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

目的：编码脂肪酸转运蛋白的CD36基因突变在自发性高血压病(SHR)胰岛素抵抗中有报道。他汀类药物可降低循环中的胆固醇和甘油三酯浓度。本研究的目的是探讨CD36在胰岛素抵抗综合征中的作用及他汀类药物治疗的意义。方法：采用胰岛素抵抗和血脂异常大鼠模型和正常对照组(Long Evans Tokushima Otsuka；Leto)大鼠，测定经乙酰胆碱或卵磷脂超氧化物歧化酶(OLETF)诱导的主动脉等长松弛作用。此外，我们还观察了西立伐他汀对主动脉CD36和PPARγ表达的影响。结果：OLETF患者对乙酰胆碱和卵磷脂引起的松弛作用减弱，小剂量西立伐他汀可恢复松弛作用，但对血清胆固醇无明显影响。大剂量的西立伐他汀显著降低了血清胆固醇和甘油三酯，也恢复了这些症状。西立伐他汀可增加LETO和OLETF大鼠主动脉CD36和PRARγ基因的表达。然而，OLETF大鼠CD36mRNA的基础水平和对西立伐他汀的反应增加显著低于LETO大鼠。虽然在OLETF中未发现SHR报告的CD36基因异常，但D4Rat151和D4Rat115的微卫星标记在OLETF和LETO大鼠中存在差异。结论：OLETF大鼠的胰岛素抵抗可能部分是由于CD36表达改变所致。西立伐他汀对主动脉CD36表达的增加可以解释他汀类药物降低血清甘油三酯浓度的原因，并可能在胰岛素抵抗综合征中具有显著的有益效果。

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.