二甲双胍对血管紧张素Ⅱ诱导的小鼠腹主动脉瘤形成的影响

Effects of metformin on angiotensin Ⅱ-induced abdominal aortic aneurysm in mice

目的观察二甲双胍对血管紧张素Ⅱ诱导的小鼠腹主动脉瘤(AAA)形成的影响。方法用皮下埋植血管紧张素Ⅱ(AngⅡ)缓释泵1000 ng·min^-1·kg^-1构建AAA模型。按照体重将小鼠分为4组:正常组、模型组、硼替佐米组和二甲双胍组,每组5只。造模后第1天开始,硼替佐米组每天给予硼替佐米50 mg·kg^-1灌胃,二甲双胍组每天给予二甲双胍50 mg·kg-1灌胃,正常组和模型组给予等体积的0.9%NaCl灌胃,连续用药4周。用全自动生化分析仪酶法测定血清总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)含量;用免疫印迹法检测腹主动脉组织中腺苷酸激活蛋白激酶(AMPK)和西罗莫司靶蛋白(mTOR)蛋白相对表达水平。结果正常组、模型组、硼替佐米组和二甲双胍组TC分别为(14.23±1.32),(17.29±1.52),(15.64±1.29)和(15.09±1.24)mmol·L^-1;这4组的TG分别为(1.64±0.14),(1.95±0.15),(1.79±0.12)和(1.76±0.13)mmol·L^-1;这4组的HDL-C分别为(14.68±0.34),(19.21±0.43),(15.71±0.53)和(15.82±0.51)mmol·L^-1;这4组的LDL-C分别为(0.39±0.05),(0.24±0.03),(0.36±0.06)和(0.35±0.04)mmol·L^-1;这4组的AMPK相对表达量分别为1.02±0.11,2.84±0.34,1.37±0.21和1.34±0.19;这4组的mTOR相对表达量分别为1.05±0.12,2.81±0.32,1.48±0.19和1.45±0.15。上述指标:模型组与正常组比较,差异均有统计学意义(均P<0.05);硼替佐米组和二甲双胍组与模型组比较,差异均有统计学意义(均P<0.05)。结论二甲双胍可以保护血管紧张素Ⅱ诱导的小鼠AAA的形成,其机制可能是通过AMPK/mTOR信号通路来完成的。

Objective To observe the effect of metformin on the formation of abdominal aortic aneurysm(AAA)induced by angiotensinⅡin mice.Methods AngiotensinⅡ(AngⅡ)was implanted subcutaneously.A sustained-release pump of 1000 ng·min^-1·kg^-1 was used to construct AAA model.Mice were randomly divided into four groups according to body weight:normal group,model group,bortezomib group and metformin group.There were 5 rats in each group.From the first day after the model was established,bortezomib group was given 50 mg·kg^-1 bortezomib orally every day,and metformin group was given daily 50 mg·kg^-1 metformin was given to the stomach,and the normal group and model group were given the same volume of normal saline for 4 weeks.The total cholesterol(TC),triglyceride(TG),high density lipoprotein-cholesterol(HDL-C),low density lipoprotein-cholesterol(LDL-C)content in serum were determined by enzymatic method with automatic biochemical analyzer.The relative protein expression of the adenosine 5’-monophosphate-activated protein kinase(AMPK)and rapamycin target protein(mTOR)in abdominal aortic tissue were detected by Western blot.Results TC in normal group,model group,bortezomib group and metformin group were(14.23±1.32),(17.29±1.52),(15.64±1.29),(15.09±1.24)mmol·L^-1,respectively;TG in the four groups were(1.64±0.14),(1.95±0.15),(1.79±0.12),(1.76±0.13)mmol·L^-1,respectively;HDL-C in the four groups were(14.68±0.34),(19.21±0.43),(15.71±0.53),(15.82±0.51)mmol·L^-1,respectively;LDL-C in the four groups were(0.39±0.05),(0.24±0.03),(0.36±0.06),(0.35±0.04)mmol·L^-1,respectively;the relative expressions of AMPK protein in the four groups were 1.02±0.11,2.84±0.34,1.37±0.21 and 1.34±0.19,respectively;the relative expressions of mTOR protein in the four groups were 1.05±0.12,2.81±0.32,1.48±0.19 and 1.45±0.15,respectively.Comparison between model group and normal group,the difference of the factors were statistically significant(all P<0.05);comparison between bortezomib group,metformin group and model group,the difference of the factors were statistically significant(all P<0.05).Conclusion Metformin could protect the formation of abdominal aortic aneurysm induced by angiotensin Ⅱ in mice,and its mechanism might be through AMPK/mTOR signaling pathway.