沙库巴曲缬沙坦灌胃对糖尿病大鼠心肌纤维化的治疗作用及其机制

Therapeutic effect and mechanism of Sac/Val on myocardial fibrosis in diabetic rats

目的 观察沙库巴曲缬沙坦(Sac/Val)灌胃治疗糖尿病大鼠心肌纤维化的疗效,并探讨其可能的作用机制。方法 雄性Wistar大鼠20只,随机分为正常对照组、模型组、实验组、培哚普利组,每组5只。模型组、实验组、培哚普利组注射链脲佐菌素制作糖尿病模型,模型组造模后给予生理盐水(每天1 mL/100 g)灌胃,实验组造模后给予Sac/Val 60 mg/(kg·d)灌胃,培哚普利组造模后给予培哚普利2 mg/(kg·d)灌胃;正常对照组不进行造模,予生理盐水(每天1 mL/100 g)灌胃。各组大鼠灌胃8周后,测算左心室/体质量指数(LVW/BW),行Masson染色观察心肌纤维化情况,采用Western blotting法检测各组大鼠心肌组织中的转化生长因子β_(1)(TGF-β_(1))、phos-Smad3、ColⅠ、ColⅢ蛋白。结果 与正常对照组相比,模型组心肌细胞排列紊乱,胶原纤维含量增加;与模型组相比,实验组和培哚普利组心肌胶原纤维减少,纤维化程度减轻。模型组LVW/BW及心肌组织ColⅠ、ColⅢ、TGF-β_(1)、phos-Smad3蛋白表达高于正常对照组,实验组、培哚普利组LVW/BW及心肌组织ColⅠ、ColⅢ、TGF-β_(1)、phos-Smad3蛋白表达低于模型组(P均<0.01)。结论 Sac/Val可减轻糖尿病大鼠心肌纤维化,其机制可能与抑制TGF-β_(1)/Smad3信号通路有关。

Objective To observe the therapeutic effect of intragastric administration of sacubitril/valsartan(Sac/Val) on myocardial fibrosis in diabetic rats and to explore its potential mechanism of action.Methods Twenty male Wistar rats were randomly divided into the normal control group,model group,experimental group and perindopril group,with 5 rats in each group.Diabetic rat models were induced by injection of streptozotocin in the model group,experimental group and perindopril group.After modeling,the rats in the model group were given normal saline(1 mL/100 g per day) by gavage.Rats in the experimental group were given Sac/Val 60 mg/(kg·d) by gavage.Rats in the perindopril group were given perindopril 2 mg/(kg·d) by gavage.Rats in the normal control group did not undergo modeling and were given normal saline(1 mL/100 g per day) by gavage.After 8 weeks,the left ventricular weight/body weight(LVW/BW) ratio was measured.Masson staining was performed to evaluate the myocardial fibrosis.Western blotting was used to detect the expression levels of transforming growth factor-β_(1)(TGF-β_(1)),phos-Smad3,collagen I and collagen Ⅲ proteins in the myocardial tissues of each group.Results Compared with the normal control group,the myocardial cells were in disorder and the content of collagen fibers increased in the model group.Compared with the model group,the myocardial collagen fibers decreased and the myocardial fibrosis was alleviated in the experimental group and perindopril group.The LVW/BW ratio and expression levels of collagen Ⅰ,collagen Ⅲ,TGF-β_(1) and phos-Smad3 proteins in the model group were higher than those of the normal control group.Compared with the model group,the LVW/BW ratio and expression levels of collagen Ⅰ,collagen Ⅲ,TGF-β_(1) and phos-Smad3 proteins decreased significantly in the experimental group and perindopril group(all P<0.01).Conclusion Sac/Val can alleviate myocardial fibrosis in diabetic rats and the mechanism may be related to the inhibition of TGF-β_(1)/Smad3 signaling pathway.