托伐普坦联合达格列净对心衰大鼠心肌纤维化的影响

doi:10.6040/j.issn.1671-7554.0.2022.0564

摘要/Abstract

摘要： 目的探讨托伐普坦(TLV)和达格列净(DAPA)对慢性心力衰竭大鼠心肌纤维化及转化生长因子β1(TGF-β1)表达的影响。方法将雄性Wistar大鼠随机分为空白对照组、模型对照组、TLV-L组、TLV-H组、DAPA组和TLV-H+DAPA组。除空白对照组外,其他各组大鼠均给予腹腔注射阿霉素3 mg/kg,1次/周,6周造模,心脏彩超检查射血分数<60%提示心衰大鼠造模成功,随机分组后药物干预30 d。采用苏木精-伊红染色法观察大鼠心脏组织形态学变化,采用Masson染色法检测心肌纤维化程度,并计算胶原容积分数(CVF);采用TUNEL染色法检测心肌细胞凋亡指数;采用Western blotting法检测各组大鼠左心室心肌组织中TGF-β1、磷酸化Smad2(p-Smad2)及磷酸化Smad3(p-Smad3)的蛋白水平。结果与空白对照组相比,模型对照组心肌纤维排列紊乱,较多炎性细胞浸润,心肌纤维化显著,细胞凋亡增加,TGF-β1蛋白表达显著升高,p-Smad2和p-Smad3蛋白水平下降(P<0.05);与模型对照组相比,TLV组、DAPA组及TLV-H+DAPA组心肌纤维化程度明显降低,心肌凋亡指数明显降低,差异有统计学意义(P<0.05),TGF-β1蛋白表达明显降低;p-Smad2和p-Smad3蛋白水平明显升高(P<0.05)。结论 TLV与DAPA单用及联合应用均可通过抑制TGF-β1/Smad2/3信号通路发挥抑制心肌纤维化的作用,且联合用药的效果优于单独用药。

关键词: 托伐普坦, 达格列净, 心力衰竭, 心肌纤维化, 转化生长因子β1

Abstract: Objective To assess the effects of tolvaptan(TLV)and dapagliflozin(DAPA)alone and in combination on the myocardial fibrosis and transforming growth factor-β1(TGF-β1)expression in rats with chronic heart failure. Methods Male Wistar rats were randomly divided into control group, model group, TLV-L group, TLV-H group, DAPA group and TLV-H+DAPA group. Except for the control group, rats in the other groups were given intraperitoneal injection of adriamycin 3 mg/kg once a week for 6 weeks for modeling. After cardiac ultrasound examination of EF<60% indicated successful modeling of heart failure, the rats were randomized into groups and received pharmacological intervention for 30 days. The morphological changes of heart tissue were observed with hematoxylin-eosin(HE)staining; the degree of myocardial fibrosis was detected with Masson staining; the collagen volume fraction(CVF)was calculated; the apoptotic index of myocardial cells was detected with TUNEL staining; the protein expressions of TGF-β1, p-Smad2 and p-Smad3 in the left ventricular myocardial tissue were detected with Western blotting. Results Compared with the control group, the model group showed disordered arrangement of myocardial fibers, more infiltrated inflammatory cells, significant myocardial fibrosis, increased apoptosis, significantly higher protein expression of TGF-β1, and decreased protein expressions of p-Smad2 and p-Smad3(P<0.05). Compared with the model group, the TLV group, DAPA group and TLV-H+DAPA group had significantly reduced myocardial fibrosis and myocardial apoptosis index(P<0.05), significantly reduced protein expression of TGF-β1, and significantly increased protein expressions of p-Smad2 and p-Smad3(P<0.05). Conclusion TLV and DAPA alone and in combination can inhibit myocardial fibrosis by inhibiting the TGF-β1/Smad2/3 signaling pathway, and the effect of combined use is better than that of single drug.

Key words: Tolvaptan, Dapagliflozin, Chronic heart failure, Myocardial fibrosis, Transforming growth factor-β1

中图分类号:

R542.2

高燕,朱庆颖,栾明亚,刘科卫. 托伐普坦联合达格列净对心衰大鼠心肌纤维化的影响[J]. 山东大学学报 (医学版), 2022, 60(12): 13-18.

GAO Yan, ZHU Qingying, LUAN Mingya, LIU Kewei. Effects of tolvaptan combined with dapagliflozin on myocardial fibrosis in rats with heart failure[J]. Journal of Shandong University (Health Sciences), 2022, 60(12): 13-18.

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