The orphan receptor TR3 participates in angiotensin II‐induced cardiac hypertrophy by controlling mTOR signalling

Rong‐Hao Wang,Mao‐Long Su,Xiao‐Dan Du,Wei‐Jia Wang,Nan Zhang,Wen‐Xiu Zhao,Jiahuai Han,Jian‐Ping He,Ming Xu,Yuan Wang,Qiao Wu,Bi‐Xing Zhao,Hang‐Zi Chen,Chawnshang Chang,Zhong‐Gui Shan,Jie Luo

doi:10.1002/emmm.201201369

Abstract

Angiotensin II (AngII) induces cardiac hypertrophy and increases the expression of TR3. To determine whether TR3 is involved in the regulation of the pathological cardiac hypertrophy induced by AngII, we established mouse and rat hypertrophy models using chronic AngII administration. Our results reveal that a deficiency of TR3 in mice or the knockdown of TR3 in the left ventricle of rats attenuated AngII-induced cardiac hypertrophy compared with the respective controls. A mechanistic analysis demonstrates that the TR3-mediated activation of mTORC1 is associated with AngII-induced cardiac hypertrophy. TR3 was shown to form a trimer with the TSC1/TSC2 complex that specifically promoted TSC2 degradation via a proteasome/ubiquitination pathway. As a result, mTORC1, but not mTORC2, was activated; this was accompanied by increased protein synthesis, enhanced production of reactive oxygen species and enlarged cell size, thereby resulting in cardiac hypertrophy. This study demonstrates that TR3 positively regulates cardiac hypertrophy by influencing the effect of AngII on the mTOR pathway. The elimination or reduction of TR3 may reduce cardiac hypertrophy; therefore, TR3 is a potential target for clinical therapy.

Highlights

It is well known that hypertension can cause cardiac hypertrophy
A mechanistic analysis demonstrates that the TR3-mediated activation of mTORC1 is associated with Angiotensin II (AngII)-induced cardiac hypertrophy
Pathological cardiac hypertrophy is a cardiovascular disease that has been associated with mortality worldwide

Summary

Introduction

It is well known that hypertension can cause cardiac hypertrophy. Angiotensin II (AngII) is produced in peripheral (1) State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China (2) Xiamen Heart Center, Zhongshan Hospital, Xiamen University, Xiamen, Fujian Province, China (3) Department of Physiology, Fourth Military Medical University, Xian, China (4) George H. AngII contributes to the development of cardiovascular diseases by causing hypertension, cardiac hypertrophy, myocardial fibrosis, thrombosis, endothelial dysfunction and even organ damage. AngII triggers molecular pathways that promote protein synthesis, enhance the production of reactive oxygen species (ROS) and induce apoptosis by binding to its receptors: angiotensin II type I receptor (AT1R) and angiotensin II type II receptor (AT2R). The physiological effect of AngII is mainly transduced by its binding with AT1R. The well-known AT1R antagonists losartan, valsartan and telmisartan are used in the clinical therapy of cardiac hypertrophy

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