Dengzhan Shengmai capsule attenuates cardiac fibrosis in post-myocardial infarction rats by regulating LTBP2 and TGF-β1/Smad3 pathway

Abstract

Background: Cardiac fibrosis contributes to myocardial remodeling after myocardial infarction (MI), which may facilitate the progression to end-stage heart failure. Dengzhan Shengmai capsule (DZSMC), a traditional Chinese formula derived from Shen-mai powder, has shown remarkable therapeutic effects against cardiovascular diseases. However, the effect of DZSMC on cardiac fibrosis and its potential mechanism are ill-defined.

Purpose: To evaluate the effects of DZSMC on cardiac fibrosis after myocardial infarction (MI) and investigate its underlying mechanism.

Method: In vivo, MI rat models were established by permanently ligation of left anterior descending coronary arteries (LAD) and then were intragastrically treated with DZSMC or captopril for 5 weeks. Ex vivo, an everted intestinal sac model was used to study the intestinal absorption components of DZSMC, which were further identified through an ultra-performance liquid chromatography tandem mass spectrometry (UHPLC-MS) method. In vitro, a myocardium fibrotic model was constructed by stimulating primary cardiac fibroblasts (CFs) with 1 μM Ang II. Subsequently, the absorbent solution of DZSMC from the intestinal sac was performed on the cell models to further elucidate its anti-fibrotic effects and underling mechanism.

Results: In vivo results showed that DZSMC significantly improved cardiac function and inhibited pathological myocardial fibrosis in post-MI rats in a dose dependent manner. Histological analysis and western blot results demonstrated that DZSMC treatment significantly reduced the expression of extracellular matrix (ECM)-related proteins, including LTBP2, TGF-βR1, Smad3 and pSmad3, in myocardial tissue of MI rats. Ex vivo results showed that 18 absorbed components were identified, mainly consisting of phenolic acids, flavonoids and lignans, which may be responsible for the anti-fibrotic effects. Further in vitro results validated that DZSMC attenuated myocardial fibrosis by suppressing the expression of LTBP2, TGF-β1 and pSmad3.

Conclusion: DZSMC ameliorates cardiac function and alleviates cardiac fibrosis, which may be mediated by inhibition of CFs activation and reduction of excessive ECM deposition via LTBP2 and TGF-β1/Smad3 pathways.

Keywords: Cardiac fibroblasts; Cardiac fibrosis; Dengzhan Shengmai capsule; LTBP2; TGF-β1/Smad3.