Nitric oxide synthase II (NOS II) gene expression correlates with atherosclerotic intimal thickening. Preventive effects of HMG-CoA reductase inhibitors (original) (raw)
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Bangladesh Journal of Physiology and Pharmacology, 2014
Background: Inhibitors of HMG-CoA-reductase reduce cardiovascular mortality through the mechanisms yet elucidated. Most ischemic events are secondary to disruption of atherosclerotic plaques highly infiltrated by macrophages.Objectives: To study the effect of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitor simvastatin on the potential mechanisms involved in the recruitment of monocytic cells into the vessel wall.Methodology: This experimental study was carried out in the Laboratory of the Department of Pharmacology & Therapeutics, BSMMU, Shahbag, Dhaka, during the period from 1st July 2008 to 30th June 2009. Fifty healthy Long-Evans Norwegian male rats aged between 3-4 months and weighing between 180-200gm were randomly selected and divided into 3 groups (A, B & C). Control group A (n=10) were fed on standard rat diet for 8 weeks, Vehicle fed group B (n=10) were fed soybean oil at a dose of 1ml once daily for 8 weeks and 2% cholesterol fed group C (n=30) wer...
Atherosclerosis, 2001
Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase are widely used in the treatment of dyslipemias and have shown beneficial effects in primary and secondary prevention of cardiovascular diseases. There is new information that seems to suggest that the beneficial effects observed may not be solely attributable to plasma cholesterol reduction. Our objective has been to evaluate the effect of two statins at similar dose, although unequivalent plasma lipid lowering potential, on vessel wall expression of two proteins involved in atherosclerotic lesion progression. We have studied the effects of treatment on vessel wall expression of monocyte chemotactic protein-1 (MCP-1) and the inducible form of nitric oxide synthase (NOS II). Atherosclerosis was induced in pigs by feeding a high cholesterol and saturated fatty acid diet for 50 days. Mild atherosclerotic lesions were found at this early stage of induction. Animals were simultaneously treated with atorvastatin (3 mg/kg/day), pravastatin (3 mg/kg/day) or placebo. Non-HDL-cholesterol levels induced by diet were reduced in the atorvastatin-treated group (63 9 8%, P = 0.03) and not as much in the pravastatin treated group (44 9 3, P= 0.08). The average MCP-1 expression in carotid, femoral and thoracic aorta was significantly reduced with both statins by 37% (PB 0.05), while NOS II expression was unaffected. Therefore, vascular MCP-1 expression was downregulated by statins regardless of their lipid lowering potential and lipo/hydrophilic characteristics. Early downregulation of MCP-1 could attenuate the inflammation within the vascular wall and prevent the development of atherosclerotic lesions.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2003
Objective-Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation. Methods and Results-Simvastatin, atorvastatin, and lovastatin (0.1 to 10 mol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-B) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay (EMSA). The inhibitory effects of statins on NF-B or AP-1-dependent transcriptional activity were examined by transient transfection studies. HMG-CoA reductase inhibitors upregulated IB-␣ protein levels in endothelial cells and decreased c-Jun mRNA expression in smooth muscle cells as analyzed by Western and Northern blotting, respectively. Furthermore, statins inhibited DNA binding of hypoxia-inducible factor-1␣. Downstream effects of statins included inhibition of plasminogen activator inhibitor-1 and vascular endothelial growth factor-A mRNA levels in endothelial cells. Conclusions-HMG-CoA reductase inhibitors downregulate the activation of transcription factors NF-B, AP-1, and hypoxia-inducible factor-1␣. These findings support the concept that statins have antiinflammatory and antiproliferative effects that are relevant in the treatment of atherosclerotic diseases. (Arterioscler Thromb Vasc Biol. 2003;23:58-63.)
Revista Espanola De Cardiologia, 2002
cently obtained evidence that cultured bovine endothelial cells contain cytosolic proteins that form complexes with the 3'-unstranslated region of endothelial nitric oxide synthase (eNOS) mRNA and are associated with its destabilization. The aim of this study was to determine the presence of such proteins and the level of eNOS expression in hypercholesterolemic rabbits as an in vivo model of endothelial dysfunction.
2016
The in vivo activity of different 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (vastatins) on neointimal formation induced by insertion of a flexible collar around one carotid artery of normocholesterolemic rabbits was investigated. The contralateral carotid artery served as a sham control. Pravastatin, lovastatin, simvastatin, and fluvastatin were given mixed with food at daily doses of 20 ing/kg body wt for 2 weeks starting on the day of collar placement. The treatment with vastatins did not modify rabbit plasma cholesterol concentrations. The neointimal formation was assessed by measuring the cross-sectional thickness of intimal and medial tissues of fixed arteries with light microscopy. Fourteen days after collar placement, intimal hyperplasia (mostly cellular) was pronounced in treated carotid arteries. The intimal/medial (I/M) tissue ratio was 12-fold higher in treated arteries than in arteries without the collar (0.36±0.04 versus 0.03±0.02). Animals tr...
HMG-CoA Reductase Inhibitors Decrease Angiotensin II–Induced Vascular Fibrosis
Hypertension, 2007
3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardiovascular diseases. Angiotensin II (Ang II) contributes to cardiovascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II–induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II–induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpres...
HMG-CoA Reductase Inhibition: Anti-Inflammatory Effects beyond Lipid Lowering?
European Journal of Cardiovascular Prevention & Rehabilitation, 2003
Atherosclerosis has many features of a chronic inflammatory disease. Atherosclerotic lesions contain inflammatory cells. Systemic markers of inflammation, such as white blood cells, C-reactive protein, serum amyloid A, interleukin-6, and soluble adhesion molecules are predictive of future cardiovascular events. Atherogenic lipoprotein particles, in particular modified low-density lipoproteins (LDL), elicit pro-inflammatory responses of cellular elements of the vessel wall, including endothelial dysfunction and activation of monocyte-derived macrophages. High-density lipoproteins (HDL) oppose these effects by inhibiting the oxidation of LDL, and by down-regulating the expression of adhesion molecules and selectins. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) has proven the most successful strategy to reduce the concentration of LDL in the circulation. These compounds lower LDL cholesterol by inhibiting the mevalonate pathway in the liver. Prospective clinical trials have convincingly demonstrated that HMG-CoA reductase inhibitors can effectively lower the incidence of cardiovascular events in primary and secondary prevention. Post hoc analyses of these trials suggest that the clinical benefit brought about by statins may not entirely be due to their effect on the levels of circulating lipoproteins. In vitro observations of anti-inflammatory actions of statins on vascular cells may contribute to explain effects beyond lipid lowering. It is, however, not clear whether these findings are relevant to the in vivo situation. Further investigation is now necessary in order to determine the relative significance of cholesterol lowering and of ancillary effects on the net clinical benefit of statin treatment. J Cardiovasc Risk 10:169-179 c 2003 Lippincott Williams & Wilkins.
HMG-CoA Reductase Inhibitors Inhibit Endothelial Exocytosis and Decrease Myocardial Infarct Size
2010
Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors protect the vasculature from inflammation and atherosclerosis by cholesterol dependent and cholesterol independent mechanisms. We hypothesized that HMG-CoA reductase inhibitors decrease exocytosis of Weibel-Palade bodies, endothelial cell granules whose contents promote thrombosis and vascular inflammation. We pretreated human aortic endothelial cells with simvastatin for 24 hours, then stimulated the cells with thrombin, and measured