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Preservation of Endothelial Function by the HMG-CoA Reductase Inhibitor Fluvastatin through Its Lipid-Lowering Independent Antioxidant Properties in Atherosclerotic RabbitsMitani H.a · Egashira K.b · Ohashi N.c · Yoshikawa M.c · Niwa S.a · Nonomura K.a · Nakashima A.a · Kimura M.a
aResearch Division, Tsukuba Research Institute, Novartis Pharma KK, Tsukuba, bDepartment of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, and cDepartment of Drug Metabolism and Pharmacokinetics, Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Tokyo, Japan
Recent evidence suggests that the beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on entothelial function and cardiovascular ischemic events may be attributed not only to their lipid-lowering effects but also to cholesterol-lowering independent (direct) effects on the atherosclerotic vessel wall. This study was designed to test the hypothesis that fluvastatin (Flu) preserves the endothelial function by its cholesterol-lowering independent actions. Rabbits were fed a 0.5% high-cholesterol (HC) diet for 12 weeks (progression phase) and then fed the HC diet either containing or not containing Flu 2 mg/kg/day for an additional 8 weeks (treatment phase). Rabbits fed a normal diet were used as controls. Plasma total and low-density lipoprotein cholesterol concentrations did not differ during the treatment phase: Endothelium-dependent/NO-mediated relaxation (acetylcholine and A23187) was impaired in the HC diet group, whereas it was preserved in the HC plus Flu treatment group. The endothelium-independent relaxation (sodium nitroprusside) was similar between the three groups. Interestingly, aortic oxidative stress (lipid peroxides and isoprostane F2α-III contents) and NADPH oxidase component (p22phox and gp91phox) mRNA expression were increased in the HC group but not in the HC plus Flu group. The A23187-induced nitric oxide production from the aorta was increased in both HC and HC plus Flu groups. There was no significant difference in tissue endothelial-type nitric oxide synthase mRNA expression. Plaque area and intimal thickening of the aorta were significantly lowered in the HC plus Flu group. Flu treatment preserved the endothelial function associated with the decrease in markers of oxidative stress in this experiment. These beneficial endothelial effects of Flu are likely to occur independently of plasma lipid concentrations and to be mediated by its antioxidant action.
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