title: The orphan receptor TR3 participates in angiotensin II-induced cardiac hypertrophy by controlling mTOR signalling.
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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Rong-Hao
authors.initials: RH
authors.lastname: Wang
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: He
authors.forename: Mao-Long
authors.initials: ML
authors.lastname: Su
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Du
authors.forename: Hang-Zi
authors.initials: HZ
authors.lastname: Chen
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Bi-Xing
authors.initials: BX
authors.lastname: Zhao
authors.forename: Wen-Xiu
authors.initials: WX
authors.lastname: Zhao
authors.forename: Zhong-Gui
authors.initials: ZG
authors.lastname: Shan
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D046912:Multiprotein Complexes; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011506:Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000804:Angiotensin II; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases