Ang II Promotes Cardiac Autophagy and Hypertrophy via Orai1/STIM1.

Chang-Bo Zheng,Yongxiang Huang,Xiaoqiang Yao,Mingxu Xie,Weimin Yang,Wen-Cong Gao,Peng Zhang,Dan Luo,Xin Ma,Jichen Yang,Zhichao Li,Yu Huang,Wencong Song

doi:10.3389/fphar.2021.622774

Abstract

The pathophysiology of cardiac hypertrophy is complex and multifactorial. Both the store-operated Ca2+ entry (SOCE) and excessive autophagy are the major causative factors for pathological cardiac hypertrophy. However, it is unclear whether these two causative factors are interdependent. In this study, we examined the functional role of SOCE and Orai1 in angiotensin II (Ang II)-induced autophagy and hypertrophy using in vitro neonatal rat cardiomyocytes (NRCMs) and in vivo mouse model, respectively. We show that YM-58483 or SKF-96365 mediated pharmacological inhibition of SOCE, or silencing of Orai1 with Orail-siRNA inhibited Ang II-induced cardiomyocyte autophagy both in vitro and in vivo. Also, the knockdown of Orai1 attenuated Ang II-induced pathological cardiac hypertrophy. Together, these data suggest that Ang II promotes excessive cardiomyocyte autophagy through SOCE/Orai1 which can be the prime contributing factors in cardiac hypertrophy.

Highlights

The pathophysiology of cardiac hypertrophy is a complex process
The main findings of this study are as follows: 1) angiotensin II (Ang II) stimulates autophagy in neonatal rat cardiomyocytes (NRCMs) which is evident by an increase in LC3-II accumulation
II-induced accumulation of LC3-II was alleviated by chelation of extracellular Ca2+ or inhibition of CaMKK. 4) In vivo experiments showed that Orai1-siRNA could attenuate Ang II-induced cardiac hypertrophy and fibrosis

Summary

Introduction

The pathophysiology of cardiac hypertrophy is a complex process. It involves dysregulation of multiple cellular factors and/or signaling pathways, including G protein-coupled receptors, autophagy, cytosolic Ca2+ signaling, and many others that may contribute to the progression of cardiac hypertrophy (Gupta et al, 2007; Collins et al, 2013).Autophagy, a highly conserved process, involves the bulk degradation of unnecessary and malfunctioned proteins and organelles (Mizushima et al, 2010). The pathophysiology of cardiac hypertrophy is a complex process. It involves dysregulation of multiple cellular factors and/or signaling pathways, including G protein-coupled receptors, autophagy, cytosolic Ca2+ signaling, and many others that may contribute to the progression of cardiac hypertrophy (Gupta et al, 2007; Collins et al, 2013). A highly conserved process, involves the bulk degradation of unnecessary and malfunctioned proteins and organelles (Mizushima et al, 2010). It plays an essential role in cardiomyocytes which are long-lived differentiated cells. Excessive myocardial autophagy has been shown to contribute to angiotensin II (Ang II)-induced pathological myocardial hypertrophy in animal models (Porrello et al, 2009; Pan et al, 2013; Kishore et al, 2015; Lin et al, 2016)

Methods

Results

Conclusion