普伐他汀对apoE缺陷小鼠主动脉粥样硬化及主动脉壁细胞间粘附分子-1表达的影响

Inhibitory effect of pravastatin on the pathogenesis of atherosclerotic lesions and the expression of intercellular adhesion molecule-1 in the aortic wall of apoE deficient mice

目的 观察普伐他汀对apoE缺陷小鼠主动脉粥样斑块形成及主动脉壁细胞间粘附分子 1(ICAM 1)表达的影响 ,以期探讨 3 羟 3 甲基戊二酰辅酶A(HMG CoA)还原酶抑制剂可能的调节血脂以外的抗动脉粥样硬化作用。 方法 选 10、2 0、30周龄雄性apoE缺陷小鼠各 8只 ,分为普伐他汀 (10mg·kg 1·d 1)和阳性对照 (等量生理盐水 )组 ,每组 10、2 0、30周龄小鼠各 4只 ,灌胃 4周 ,从主动脉血管根部连续横断切片 ,常规HE组织化学染色 ,计算机图像扫描 ,定量分析主动脉粥样硬化斑块的大小及斑块占管腔的面积 ;采用免疫组织化学及Western杂交方法测定主动脉壁ICAM 1表达。 结果 普伐他汀延缓斑块形成 ,与阳性对照组比较 ,普伐他汀组小鼠的主动脉粥样斑块面积〔分别为(16 1786 1± 380 4 1 2 ) μm2 与 (9912 7 9± 136 0 0 3) μm2 ,P <0 0 1〕 ,斑块占管腔面积 (分别为 4 1 8%与2 6 2 % ,P <0 0 1)明显缩小 ;普伐他汀有抑制apoE缺陷小鼠主动脉壁ICAM 1表达的作用 ,其中对 14和 2 4周龄小鼠主动脉壁ICAM 1表达的抑制作用强于 34周龄小鼠 (抑制率分别为 38 1%、31 1%、18 8% )。 结论 普伐他汀明显下调主动脉壁ICAM 1表达 ,并抑制或延缓apoE缺陷小鼠主动脉粥样斑块的形成 ,其效果与降胆固醇作用不成比例 。

Objective In order to understand the mechanisms beyond lipid regulation of 3 hydroxy 3 methyl glutaryl coenzyme A(HMG CoA) reductase inhibitors in anti atherosclerosis, we observed the influence of pravastatin on the pathogenesis of atherosclerotic lesions and the expression of intercellular adhesion molecule (ICAM) 1 in aortic wall of the apoE deficient mice. Methods Pravastatin(10 mg·kg·d -1 ) was fed to 10 , 20 , and 30 week old male apoE deficient mice respectively for 4 weeks. The atherosclerotic plaque size and the ratio of plaque area to aortic luminal area (PA/LA) were determined by histochemical staining and analyzed quantitatively. The expression of ICAM 1 in aortic wall of apoE deficient mice was detected by immunohistochemistry and Western blotting. Results Compared with controls, pravastatin delayed the plaque formation in apoE deficient mice 〔(161 786 1±38 041 2) μm 2 vs (99 127 9±13 600 3) μm 2, P <0 01〕 and diminished the plaque size (41 8% vs 26 2%, P <0 01). The inhibition of the ICAM 1 expression by pravastatin in 14 and 24 week old mice was slightly stronger than that in 34 week old mice(inhibitory rates were 38 1%, 31 1%, and 18 8% respectively). Conclusions The inhibitory effect of pravastatin on the pathogenesis of atherosclerotic lesions may crucially contribute to the clinical benefits of HMG CoA reductase inhibitors on coronary artery disease. The downregulation of pravastatin on the ICAM 1 expression in aortic wall of apoE deficient mice which was inconsistent with its cholesterol lowering effect may play an important role in the reduction of ICAM 1 dependent monocytes adhesion to endothelium and reflect a new mechanism of statins on the anti atherosclerosis. This might be independent of lipid regulation mechanism.