The orphan receptor TR3 participates in angiotensin II-induced cardiac hypertrophy by controlling mTOR signalling.
Bottom Line: 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.The elimination or reduction of TR3 may reduce cardiac hypertrophy; therefore, TR3 is a potential target for clinical therapy.
Affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.Show MeSH
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Mentions: Because the stimulation of mTOR signalling occurs mainly in the cytoplasm and because our study shows that the regulation of mTORC1 activity by AngII is not associated with transcriptional activation by TR3, we postulated that cytoplasmic rather than nuclear TR3 may mediate AngII-induced mTORC1 activity. We analysed the distribution of TR3 in the nuclei and cytoplasms of H9C2 cells, NRCMs isolated from WT rats and fresh cardiomyocytes isolated from adult WT mice. Although TR3 was present in the nuclei and the cytoplasms, the AngII-induced expression of TR3 occurred only in the cytoplasms of these three cell types (Fig 4A). Immunohistochemical analysis verified the presence of cytoplasmic TR3 in normal and hypertrophied human heart tissue (Supporting Information Fig S4A), and AngII clearly induced cytoplasmic TR3 expression in the hearts of the WT mice (Supporting Information Fig S1B). These results suggest a possible function for TR3 in the cytoplasm.
Affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.