二甲双胍对心肌纤维化模型大鼠的影响

Effect of Metformin on Myocardial Firbosis in Model Rats

目的观察二甲双胍对异丙肾上腺素诱导心肌纤维化模型大鼠的影响及作用机制。方法将48只雄性SD大鼠随机分为空白对照组、模型对照组、缬沙坦组及二甲双胍组,每组12只。模型对照组、缬沙坦组及二甲双胍组大鼠背部皮下注射异丙肾上腺素溶液,qd,首日10 mg·kg^(-1),次日5 mg·kg^(-1),第3—10天3 mg·kg^(-1)。二甲双胍组于第2天开始给予二甲双胍100 mg·kg^(-1)灌胃,bid;缬沙坦组于第2天开始给予缬沙坦10 mg·kg^(-1)灌胃,qd。均连续28 d。分别于给药第3天、第7天、第14天、第28天处死大鼠,测量并计算心脏质量指数(HMI)、左室质量指数(LVMI)、左室质量/胫骨长度(LVW/TL)等指标;苏木精-伊红(HE)染色、Masson染色、Western blotting法测定左室心肌转化生长因子-β(TGF-β)、Smad3蛋白表达,ELISA法测定大鼠血清白细胞介素-6(IL-6)水平。结果与空白对照组比较,模型对照组大鼠各时间点HMI、LVMI、LVW/TL均显著升高(P<0.01);与模型对照组比较,二甲双胍组各时间点上述指标均显著降低(P<0.01)。与空白对照组比较,模型对照组大鼠各时间点左室TGF-β、Smad3蛋白表达显著升高(P<0.01);与模型对照组比较,二甲双胍组各时间点上述指标显著降低(P<0.05)。第28天空白对照组血清IL-6含量(59.18±0.86) pg·mL^(-1),模型对照组(71.90±1.35) pg·mL^(-1),缬沙坦组(64.33±2.59) pg·mL^(-1),二甲双胍组(65.45±1.92) pg·mL^(-1),与空白组对照组比较,模型对照组血清IL-6含量显著升高(P<0.01),与模型对照组比较,二甲双胍组血清IL-6含量显著降低(P<0.05)。结论二甲双胍可能通过TGF-β/Smads信号通路发挥抑制心肌纤维化的作用。

Objective To investigate the effects of metformin on myocardial fibrosis induced by isoproterenol（ISO） in rats and its mechanism.Methods A total of 48 SD male rats were randomly divided into four groups,normal control group,model control group,valsartan group and metformin group.Cardiac fibrosis models were induced in model group,Valsartan group and metformin group by subcutaneous injection of ISO 10 mg·kg -1 ·d -1 in the 1 st day,5 mg·kg -1 ·d -1 in the 2 nd day, 3 mg·kg -1 ·d -1 in the 3 rd -10 th day.Valsartan group and metformin group were fed valsartan 10 mg·kg -1 ,qd or metformin 100 mg·kg -1 ,bid for 28 days respectively.Rats were killed at the 3 rd day,the 7 th day,the 14 th day and the 28 th day.The value of HMI,LVMI,LVW/TL were measured,and pathological alteration were observed by HE staining and Masson staining,TGF-β and Smad3 protein expression in left ventricular myocardium were detected by western blotting,and IL-6 level in serum were detected by ELISA.Results The serum levels of IL-6 in control group, model group, valsartan group and metformin group were （ 59.18± 0.86 ） pg·mL -1 , （71.90±1.35） pg·mL -1 , （64.33±2.59） pg·mL -1 and （65.45±1.92） pg·mL -1 respectively on the 28th day.Compared with control group, the serum levels of IL-6 in model group were significantly increased（ P 〈0.01）, while their levels significantly reduced in rats received metformin （ P 〈0.05）.Conclusion Metformin may inhibit myocardial firbosis by TGF-β/Smads pathway.