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The orphan receptor TR3 participates in angiotensin II-induced cardiac hypertrophy by controlling mTOR signalling.

Wang RH, He JP, Su ML, Luo J, Xu M, Du XD, Chen HZ, Wang WJ, Wang Y, Zhang N, Zhao BX, Zhao WX, Shan ZG, Han J, Chang C, Wu Q - EMBO Mol Med (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.

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Related in: MedlinePlus

TR3 knockout mice (TR3-KO) or rats with knockdown of TR3 in the left ventricle (TR3-KD) had less cardiac dysfunction following AngII treatment compared with the respective controlsThe mice were sham-operated or treated with AngII for 4 weeks as described above. The rats were treated with AngII for 2 weeks.Gene expression analysis of ANP, BNP and MHC in the WT and TR3-KO mice. Total RNA was isolated from the left ventricles of the mice (n = 5 per group). Real-time PCR analysis was performed to determine the expression of the indicated genes.Masson's trichrome staining shows cardiac fibrosis. A Masson's trichrome staining kit was used to visualize deposited collagen in the heart sections. The area of cardiac fibrosis was quantified using ImageJ (scale bar = 50 µm).TUNEL staining was used to detect apoptotic cells in the heart sections. Apoptotic cells were counted in three independent sections, and 300 nuclei were calculated in each section.IVSd and LVPWd were measured in the WT and TR3-KD rats before and after the administration of AngII (n = 5 per group).Gene expression levels of ANP, BNP and MHC in the WT and TR3-KD rats. Total RNA was isolated from the left ventricles of the rats (n = 5 per group). Real-time PCR analysis was then performed to determine the expression levels of the indicated genes. **p < 0.01, *p < 0.05 and NS: non-significant.
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fig02: TR3 knockout mice (TR3-KO) or rats with knockdown of TR3 in the left ventricle (TR3-KD) had less cardiac dysfunction following AngII treatment compared with the respective controlsThe mice were sham-operated or treated with AngII for 4 weeks as described above. The rats were treated with AngII for 2 weeks.Gene expression analysis of ANP, BNP and MHC in the WT and TR3-KO mice. Total RNA was isolated from the left ventricles of the mice (n = 5 per group). Real-time PCR analysis was performed to determine the expression of the indicated genes.Masson's trichrome staining shows cardiac fibrosis. A Masson's trichrome staining kit was used to visualize deposited collagen in the heart sections. The area of cardiac fibrosis was quantified using ImageJ (scale bar = 50 µm).TUNEL staining was used to detect apoptotic cells in the heart sections. Apoptotic cells were counted in three independent sections, and 300 nuclei were calculated in each section.IVSd and LVPWd were measured in the WT and TR3-KD rats before and after the administration of AngII (n = 5 per group).Gene expression levels of ANP, BNP and MHC in the WT and TR3-KD rats. Total RNA was isolated from the left ventricles of the rats (n = 5 per group). Real-time PCR analysis was then performed to determine the expression levels of the indicated genes. **p < 0.01, *p < 0.05 and NS: non-significant.

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).


The orphan receptor TR3 participates in angiotensin II-induced cardiac hypertrophy by controlling mTOR signalling.

Wang RH, He JP, Su ML, Luo J, Xu M, Du XD, Chen HZ, Wang WJ, Wang Y, Zhang N, Zhao BX, Zhao WX, Shan ZG, Han J, Chang C, Wu Q - EMBO Mol Med (2012)

TR3 knockout mice (TR3-KO) or rats with knockdown of TR3 in the left ventricle (TR3-KD) had less cardiac dysfunction following AngII treatment compared with the respective controlsThe mice were sham-operated or treated with AngII for 4 weeks as described above. The rats were treated with AngII for 2 weeks.Gene expression analysis of ANP, BNP and MHC in the WT and TR3-KO mice. Total RNA was isolated from the left ventricles of the mice (n = 5 per group). Real-time PCR analysis was performed to determine the expression of the indicated genes.Masson's trichrome staining shows cardiac fibrosis. A Masson's trichrome staining kit was used to visualize deposited collagen in the heart sections. The area of cardiac fibrosis was quantified using ImageJ (scale bar = 50 µm).TUNEL staining was used to detect apoptotic cells in the heart sections. Apoptotic cells were counted in three independent sections, and 300 nuclei were calculated in each section.IVSd and LVPWd were measured in the WT and TR3-KD rats before and after the administration of AngII (n = 5 per group).Gene expression levels of ANP, BNP and MHC in the WT and TR3-KD rats. Total RNA was isolated from the left ventricles of the rats (n = 5 per group). Real-time PCR analysis was then performed to determine the expression levels of the indicated genes. **p < 0.01, *p < 0.05 and NS: non-significant.
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fig02: TR3 knockout mice (TR3-KO) or rats with knockdown of TR3 in the left ventricle (TR3-KD) had less cardiac dysfunction following AngII treatment compared with the respective controlsThe mice were sham-operated or treated with AngII for 4 weeks as described above. The rats were treated with AngII for 2 weeks.Gene expression analysis of ANP, BNP and MHC in the WT and TR3-KO mice. Total RNA was isolated from the left ventricles of the mice (n = 5 per group). Real-time PCR analysis was performed to determine the expression of the indicated genes.Masson's trichrome staining shows cardiac fibrosis. A Masson's trichrome staining kit was used to visualize deposited collagen in the heart sections. The area of cardiac fibrosis was quantified using ImageJ (scale bar = 50 µm).TUNEL staining was used to detect apoptotic cells in the heart sections. Apoptotic cells were counted in three independent sections, and 300 nuclei were calculated in each section.IVSd and LVPWd were measured in the WT and TR3-KD rats before and after the administration of AngII (n = 5 per group).Gene expression levels of ANP, BNP and MHC in the WT and TR3-KD rats. Total RNA was isolated from the left ventricles of the rats (n = 5 per group). Real-time PCR analysis was then performed to determine the expression levels of the indicated genes. **p < 0.01, *p < 0.05 and NS: non-significant.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.

Show MeSH
Related in: MedlinePlus