心阴片激活 SIRT1 抑制内皮间质转化改善慢性心力衰竭大鼠心肌纤维化的作用及机制OA

Objective To investigate the effect and mechanism of Xinyin Tablets(XYT)in ameliorating myocardial fibrosis in rats with chronic heart failure(CHF)by activating sirtuin 1(SIRT1)to inhibit endothelial-mesenchymal transition(EndMT).Methods A pressure overload-induced CHF rat model was established by transverse aortic constriction.Sixty SD rats were randomly divided into six groups(n=10 per group):sham-operated group,model group,low-dose XYT group(0.315 g·kg-1),medium-dose XYT group(0.63 g·kg-1),high-dose XYT group(1.26 g·kg-1),and EX527 group(1.26 g·kg-1 XYT+5 mg·kg-1 EX527,a SIRT1 inhibitor).Drugs were administered daily by gavage for 8 consecutive weeks.Echocardiography was used to assess cardiac function,including left ventricular ejection fraction(LVEF),fractional shortening(LVFS),left ventricular internal dimension at end-diastole(LVIDd),and left ventricular internal dimension at end-systole(LVIDs).Myocardial pathological changes were observed via HE and Masson staining,and the relative collagen fiber area was calculated.The expression levels of related proteins and genes in myocardial tissue were detected by Western Blot and qRT-PCR,respectively.Results Compared with the sham-operated group,the model group showed significantly decreased LVEF and LVFS(P＜0.05),and increased LVIDd and LVIDs(P＜0.05).Myocardial cells were enlarged with significant inflammatory cell infiltration,disorganized myofibrils,increased collagen deposition,and a significantly elevated relative collagen fiber area(P＜0.05).Protein expression of Collagen Ⅰ and Collagen Ⅲ was increased(P＜0.05),while SIRT1,CD31,and VE-cadherin protein expression was downregulated(P＜0.05).Protein expression of α-SMA,FSP1,TGF-β1,and p-Smad2/3 was upregulated(P＜0.05).mRNA expression of SIRT1 and VE-cadherin was downregulated(P＜0.05),while α-SMA,TGF-β1,and Smad2/3 mRNA expression was upregulated(P＜0.05).Compared with the model group,the medium-and high-dose XYT groups exhibited significantly increased LVEF and LVFS(P＜0.05),upregulated protein expression of CD31 and VE-cadherin(P＜0.05),and downregulated protein expression of α-SMA and FSP1(P＜0.05).All XYT dose groups showed significantly decreased LVIDd and LVIDs(P＜0.05),reduced myocardial cell size,alleviated inflammatory infiltration,decreased collagen deposition,and a significantly reduced relative collagen fiber area(P＜0.05).Protein expression of Collagen I and Collagen Ⅲ was decreased(P＜0.05),SIRT1 expression was upregulated(P＜0.05),and TGF-β1 and p-Smad2/3 expression was downregulated(P＜0.05).mRNA expression of SIRT1 and VE-cadherin was upregulated(P＜0.05),while α-SMA,TGF-β1,and Smad2/3 mRNA expression was downregulated(P＜0.05).No significant changes were observed in cardiac function,myocardial histopathological changes and other detected indicators in the EX527 group compared with the model group(P＞0.05).Conclusion XYT can effectively prevent and treat myocardial fibrosis and significantly improve cardiac function in rats with CHF.Its mechanism may involve activating SIRT1 to regulate the TGF-β1/Smad2/3 signaling pathway,thereby inhibiting EndMT.