R. Wang1, Jianping He1, Maolong Su2, Jie Luo1, Ming Xu3, Xiao‐Dan Du1, Hang‐Zi Chen1, Weijia Wang1, Yuan Wang1, Nan Zhang2, Bixing Zhao2, Wenxiu Zhao2, Zhonggui Shan2, Jiahuai Han1, Chawnshang Chang4, Qiao Wu1
1State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China
2Xiamen Heart Center, Zhongshan Hospital, Xiamen University, Xiamen, Fujian Province, China
3Department of Physiology, Fourth Military Medical University, Xian, China
4George H. Whipple Lab for Cancer Research, Departments of Pathology and Urology and the Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
Tóm tắt
AbstractAngiotensin 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.
