Exploring the anti-myocardial fibrosis mechanism of Sacubitril/Valsartanin heart failure with preserved ejection fraction based on MicroRNA21-5p targeting Smad7
OBJECTIVE To explore the anti-myocardial fibrosis mechanism of sacubitril/valsartan(LCZ696)in heart fail-ure with preserved ejection fraction(HFpEF)based upon MicroRNA21-5p(miRNA21)targeting Smad7.METHODS Ten Wistar Kyoto(WKY)rats and 10 spontaneously hypertensive rats(SHR)served as controls.Twenty SHR rats were equally divided into HFpEF and LCZ696 groups.High-fat/salt/sugar diets and intraperitoneal injections of streptozotocin were utilized for establishing a rat model of HFpEF.After successful modeling,intervention group received LCZ696(18 mg·kg-1·d-1)for 6 weeks.At the end of treatment period,echocardiography was performed for measuring the parameters of left ventricular end-diastolic internal diameter(LVEDd),anterior wall thickness(LVAWd),posterior wall thickness(LVPWd),ejection fraction(LVEF),isovolumetric diastolic time(IVRT)and peak early diastolic passive filling velocity(E)/early diastolic mitral annular velocity(e).Speckle tracking echocardiography was conducted for determining global longitudinal strain(GLS)and strain rate(GLSr).Enzyme-linked immunosorbent assay(ELISA)was employed for quantifying the serum levels of atrial natriuretic pep-tide(ANP),B-type brain natriuretic peptide(BNP)and Galectin-3(Gal-3).Myocardium was subjected to Masson stain for myocardial fibrosis and collagen volume fraction(CVF)and perivascular fibrosis ratio(PFR)were calculated.And quantitative polymerase chain reaction(qPCR)and Western blot(WB)were utilized for detecting the expressions of target genes and proteins in LV myocardium.RESULTS As compared with control group,HFpEF group showed significantly higher values of LVEDd,LVAWd,LVPWd,IVRT,E/e',absolute values of GLS,GLSr,ANP,BNP,Gal-3,CVF and PFR(P＜0.01);up-regulated expression of miRNA21,mRNA/protein expressions of α-SMA,Coll Ⅰ,Coll Ⅲ,Smad2 and Smad3(P＜0.01);down-regulated mRNA/protein xpression of Smad7(P＜0.01).As compared with HFpEF group,LVEDd,LVAWd,LVPWd,E/e',absolute values of GLS,GLSr,ANP,BNP,Gal-3,CVF and PFR dropped markedly in LCZ696 group(P＜0.05 or 0.01);miRNA21,mRNA expressions of α-SMA,Coll Ⅰ,Coll Ⅲ,Smad2 and Smad3,and protein expressions of α-SMA,Coll Ⅰ,P-Smad2 and P-Smad3 became obviously down-regulated(P＜0.05 or 0.01);Smad7 mRNA/protein expres-sion was significantly up-regulated(P＜0.05 or 0.01).CONCLUSION LCZ696 may suppress myocardial fibrosis by promot-ing Smad7 expression through a down-regulation of miRNA21,thereby attenuating LV remodeling and dysfunction in HFpEF rats.
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