Hereditary Abnormalities of Multiple Risk Factors for Atherosclerosis ; Role of Endothelial Dysfunction and Aortic CD36 Expression in Diabetic Hyperlipidemic Rats

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Objective : A mutation of the CD 36 gene that encodes a fatty acid transporter has been reported in insulin resistance in SHR. Statins reduce circulating cholesterol and triglyceride concentrations. The objective of this study is to determine the role of CD36 and the significance of statin therapy in insulin resistance syndromes.Methods : We determined the isometric relaxation induced by acetylcholine or lecithinized superoxide dismutase (SOD) in aortas obtained from the Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of insulin resistance and dyslipidemia, and normal control (Long Evans Tokushima Otsuka ; LETO) rats with or without cerivastatin treatment. We also determined the effect of cerivastatin on aortic expression of CD36 and PPARγ. The CD36 genotype and microsatellite markers on chromosome 4 were also determined.Results : The relaxation induced by acetylcholine and lecithinized SOD were attenuated in OLETF but restored by low dose of cerivastatin without significant changes in serum cholesterol. Those were also restored by high dose of cerivastatin with significant reductions in serum cholesterol and triglyceride. Cerivastatin increased aortic expression of CD36 and PRARγ mRNA in both LETO and OLETF rats. However, the basal level of CD36 mRNA and the increase in CD36 mRNA in response to cerivastatin were significantly lower in OLETF rats than in LETO rats. Although the abnormal CD36 genotype reported in SHR was not found in OLETF, the microsatellite markers of D4Rat151 and D4Rat115 differed between OLETF and LETO rats.Conclusions : Insulin resistance in OLETF rats may be partially due to an altered expression of CD36. Increased aortic expression of CD36 in response to cerivastatin could explain the reduction in serum triglyceride concentrations with statin therapy and may have the pronounced beneficial effects in insulin resistance syndromes.