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

EMBO Molecular Medicine

Rong-Hao Wang²  Jian-Ping He²  Mao-Long Su³  Jie Luo²  Ming Xu⁴  Xiao-Dan Du²  Hang-Zi Chen²  Wei-Jia Wang²  Yuan Wang²  Nan Zhang³  Bi-Xing Zhao³  Wen-Xiu Zhao³  Zhong-Gui Shan³  Jiahuai Han²  Chawnshang Chang¹ 

[1] George H. Whipple Lab for Cancer Research, Departments of Pathology and Urology and the Cancer Center, University of Rochester Medical Center, Rochester, NY, USA;State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China;Xiamen Heart Center, Zhongshan Hospital, Xiamen University, Xiamen, Fujian Province, China;Department of Physiology, Fourth Military Medical University, Xian, China

关键词: angiotensin II;    cardiac hypertrophy;    mammalian target of rapamycin;    orphan receptor TR3;    tuberous sclerosis complex;   

DOI  :  10.1002/emmm.201201369

来源: Wiley

【 摘 要 】

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.

【 授权许可】

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