Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition (EndMT) mediated by autophagy

Lu Zhang,Zhongqi Yang,Junyan Wang,Zixin Chen,Lan Wei,Hanqin Wu,Lu Lu,Bo Deng,Birong Liang,Jing Liu,Shaoxiang Xian,Huan Li,Jiaqi He,Yusheng Huang,Lingjun Wang

doi:10.1038/s41419-021-03750-4

Abstract

Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to cardiac fibrosis and heart failure (HF). Recent studies have demonstrated that EndMT is regulated by autophagy, and we previously showed suppression of excessive autophagy and alleviation of cardiac fibrosis in HF mice with inactivated receptor for advanced glycation end products (RAGE). Thus, we investigated whether reduced cardiac fibrosis due to RAGE knockout occurred by inhibiting EndMT mediated by excessive autophagy. We found a decrease in endothelial cells (CD31+/VE-Cadherin+) and an increase in cells co-expressing CD31 and α-smooth muscle actin (α-SMA, myofibroblast marker) at 8 weeks in heart tissue of mice subjected to transverse aortic constriction (TAC), which implied EndMT. Knockout RAGE decreased EndMT accompanied by decreased expression of autophagy-related proteins (LC3BII/I and Beclin 1), and alleviated cardiac fibrosis and improved cardiac function in TAC mice. Moreover, 3-methyladenine (3-MA) and chloroquine (CQ), inhibitors of autophagy, attenuated EndMT, and cardiac fibrosis in TAC mice. Importantly, EndMT induced by AGEs could be blocked by autophagy inhibitor in vivo and in vitro. These results suggested that AGEs/RAGE-autophagy-EndMT axis involved in the development of cardiac fibrosis and knockout RAGE ameliorated cardiac fibrosis through decreasing EndMT regulated by autophagy, which could be a promising therapeutic strategy for HF.

Highlights

Heart failure (HF) occurs as the final stage of many cardiovascular diseases and is a major health challenge worldwide
Endothelial-to-mesenchymal transition (EndMT) induced by advanced glycation end products (AGEs) could be blocked by autophagy inhibitor in vivo and in vitro. These results suggested that AGEs/receptor for advanced glycation end products (RAGE)-autophagyEndMT axis involved in the development of cardiac fibrosis and knockout RAGE ameliorated cardiac fibrosis through decreasing EndMT regulated by autophagy, which could be a promising therapeutic strategy for HF
We previously showed that excessive autophagy could be inhibited by deletion of the receptor for advanced glycation end products (RAGE), resulting in amelioration of cardiac fibrosis in HF30

Summary

Introduction

Heart failure (HF) occurs as the final stage of many cardiovascular diseases and is a major health challenge worldwide. Cardiac remodeling is the process of structural and functional changes in the left ventricle and is associated with hypertrophy and apoptosis of cardiomyocytes, ventricular fibrosis[1], which is pivotal in developing HF2,3. The ventricular fibrotic process is initially triggered by the differentiation of cardiac fibroblasts into myofibroblasts. An increasing number of studies indicate EndMT is a common and potentially disease-causing process[11,12,13,14,15] and contributes to cardiac fibrosis. MRNA levels of EndMT-related genes are increased in the human fibrotic heart tissue[17], and Official journal of the Cell Death Differentiation Association. Zhang et al Cell Death and Disease (2021)12:470 repression of EndMT attenuates isoproterenol-induced cardiac fibrosis[18]. Understanding the mechanism of EndMT is essential to potentially prevent cardiac fibrosis and HF

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