瑞舒伐他汀对LDL受体基因缺陷小鼠MMP-2表达和粥样斑块形成的抑制作用

摘要

目的 观察瑞舒伐他汀对LDL受体基因缺陷(LDLR-/-)小鼠MMP-2的表达及动脉粥样斑块进展的影响及其作用机制.方法 以高脂+高胆固醇饲料喂养建立高脂血症及动脉粥样硬化模型,16只7周龄小鼠随机分为瑞舒伐他汀组和对照组,每组8只.12周后处死小鼠,观察主动脉大体标本,检测主动脉窦部动脉粥样硬化斑块情况;H&E染色观察主动脉窦部切片动脉粥样硬化斑块面积;检测血脂、oxLDL、血糖和胰岛素水平;明胶酶谱法检测主动脉弓处基质金属蛋白酶-2、9(MMP-2、9)的活性;免疫组化染色检测主动脉窦部MMP-2的表达情况.结果 除HDL-C外,瑞舒伐他汀组其他各血脂指标与对照组的差异均有统计学意义(P＜0.05或0.01).大体标本可见,瑞舒伐他汀组的粥样硬化斑块面积较对照组减少了约80%.主动脉窦切片H&E染色观察可见,瑞舒伐他汀组动脉粥样硬化面积较对照组减少了约74.1%.免疫组化检测结果示,瑞舒伐他汀组MMP-2的表达较对照组减少了45.9%.Zymography法检测结果示,与对照组比较,瑞舒伐他汀组MMP-2表达减少了42.3%,MMP-9表达减少了35.3%.结论 瑞舒伐他汀能够抑制LDLR-/-小鼠MMP-2、9的表达并改善动脉粥样硬化斑块的进展,这可能是瑞舒伐他汀能够干预动脉粥样硬化进展的机制之一.%Objective To investigate the effects of rosuvastatin on atherosclerosis and the expression of Matrix metalloproteinase- 2 (MMP- 2) in LDLR- deficient (LDLR-/-) mice.Methods Seven weeks old LDLR-/- mice (n=16) were fed on a high- fat and high- cholesterol diet to developed hyperlipoidemia and atherosclerosis.They were randomly divided into rosuvastatin group (n=8), control group (n=8).After 12 weeks they were sacrificed.The atherosclerosis lesion area in aorta artery and aortic sinus was examined.The levels of plasma lipid, glucose and insulin were measured, as well as the expression of MMP- 2 and MMP- 9 in the atherosclerosis plaques.Results Versus control group, except for HDL- C, the levels of plasma TC, TG, LDL- C, oxLDL in the rosuvastatin group were decreased significantly (P＜0.05 or 0.01).Compared to the control group, rosuvastatin reduced the atherosclerosis lesion area by 80％, and rosuvastatin reduced the lesion area by 74.1％ in the aortic sinus.The production of MMP- 2 in the aortic sinus through immunohistochemical method was reduced 45.9％ in rosuvastatin group.The activation of MMP- 2 and MMP- 9 in aorta arch with gelatin zymography was reduced 42.3 ％and 35.3 ％ in rosuvastatin group.Conclusion Rosuvastatin inhibits the expression of MMP- 2/- 9 and improves the progression of atherosclerosis in LDLR-/- mice.This may be one of the pathways of rosuvastatin on atherosclerosis, through which that rosuvastatin induced its benefit to the therapy of coronary heart disease.