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: To further characterize the role of TR3, we determined whether AngII influences the transcriptional activity of TR3 in the cardiac myoblast cell line H9C2. Transfection of a reporter gene for NurRE (the response element of TR3) into cells revealed that TR3 transcriptional activity was not affected by AngII treatment (Supporting Information Fig S3A). To verify this finding, EMSA was performed; the result excluded the possibility that AngII affected endogenous TR3 targeting to DNA (Supporting Information Fig S3B). In addition, AngII elevated the expression of the TR3 protein but not the mRNA levels in H9C2 cells and neonatal rat cardiomyocytes (NRCMs) isolated from WT rats (Fig 3A and Supporting Information Fig S3C). This finding might have been the result of the extension of the half-life of TR3 by AngII because when cycloheximide (CHX) was used to block in vivo protein synthesis, the half-life (i.e., the time required for the degradation of 50% of the protein) of TR3 was prolonged by AngII (Supporting Information Fig S3D). These findings do not support the possibility that TR3 functions as a transcription factor to regulate cardiac hypertrophy; rather, the results suggest that TR3 is likely to be involved in regulation via protein–protein interactions.
Affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.