Qindan Capsule Attenuates Myocardial Hypertrophy and Fibrosis in Pressure Overload-Induced Mice Involving mTOR and TGF-β1/Smad Signaling Pathway Inhibition.

Wenwu Bai,Wen Cheng,Xiaoting Lu,Deshan Liu,Bo Wang,Min Ren,Hai-Dong Guo

doi:10.1155/2021/5577875

Abstract

Qindan capsule (QC), a traditional Chinese medicine compound, has been used to treat hypertension in the clinic for over 30 years. It is still not known about the effects of QC on pressure overload-induced cardiac remodeling. Hence, this study aims to investigate the effects of QC on pressure overload-induced cardiac hypertrophy, fibrosis, and heart failure in mice and to determine the possible mechanisms. Transverse aortic constriction (TAC) surgery was used to induce cardiac hypertrophy and heart failure in C57BL/6 mice. Mice were treated with QC or losartan for 8 weeks after TAC surgery. Cardiac function indexes were evaluated with transthoracic echocardiography. Cardiac pathology was detected using HE and Masson's trichrome staining. Cardiomyocyte ultrastructure was detected using transmission electron microscopy. Hypertrophy-related fetal gene expression was investigated using real-time RT-PCR. The expression of 8-OHdG and the concentration of MDA and Ang-II were assessed by immunohistochemistry stain and ELISA assay, respectively. The total and phosphorylated protein levels of mTOR, p70S6K, 4EBP1, Smad2, and Smad3 and the expression of TGF-β1 and collagen I were measured using western blot. The results showed that low- and high-dose QC improved pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. QC inhibited ANP, BNP, and β-MHC mRNA expression in failing hearts. QC improved myocardial ultrastructure after TAC surgery. Furthermore, QC downregulated the expression of 8-OHdG and the concentration of MDA, 15-F2t-IsoP, and Ang-II in heart tissues after TAC surgery. We also found that QC inhibited the phosphorylation of mTOR, p70S6K, and 4EBP1 and the expression of TGF-β1, p-Smad2, p-Smad3, and collagen I in pressure overload-induced failing hearts. These data indicate that QC has direct benefic effects on pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. The protective effects of QC involve prevention of increased oxidative stress injury and Ang-II levels and inhibition of mTOR and TGF-β1/Smad pathways in failing hearts.

Highlights

Hypertension- or aortic stenosis-induced left ventricular pressure overload leads to heart failure or sudden death in clinical practice [1]
Myocardial hypertrophy induced by pressure overload develops from compensation to decompensation. ese developments of myocardial remodeling are characterized by hypertrophic cardiomyocytes, upregulated expression of fetal genes, activated protein synthesis, extracellular matrix deposition, and fibrosis [2]
Four weeks after Transverse aortic constriction (TAC) surgery, increased left ventricular posterior wall at diastole (LVPWd) was alleviated in the TAC + QCH group compared with the TAC group (Table S3). en, 8 weeks after TAC surgery, decreased FS%, EF%, and increased LVPWd were significantly rescued in TAC + QCL, TAC + QCH, and TAC + LST groups compared with the TAC group (Table S3, Figures 1(a)–1(d))

Summary

Introduction

Hypertension- or aortic stenosis-induced left ventricular pressure overload leads to heart failure or sudden death in clinical practice [1]. Myocardial hypertrophy induced by pressure overload develops from compensation to decompensation. Ese developments of myocardial remodeling are characterized by hypertrophic cardiomyocytes, upregulated expression of fetal genes, activated protein synthesis, extracellular matrix deposition, and fibrosis [2]. The cardiac remodeling represents that the heart tries to maintain the contractile function, it is getting worse under sustained pressure overload stress and eventually leads to heart failure. The underlying mechanism mediating the pathological process of cardiac hypertrophy and fibrosis is complex and involves multifarious regulators and signaling pathways. Some clinical and experimental studies have shown that Chinese herbal medicine has the beneficial effects on heart failure [4, 5].

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