虎杖苷抑制TGF-β/Smad/ERK信号通路挽救急性心肌梗死大鼠心肌纤维化

Polydatin attenuates acute myocardial infarction-induced myocardial fibrosis by inhibiting the TGF-β/Smad/ERK signaling pathway

探讨虎杖苷(polydatin,PD)抑制TGF-β/Smad/细胞外调节蛋白激酶(extracellular regulated protein kinase,ERK)通路对挽救急性心肌梗死(acute myocardial infarction,AMI)大鼠心肌纤维化的影响。随机将大鼠分为对照(control,Ct)组、模型(Model)组、低剂量PD组(PD-L,40 mg/kg)、高剂量PD组(PD-H,100 mg/kg)、卡托普利治疗组(captopril,CTP,20 mg/kg,阳性对照)及PD-H+TGF-β激动剂SRI-011381组(100 mg/kg+30 mg/kg)。除Ct组外其余各组均用左冠状动脉前降支结扎法构建AMI模型。通过小型动物心脏超声及Masson染色观察PD对大鼠心脏结构及功能的挽救效果;免疫组化法检测心肌组织中胶原蛋白的沉积情况;ELISA试剂盒检测血清中促炎细胞因子IL-6及TNF-α的分泌水平;Western blotting检测各组大鼠心肌组织中TGF-β1、p-Smad2/3及p-ERK1/2蛋白的表达情况。结果显示,与Ct组比较,Model组大鼠出现显著的心功能下降、心肌组织纤维化和全身性炎症反应(均P<0.05)。而PD治疗可以计量依赖性地改善AMI诱导的心肌纤维化和心功能下降,并能抑制炎性因子表达和TGF-β/Smad/ERK信号通路的异常激活(均P<0.05)。高剂量PD治疗效果与阳性对照药物卡托普利相当。同时给药SRI-011381(TGF-β激动剂)后可抑制PD对AMI诱导的心肌纤维化的挽救作用,大鼠心脏结构和功能再次显著恶化(均P<0.05)。由此,PD可能通过抑制TGF-β/Smad/ERK信号通路抑制心肌炎症浸润和逆转AMI大鼠模型心肌纤维化程度,促进受损心肌的修复。

The aim of this research was to investigate the pharmaceutical effect of polydatin(PD)on the amelioration of acute myocardial infarction(AMI)-induced myocardial fibrosis in rat model.To this end,SD rats were randomly divided into control group(Ct),model group(Model),low-dose PD treatment group(PD-L,40 mg/kg),high-dose PD treatment group(PD-H,100 mg/kg),captopril treatment group(CTP,20 mg/kg),and PD-H+TGF-βagonist group(100 mg/kg+30 mg/kg).AMI was induced by left anterior descending coronary artery ligation in all rats except those in the Ct group.Myocardial function and tissue structure were evaluated by animal ultrasound system and Masson staining of the heart.The collagen sedimentation in the myocardial tissue was evaluated by immunohistochemistry and the levels of IL-6 and TNF-αwere measured by ELISA kits.The protein expressions of TGF-β1,p-Smad2/3,and p-ERK1/2 were assessed by Western blotting.Compared to those in the Ct group,rats in the model group exhibited worse myocardial function with severe myocardial fibrosis and systematic inflammatory responses(all P<0.05).Notably,PD treatment significantly ameliorated AMI-induced myocardial injury in a dose-dependent manner,evidenced by improved myocardial function,less fibrotic collagen deposition,less inflammatory factors secretion along with the inhibition of the TGF-β/Smad/ERK signaling pathway(all P<0.05).Moreover,the therapeutic effect of high-dose PD was comparable to that of positive control captopril whereas SRI-011381(a type of TGF-βagonist)remarkedly abrogated the rescue effect of PD on the AMI-induced myocardial fibrosis.In conclusion,our study demonstrates that PD may relieve the degree of myocardial inflammatory infiltration and improve AMI-induced myocardial fibrosis in rats by inhibiting the TGF-β/Smad/ERK signaling pathway,which may promote damaged myocardium repairments.