Influence of sakubatril-valsartan on myocardial fibrosis through regulating PTEN/Akt/TFEB signaling pathway in rats with chronic heart failure
Ji Jiani
Cheng Na
Zhu Jia
Chen Fei
Meilibanna
Tunike
Abstract：Objective To investigate the influence of sakubatril-valsartan(LCZ696)on myocardial fibrosis through regulating signaling pathway of phosphatase and tensin homology deleted on chromosome 10/protein kinase B/transcription factor EB(PTEN/Akt/TFEB in rats with chronic heart failure(CHF).Methods The rat model of CHF was established by intraperitoneal injection of doxorubicin hydrochloride(1.5 mg/kg).The successfully modeled SPF grade SD male rats were divided randomly into CHF group,low-dose LCZ696 group(LCZ696-L group),high-dose LCZ696 group(LCZ696-H group)and high-dose LCZ696+Bpv(PTEN inhibitor)group(LCZ696-H+Bpv group,each n=12).Other rats were chosen into normal group(n=12).The LCZ696-L group and LCZ696-H group were orally given LCZ696 suspension(30 mg/kg,60 mg/kg),and LCZ696-H+Bpv group was additionally given intraperitoneal injection of Bpv(0.2 mg/kg).The normal group and CHF group were orally given normal saline(NS).After 4 weeks,the changes of heart function were detected by using cardiac ultrasonography.The morphological changes of myocardial tissue were observed after HE staining.The myocardial fibrosis and myocardial collagen area were observed and detected after Masson staining.The levels of serum N-terminal pro-brain natriuretic peptide(NT-proBNP)and creatine kinase(CK)were detected by using ELISA.The expressions of collage-Ⅰ and collage-Ⅲrelated to PTEN/Akt/TFEB signal pathway and myocardial fibrosis were detected by using Western blotting assay.Results The expressions of left ventricular fraction shortening(LVFS),left ventricular ejection fraction(LVEF),PTEN and TFEB decreased significantly(P＜0.05),and levels of left ventricular end-diastolic diameter(LVEDD),left ventricular end-diastolic diameter(LVEDD),pathological scores of myocardial tissue,collagen volume fraction(CVF),NT-proBNP,CK,p-Akt/Akt,collage-Ⅰ and collage-Ⅲ increased significantly(P＜0.05)in CHF group compared with normal group.There were disordered myocardial striations,significant myocardial fibrosis and a large amount of inflammatory cell infiltration in CHF group.The changes of corresponding indexes were contrary to the above ones(P＜0.05),and of myocardial pathological damage and myocardial fibrosis were relieved in LCZ696-L group and LCZ696-H group compared with CHF group.Bpv weakened the alleviating effect of LCZ696 on myocardial fibrosis in CHF rats.Conclusion LCZ696 can relieve myocardial fibrosis through activating,PTEN,inhibiting Akt and promoting TFEB expression in CHF rats.
Keywords：Chronic heart failureMyocardial fibrosisSakubatril-valsartan
Publication Date：2024-08-28
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：6( 986-991 )