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: AngII-induced cardiac hypertrophy is accompanied by a series of pathological changes, including apoptosis, fibrosis and the reprogramming of certain fetal genes (Braunwald & Bristow, 2000; Rame & Dries, 2007). Therefore, we measured the mRNA levels of ANP, BNP and MHC, which are often used as markers of pathological cardiac hypertrophy. Treatment with AngII effectively increased the mRNA levels of these three genes in the WT mice but not in the TR3-KO mice (Fig 2A). To further characterize the cardiac dysfunction caused by hypertrophy, we measured fibrosis and apoptosis, both of which are responsible for heart failure (Diez et al, 1997; Swynghedauw, 1998). The administration of AngII caused marked cardiac fibrosis in the hearts of the WT mice compared with those of the TR3-KO mice (Fig 2B). Additionally, more apoptotic cells were found in the hearts of the WT mice than in those of the TR3-KO mice following the AngII treatment; the rate of apoptosis increased from approximately 2–16% following the AngII treatment in the WT mice (Fig 2C).
Affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.