Antiapoptosis and Antifibrosis Effects of Qishen Granules on Heart Failure Rats via Hippo Pathway.

Jian Zhang,Ruixin Zhu,Weili Lin,Pengrong Gao,Kuo Gao,Junjie Liu,Wei Wang,Yong Wang,Yili Zhang,Kangjia Du,Sheng Gao,Xiaomin Yang

doi:10.1155/2019/1642575

Abstract

Qishen granules (QSG) are a famous formula with cardioprotective properties to heart failure (HF). The aim of this study was to investigate the underlying mechanism of QSG on apoptosis and fibrosis in the treatment of HF. HF model was induced by left anterior descending artery ligation on Sprague-Dawley rats. Transcriptome analysis was used to investigate the regulatory pathways of QSG on HF. Interestingly, downregulated genes of QSG were significantly enriched in Hippo pathway which plays a crucial role in regulating cell apoptosis and proliferation. We found that QSG inhibited the expressions of proapoptotic key proteins P-53 and fibrosis-related proteins TGF-β1, SMAD3, and CTGF. Further, we conducted research on the key proteins in the Hippo pathway upstream of CTGF and P-53. The results showed that MST1, P-MST1, P-LATS1, and RASSF1A that exert proapoptotic function were downregulated after QSG intervention. Similarly, P-YAP and P-TAZ, mediating self-degradation and apoptosis, were both observably decreased after QSG administration. Taken together, QSG are shown to be likely to exert cardioprotective effects by inhibiting the progression of apoptosis and fibrosis through Hippo pathway.

Highlights

Heart failure (HF) imposes a major global health care burden on society and suffering on the individual [1, 2]
Given that the Hippo pathway plays a crucial role in regulating cell apoptosis and proliferation, we investigated the regulatory mechanism of Qishen granules (QSG) on apoptosis and fibrosis effects via Hippo pathway in the prevention of HF
ejection fraction (EF) and fractional shortening (FS) increased obviously while left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) decreased significantly in the QSG and fosinopril groups compared to the model group (P < 0.01 or P < 0.05, Figure 1), suggesting that QSG could improve cardiac functions in HF

Summary

Introduction

Heart failure (HF) imposes a major global health care burden on society and suffering on the individual [1, 2]. Anticardiomyocyte apoptosis and reversing fibrosis are the most attractive strategies for HF treatment [6]. E Hippo pathway, originally identified in drosophila as an important regulator of cardiomyocyte apoptosis and proliferation [7], has attracted recent interest as a potential approach to treat HF [8,9,10]. Mammalian sterile 20-like kinase 1/2 (MST1/2), the chief component of the Hippo pathway [11, 12], can translocate to mitochondria and phosphorylate B-cell lymphoma-2 (Bcl-2), causing Bcl-2associated X protein (Bax) activation with a subsequence of cardiomyocyte apoptosis during myocardial ischemic injury [13]. MST1/2 can activate large tumor suppressor kinase 1/2 (LATS1/2) to activate P53 or phosphorylates yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which can contribute to apoptosis [14]. YAP/ TAZ can initiate the transcription of connective tissue growth factor (CTGF) that mediates the expressions of extracellular matrix genes and promotes cardiac remodeling and fibrosis by interacting with TEA domain (TEAD) family

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Conclusion