is implicated in the pathogenesis of cancer, rheumatoid arthritis, and atherosclerosis and in the treatment of coronary artery and peripheral vascular disease. Here, cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are shown to interfere with angiogenesis. In vivo, the HMG-CoA reductase inhibitor simvastatin dose-dependently inhibited capillary growth in both vascular endothelial growth factor-stimulated chick chorioallantoic membranes and basic fibroblast growth factor-stimulated mouse corneas. In vitro, the development of tubelike structures by human microvascular endothelial cells cultured on 3D collagen gels was inhibited at simvastatin concentrations similar to those found in the serum of patients on therapeutic doses of this agent. HMG-CoA reductase inhibitors interfered with angiogenesis via inhibition of the geranylgeranylation and membrane localization of RhoA. Simvastatin inhibited membrane localization of RhoA with a concentration dependence similar to that for the inhibition of tube formation, whereas geranylgeranyl pyrophosphate, the substrate for the geranylgeranylation of Rho, reversed the effect of simvastatin on tube formation and on the membrane localization of RhoA. Furthermore, tube formation was inhibited by GGTI, a specific inhibitor of the geranylgeranylation of Rho; by C3 exotoxin, which inactivates Rho; and by the adenoviral expression of a dominant-negative RhoA mutant. The expression of a dominant-activating RhoA mutant reversed the effect of simvastatin on tube formation. Finally, HMG-CoA reductase inhibitors inhibited signaling by vascular endothelial growth factor, Akt, and focal adhesion kinase, three RhoA-dependent pathways known to be involved in angiogenesis. This study demonstrates a new relationship between lipid metabolism and angiogenesis and an antiangiogenic effect of HMG-CoA reductase inhibitors with possible important therapeutic implications.
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PMID:3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA. 1214 47

Postischemic acute renal failure (ARF) is common and often fatal. Cellular mechanisms include cell adhesion, cell infiltration and generation of oxygen free radicals, and inflammatory cytokine production. Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") directly influence inflammatory mechanisms. The hypothesis that ischemia-induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were analyzed in a uninephrectomized rat model. Male Sprague-Dawley rats were pretreated with cerivastatin (0.5 mg/kg) or vehicle for 3 d. Ischemic ARF was induced by left renal artery clipping for 45 min, while the right kidney was being removed. After 24 h of ARF, serum creatinine levels were increased 7.5-fold in vehicle-treated control animals with ARF, compared with sham-operated animals (P < 0.005). Statin treatment reduced the creatinine level elevation by 40% (P < 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 +/- 0.09 ml/min, n = 13; ischemia without treatment, 0.06 +/- 0.02 ml/min, n = 9; ischemia with statin pretreatment, 0.21 +/- 0.03 ml/min, n = 11; P < 0.001). Furthermore, statin pretreatment prevented the occurrence of tubular necrosis, with marked loss of the brush border, tubular epithelial cell detachment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infiltration was almost completely prevented, intercellular adhesion molecule-1 upregulation was greatly decreased, and inducible nitric oxide synthase expression was reduced. Fibronectin and collagen IV expression was reduced, approaching levels observed in sham-operated animals. In vehicle-treated rats with ARF, mitogen-activated protein kinase extracellular activated kinase-1/2 activity was increased and the transcription factors nuclear factor-kappaB and activator protein-1 were activated. Statin treatment reduced this activation toward levels observed in sham-operated rats. The data suggest that hydroxy-3-methylglutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus reduces the severity of ARF. The chain of events may involve anti-inflammatory effects, with inhibition of mitogen-activated protein kinase activation and the redox-sensitive transcription factors nuclear factor-kappaB and activator protein-1.
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PMID:Postischemic acute renal failure is reduced by short-term statin treatment in a rat model. 1219 73

3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-gamma release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.
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PMID:A novel anti-inflammatory role for simvastatin in inflammatory arthritis. 1253 17

This study investigated the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A ( HMG-CoA ) reductase inhibitor with strong cholesterol-lowering activity, on the composition of atherosclerotic plaque. Pitavastatin ( 0.5mg/kg ) was administered to Watanabe heritable hyperlipidemic ( WHHL ) rabbits for 16 weeks, with the result that plasma total cholesterol ( TC ), very low density lipoprotein ( VLDL )-C, intermediate density lipoprotein ( IDL )-C and low density lipoprotein ( LDL )-C decreased by 28.6, 60.0, 42.3 and 21.7%, respectively. In the aorta, pitavastatin reduced the area of the lesion by 38.6%. In the pitavastatin group, the macrophage-positive area in the aortic plaque was reduced by 39.4%, and the areas occupied by collagen and a-smooth muscle actin ( alpha-SMA )-positive area increased by 66.4 and 91.7%, respectively. In the aortic arch, pitavastatin increased the average thickness of alpha-SMA in the plaque by 96.7% and reduced the vulnerability index by 76.0%. Furthermore, pitavastatin reduced the positive areas of monocyte chemoattractant protein ( MCP )-1, matrix metalloproteinase ( MMP )-3 and MMP-9 by 39.1, 40.6 and 52.3%, respectively. These results indicated that pitavastatin had an excellent lipid-lowering effect in WHHL rabbits, suppressing the progression of atherosclerosis and stabilizing atherosclerotic plaque.
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PMID:Plaque-stabilizing effect of pitavastatin in Watanabe heritable hyperlipidemic (WHHL) rabbits. 1274 Apr 85

Retinal vein occlusion (RVO) is associated with hyperhomocysteinaemia and the antiphospholipid syndrome-disorders known to contribute to both arterial and venous thrombosis. In both of these conditions and RVO, platelet activation occurs. Aspirin, not warfarin, is the most effective antithrombotic agent in RVO and, taken together, these observations suggest an important role for platelets in this common ocular thrombotic condition. Platelet glycoprotein Ia/IIa (GpIa/IIa) is an adhesion molecule mediating platelet-collagen interactions and is key to the initiation of thrombosis. Recently, the cellular density of this molecule was shown to be determined by two silent, linked polymorphisms (C807T/G873A) within the GpIa/IIa gene. There is evidence that some of the resulting genotypes are associated with thrombo-embolic disease. This study therefore aimed to establish the prevalence of the GpIa/IIa polymorphisms and the three commonest hereditary thrombophilic disorders (prothrombin gene G20210A (PT) mutation, Factor V Leiden (FVL), and the thermolabile methylene tetrahydrofolate reductase C677T (MTHFR) mutation) in patients with RVO and normal controls. The GpIa/IIa polymorphisms and thrombophilic abnormalities were all identified using the polymerase chain reaction.Our results show that the frequency of the GpIa/IIa polymorphisms was similar in our normal control population to previously published series. Patients with RVO, however, had only a 10% (4/40) frequency of the lowest risk subtype (CC/GG) compared to 37.5% (15/40) in the control group-P 0.0039. The incidence of the PT, FVL, and MTHFR thrombophilic mutations was not different between the two groups, but interestingly none of the 7/40 RVO cases with a PT, FVL, or MTHFR mutation had the low-risk GpIa/IIa genotype while all but one of the controls did-P<0.05. Thus, 17.5% of RVO patients harboured more than one prothrombotic abnormality. The principal difference between the RVO and control group was the very high incidence of the intermediate-risk GpIa/IIa subtype (CT/GA)-82.5 vs 50%, P&<0.05. These results suggest a major role for GpIa/IIa polymorphisms in the pathogenesis of RVO.
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PMID:The platelet glycoprotein Ia/IIa gene polymorphism C807T/G873A: a novel risk factor for retinal vein occlusion. 1504 38

Recent clinical studies suggest that some of the beneficial effects of 3-hydroxy-3-metylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the incidence of myocardial infarctions and ischemic strokes may be through their non-cholesterol-lowering "direct" effects on atherosclerotic vessels. We designed this study to test the hypothesis that fluvastatin inhibits atheroma formation and increase plaque stability independent of cholesterol-lowering effects. Rabbits were fed 0.5% high-cholesterol diet for 12 weeks (progression phase) and then fed the high-cholesterol diet either containing or not containing fluvastatin 2mg/kg per day for additional 8 weeks (treatment phase). Rabbits fed normal diet were used as control. Plasma total and LDL-cholesterol concentrations did not differ during the treatment phase of the experiment. Atherosclerotic changes (plaque formation, lipid- and macrophage-rich intimal thickening, the increase in MCP-1, IL-8, TNF-alpha, IL-1beta, M-CSF, MMP-1, MMP-9, MMP-12, and ACE mRNA expression, and the increase in plasma MCP-1 levels) were observed in the high-cholesterol diet group (HC). All of these changes were less in the fluvastatin-treated group (HC+Flu) than in HC. There was no significant difference in aortic collagen (type I and type IV) mRNA expression between groups. Furthermore, fluvastatin increased the extracellular matrix content (collagen) and vascular smooth muscle cell composition in the atherosclerotic lesion, leading to the increase in plaque stability score (collagen+smooth muscle cell area)/(macrophage+lipid deposition area) in HC+Flu. Fluvastatin not only reduced atherogenesis but also to stabilized vulnerable atheromatous plaques in atherosclerotic rabbits, presumably through the macrophage recruitment and activation in the aortic lesion, at a low dose without cholesterol-lowering effects.
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PMID:HMG-CoA reductase inhibitor, fluvastatin, has cholesterol-lowering independent "direct" effects on atherosclerotic vessels in high cholesterol diet-fed rabbits. 1296 85

Treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been accompanied by a reduced risk of cardiovascular events. Rapid onset of clinical benefit and weak correlations between plasma low density lipoprotein-cholesterol levels and coronary lumen change or cardiovascular events indicates that nonlipid mechanisms are involved in this beneficial effects with HMG-CoA reductase inhibitors. Furthermore, more rapid onset of clinical benefit with HMG-CoA reductase inhibitors in patients with acute coronary syndromes or acute myocardial infarction than in those with stable coronary heart disease suggest that HMG-CoA reductase inhibitors facilitate repair of ruptured or ulcerated atherosclerotic plaque, facilitate plaque stabilization and/or reduce thrombus formation on ruptured plaques. Treatment with HMG-CoA reductase inhibitors improved endothelial dysfunction in patients with hypercholesterolemia and this improvement in endothelial function was not correlated with reduction in total serum cholesterol levels. Similarly, reduction in endothelial pre-proendothelin mRNA expression and endothelin synthesis and blood pressure lowering with HMG-CoA reductase inhibitors occurred independent of lipid-lowering. Finally, HMG-CoA reductase inhibitors increased endothelial nitric oxide levels i.e. upregulated endothelial nitric oxide synthetase expression via post-transcriptional mechanisms and prevented its down-regulation by oxidized LDL-C. HMG-CoA reductase inhibitors have been shown to modulate the immune response by inhibiting activation of immune-competent cells such as macrophages, and antigen presentation to macrophages by T cells. Treatment with HMG-CoA reductase inhibitors can reduce expression, production and circulating levels of chemokines (monocyte chemoattractant protein-1) and proinflammatory cytokines [tumor necrosis factoralpha, interleukin (IL)-6 and IL-1beta]. HMG-CoA reductase inhibitors reduced inflammation in human atheroma: significantly fewer macrophages and T cells, less oxidized LDL-C and higher collagen content. In addition, treatment with HMG-CoA reductase inhibitor led to decreased cell death within the atheroma. Treatment with these agents also reduced expression of inducible cellular adhesion molecules, decreased secretion of metalloproteinases by macrophages, reduced vascular smooth muscle cell apoptosis. Lastly, HMG-CoA reductase inhibitors appear to have important effects on the thrombogenesis: reduced expression of tissue factor production and activity; increased production of tissue factor package inhibitor; decreased platelet thrombus formation and improved fibrinolysis as a result of lowered plasminogen activator inhibitor-1 levels. As the pluripotential cardioprotective mechanisms of HMG-CoA reductase inhibitors are further elucidated, it is envisaged that treatment with HMG-CoA reductase inhibitors will be initiated earlier and more frequently in patients with hypercholesterolemia.
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PMID:Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy. 1472

Constrictive arterial remodeling plays a major role in lumen narrowing following angioplasty. We investigated the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, on vascular smooth muscle cell (SMC)-populated collagen lattice contraction, an in vitro model of vascular contraction. Type I collagen gel contraction by SMCs, which are cultured in collagen gel, was used as a model of vascular remodeling. Pitavastatin pretreatment inhibited 10% serum- or platelet-derived growth factor-BB (PDGF)-induced SMC-mediated collagen lattice contraction in a concentration-dependent manner. The effect of pitavastatin was prevented by mevalonate or geranylgeranyl pyrophosphate, but not by squalene, a precursor of cholesterol, or farnesyl pyrophosphate. The serum- or PDGF-induced SMC-mediated collagen gel contraction was inhibited by GGTI-298, a geranylgeranyltransferase inhibitor, C3 exoenzyme, an inhibitor of Rho, or Y27634, a Rho kinase inhibitor, but not by FTI-277, a farnesyltransferase inhibitor. Serum or PDGF treatment increased the stress fiber organization in SMCs, which was blocked by the pitavastatin pretreatment. Pitavastatin had no effect on the serum- and PDGF-induced lamelliopodia extension of SMC. These results may suggest that pitavastatin attenuates SMC-mediated collagen gel contraction probably via an inhibition of geranylgeranylated Rho protein and a disruption of actin cytoskeletal reorganization.
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PMID:Pitavastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, blocks vascular smooth muscle cell populated-collagen lattice contraction. 1516 74

The goal of the present study was to investigate the antifibrotic role of inducible nitric oxide synthase (iNOS) in Peyronie's disease (PD) by determining whether a plasmid expressing iNOS (piNOS) injected into a PD-like plaque can induce regression of the plaque. A PD-like plaque was induced with fibrin in the penile tunica albuginea of mice and then injected with a luciferase-expressing plasmid (pLuc), either alone or with piNOS, following luciferase expression in vivo by bioluminescence imaging. Rats were treated with either piNOS, an empty control plasmid (pC), or saline. Other groups were treated with pC or piNOS, in the absence of fibrin. Tissue sections were stained for collagen, transforming growth factor (TGF) beta1, and plasminogen-activator inhibitor (PAI-1) as profibrotic factors; copper-zinc superoxide dismutase (CuZn SOD) as scavenger of reactive oxygen species (ROS); and nitrotyrosine to detect nitric oxide reaction with ROS. Quantitative image analysis was applied. Both iNOS and xanthine oxido-reductase (XOR; oxidative stress) were estimated by Western blot analysis. Luciferase reporter expression was restricted to the penis, peaked at 3 days after injection, but continued for at least 3 wk. In rats receiving piNOS, iNOS expression also peaked at 3 days, but expression decreased at the end of treatment, when a considerable reduction of plaque size occurred. Protein nitrotyrosine, XOR, and CuZn SOD increased, and TGFbeta1 and PAI-1 decreased. The piNOS gene transfer regressed the PD plaque and expression of profibrotic factors, supporting the view that endogenous iNOS induction in PD is defense mechanism by the tissue against fibrosis.
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PMID:Gene transfer of inducible nitric oxide synthase complementary DNA regresses the fibrotic plaque in an animal model of Peyronie's disease. 1524 Apr 26


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