Rap1GAP Mediates Angiotensin II-Induced Cardiomyocyte Hypertrophy by Inhibiting Autophagy and Increasing Oxidative Stress.

Yan Gao,Zhuo Zhao,Di Zhao,Tingting Meng,Pengfei Zhang,Wen-Zhi Xie,Yutong Liu,Xiuping Bi,Chunxiao Xu,Rodrigo Franco

doi:10.1155/2021/7848027

Abstract

Abnormal autophagy and oxidative stress contribute to angiotensin II- (Ang II-) induced cardiac hypertrophy and heart failure. We previously showed that Ang II increased Rap1GAP gene expression in cardiomyocytes associated with hypertrophy and autophagy disorders. Using real-time PCR and Western blot, we found that Rap1GAP expression was increased in the heart of Sprague Dawley (SD) rats infused by Ang II compared with saline infusion and in Ang II vs. vehicle-treated rat neonatal cardiomyocytes. Overexpression of Rap1GAP in cultured cardiomyocytes exacerbated Ang II-induced cardiomyocyte hypertrophy, reactive oxygen species (ROS) generation, and cell apoptosis and inhibited autophagy. The increased oxidative stress caused by Rap1GAP overexpression was inhibited by the treatment of autophagy agonists. Knockdown of Rap1GAP by siRNA markedly attenuated Ang II-induced cardiomyocyte hypertrophy and oxidative stress and enhanced autophagy. The AMPK/AKT/mTOR signaling pathway was inhibited by overexpression of Rap1GAP and activated by the knockdown of Rap1GAP. These results show that Rap1GAP-mediated pathway might be a new mechanism of Ang II-induced cardiomyocyte hypertrophy, which could be a potential target for the future treatment of cardiac hypertrophy and heart failure.

Highlights

Cardiac hypertrophy is an adaptive response of the heart to various pathological stimuli, including pressure overload, myocardial infarction and ischemia, and hypoxia [1]
The reactive oxygen species (ROS) reduction caused by Rap1 GTPase-activating protein (Rap1GAP) knockdown was increased in the 3-MAtreated group (P < 0:05 or P < 0:01; Figure 8(d)). This is the first study demonstrating that Rap1GAP is a critical mediator in angiotensin II- (Ang II-)induced cardiomyocyte hypertrophy
We found that Rap1GAP was expressed in cardiomyocytes and elevated in angiotensin II (Ang II)-induced hypertrophic cardiomyocytes

Summary

Introduction

Cardiac hypertrophy is an adaptive response of the heart to various pathological stimuli, including pressure overload, myocardial infarction and ischemia, and hypoxia [1]. The main effector of RAS is angiotensin II (Ang II) [4], which results in ventricular remodeling by mechanisms including the regulating of cardiac autophagy and oxidative stress. A growing body of evidence shows that the pathological process of cardiac hypertrophy is associated with excessive autophagy and reactive oxygen species (ROS), which eventually leads to cardiomyocyte necrosis and apoptosis [5, 6]. Cardiac autophagy plays an important role in maintaining cell activity and heart function under stresses. Cardiac hypertrophy leads to increased oxygen consumption, and excessive ROS is produced in mitochondria, resulting in irreversible damage of mitochondrial DNA and further induces cardiac remodeling and failure [8, 9]. ROS regulates autophagy through various mechanisms involving catalase, Atg, mitochondrial electron transport chains, and the Ca2+ release channel on the lysosomal membrane [10, 11]

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Conclusion