Effects Of Simvastatin On Early Oxidative Stress And Caveolin-1 In Apolipoprotein E-Deficient Mice

Objective: To investigate the mechanisms by which Simvastatin, one kind of 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitor, plays an important role in primary prevention of atherosclerosis independently of its lipid-lowering effect in Apolipoprotein E -deficient mice in the early stage of atherosclerosis. Methods : Twenty-four 6-week old male apoE-deficient mice were randomly divided into two groups: control group(normal saline) and treatment group(simvastatin (5 mg/(kg.d)). Simvastatin was administered to treatment group mice by gavage and the same volume of normal saline was administered to control group mice by the same method for 4 weeks. Total cholesterol (TC), super-oxide dismutase (SOD), malondialdehyde (MDA) and serum nitric oxide (NO) were measured by spectrophotometer analysis. Endothelium tissue was observed by HE dyeing; The expression of caveolin-1 in aortic wall was detected by immunohistochemistry. Results: There was no significant difference in serum TC (U.8963±0.2036 mmol/L vs control's :10.8014±2.0984 mmol/L,P >0.05, at 4-week) between control and treatment groups. Compared with the control's, the effects of simvastatin were more significant in decreasing serum MDA level(10.5641±0.5941 nmol/l vs control's: 17.3846±1.0562 nmol/l,P<0.01,at 4-week), increasing serum SOD level (135.3897±5.5664 u/l vs control's : 97.2866±7.6414 u/l,P<0.01 , at 4-week) and NO level (28.4946±4.1529 umol/l vs control's: 12.3656±2.1816 umol/1, P <0.01 , at 4-week)at 4 weeks. More damaged endothelium was discovered in control group than simvastatin treatment group(33.33%vs control's :75.00%, P <0.05 ,at 4-week). Expression of caveolin-1 was significantly inhibited in the simvastatin treatment group(41.67%vs control's: 83.33%, P <0.05, at 4-week) than in control group. Conclusions: Simvastatin attenuates oxidative stress and protects endothelial function by the mechanisms of downregulating of caveolin-1 expression , decreasing serum MDA level in aortic wall , increasing serum SOD level and NO level, which were inconsistent with its cholesterol-lowering effect. It may play an important role in primary prevention of atherosclerosis and might be independent of lipid-regulation mechanism , if not all.