Wang Yi Xin, Martin-McNulty Baby, Huw Ling Yuh, da Cunha Valdeci, Post Joe, Hinchman Josephine, Vergona Ronald, Sullivan Mark E, Dole William, Kauser Katalin
Department of Pharmacology, Berlex Biosciences, P.O. Box 4099, 15049 San Pablo Avenue 15049 San Pablo Avenue, Richmond, CA 94804-0099, USA.
Atherosclerosis. 2002 May;162(1):23-31. doi: 10.1016/s0021-9150(01)00678-5.
Low density lipoprotein receptor deficient (LDLR-KO) and apolipoprotein E deficient (apo E-KO) mice both develop hyperlipidemia and atherosclerosis by different mechanisms. The aim of the present study was to compare the effects of simvastatin on cholesterol levels, endothelial dysfunction, and aortic lesions in these two models of experimental atherosclerosis. Male LDLR-KO mice fed a high cholesterol (HC; 1%) diet developed atherosclerosis at 8 months of age with hypercholesterolemia. The addition of simvastatin (300 mg/kg daily) to the HC diet for 2 more months lowered total cholesterol levels by approximately 57% and reduced aortic plaque area by approximately 15% compared with the LDLR-KO mice continued on HC diet alone, P<0.05. Simvastatin treatment also improved acetylcholine (ACh)-induced endothelium-dependent vasorelaxation in isolated aortic rings, which was associated with an increase in NOS-3 expression by approximately 88% in the aorta measured by real time polymerase chain reaction (PCR), P<0.05. In contrast, in age-matched male apo E-KO mice fed a normal diet, the same treatment of simvastatin elevated serum total cholesterol by approximately 35%, increased aortic plaque area by approximately 15%, and had no effect on endothelial function. These results suggest that the therapeutic effects of simvastatin may depend on the presence of a functional apolipoprotein E.
低密度脂蛋白受体缺陷（LDLR-KO）小鼠和载脂蛋白E缺陷（apo E-KO）小鼠均通过不同机制发生高脂血症和动脉粥样硬化。本研究的目的是比较辛伐他汀对这两种实验性动脉粥样硬化模型中胆固醇水平、内皮功能障碍和主动脉病变的影响。喂食高胆固醇（HC；1%）饮食的雄性LDLR-KO小鼠在8个月大时出现动脉粥样硬化并伴有高胆固醇血症。在HC饮食中再添加辛伐他汀（每日300 mg/kg）2个月，与仅继续喂食HC饮食的LDLR-KO小鼠相比，总胆固醇水平降低了约57%，主动脉斑块面积减少了约15%，P<0.05。辛伐他汀治疗还改善了离体主动脉环中乙酰胆碱（ACh）诱导的内皮依赖性血管舒张，通过实时聚合酶链反应（PCR）测量，这与主动脉中一氧化氮合酶3（NOS-3）表达增加约88%相关，P<0.05。相比之下，在喂食正常饮食的年龄匹配雄性apo E-KO小鼠中，相同的辛伐他汀治疗使血清总胆固醇升高了约35%，主动脉斑块面积增加了约15%，并且对内皮功能没有影响。这些结果表明，辛伐他汀的治疗效果可能取决于功能性载脂蛋白E的存在。
