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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-mediated AngII-induced cardiac hypertrophy in miceIn the AngII-induced hypertrophy model, AngII was continuously provided for 4 weeks using an osmotic minipump. The same volume of 0.9% saline including 0.01 M acetic acid was substituted for AngII in sham-operated mice.AngII elevated TR3 protein levels. The left ventricles from individual hearts (n = 5 per group) were removed, and the proteins were extracted. The expression levels of TR3 were determined by Western blotting using a TR3 antibody followed by quantification (bottom: fold induction). Tubulin was used as a loading control.Echocardiographic analysis of WT mice and TR3-KO littermates (n = 15 per group). IVSd and LVPWd were measured weekly.The heart weight to body weight (mg/g) ratios (top panel) (n = 5 per group) and representative heart images (bottom panel) from 4-week sham-operated and AngII-treated mice. Hearts were dissected from the euthanized mice, weighed and normalized to body weight.Cardiomyocyte size in left ventricle sections of the sham-operated or AngII-treated WT and KO mice. H&E staining was performed (top), and the mean cross-sectional area was calculated using ImageJ (bottom) (scale bar = 50 µm).The size of cardiomyocytes isolated from the hearts of WT and TR3-KO adult mice. The mice were treated with AngII for 4 weeks using implanted osmotic minipumps. The cardiomyocytes were isolated as described in the Supporting Information Methods. The cardiomyocytes were stained with an anti-α-actinin antibody (left), and the mean cardiomyocyte size was calculated using ImageJ (right).AngII upregulates TR3 expression through its own receptor. During the administration of AngII, the mice (n = 5 per group) received losartan (200 mg/L) or propranolol (100 mg/L) in their drinking water for 2 weeks. The left ventricles were removed, and the proteins were extracted for the analysis of TR3 expression by Western blotting.IVSd and LVPWd were measured in the same mice as in Fig 1F. In each panel shown above, the following symbols were used: ***p < 0.001, **p < 0.01, *p < 0.05 and NS: non-significant.
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fig01: TR3-mediated AngII-induced cardiac hypertrophy in miceIn the AngII-induced hypertrophy model, AngII was continuously provided for 4 weeks using an osmotic minipump. The same volume of 0.9% saline including 0.01 M acetic acid was substituted for AngII in sham-operated mice.AngII elevated TR3 protein levels. The left ventricles from individual hearts (n = 5 per group) were removed, and the proteins were extracted. The expression levels of TR3 were determined by Western blotting using a TR3 antibody followed by quantification (bottom: fold induction). Tubulin was used as a loading control.Echocardiographic analysis of WT mice and TR3-KO littermates (n = 15 per group). IVSd and LVPWd were measured weekly.The heart weight to body weight (mg/g) ratios (top panel) (n = 5 per group) and representative heart images (bottom panel) from 4-week sham-operated and AngII-treated mice. Hearts were dissected from the euthanized mice, weighed and normalized to body weight.Cardiomyocyte size in left ventricle sections of the sham-operated or AngII-treated WT and KO mice. H&E staining was performed (top), and the mean cross-sectional area was calculated using ImageJ (bottom) (scale bar = 50 µm).The size of cardiomyocytes isolated from the hearts of WT and TR3-KO adult mice. The mice were treated with AngII for 4 weeks using implanted osmotic minipumps. The cardiomyocytes were isolated as described in the Supporting Information Methods. The cardiomyocytes were stained with an anti-α-actinin antibody (left), and the mean cardiomyocyte size was calculated using ImageJ (right).AngII upregulates TR3 expression through its own receptor. During the administration of AngII, the mice (n = 5 per group) received losartan (200 mg/L) or propranolol (100 mg/L) in their drinking water for 2 weeks. The left ventricles were removed, and the proteins were extracted for the analysis of TR3 expression by Western blotting.IVSd and LVPWd were measured in the same mice as in Fig 1F. In each panel shown above, the following symbols were used: ***p < 0.001, **p < 0.01, *p < 0.05 and NS: non-significant.

Mentions: A recent study demonstrated increased TR3 expression in the transverse aorta constriction (TAC) mouse model, which can induce pathological cardiac hypertrophy (Cheng et al, 2011). Similar to TAC, AngII has been reported to cause pathological cardiac hypertrophy. Therefore, we investigated whether TR3 is involved in AngII-induced cardiac hypertrophy. To establish a model of AngII-induced cardiac hypertrophy, 12-week-old WT mice and age-matched TR3-knockout (TR3-KO) littermates were implanted with osmotic minipumps to administer AngII continuously for 4 weeks. TR3 expression in the WT mice and the BP of mice with both genotypes were upregulated within 4 weeks. However, the increase in BP by AngII was comparable between the WT and TR3-KO mice (Fig 1A and Supporting Information Fig S1A). These results suggest that TR3 expression, rather than BP, may cause the difference in phenotype between the WT and TR3-KO mice.


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-mediated AngII-induced cardiac hypertrophy in miceIn the AngII-induced hypertrophy model, AngII was continuously provided for 4 weeks using an osmotic minipump. The same volume of 0.9% saline including 0.01 M acetic acid was substituted for AngII in sham-operated mice.AngII elevated TR3 protein levels. The left ventricles from individual hearts (n = 5 per group) were removed, and the proteins were extracted. The expression levels of TR3 were determined by Western blotting using a TR3 antibody followed by quantification (bottom: fold induction). Tubulin was used as a loading control.Echocardiographic analysis of WT mice and TR3-KO littermates (n = 15 per group). IVSd and LVPWd were measured weekly.The heart weight to body weight (mg/g) ratios (top panel) (n = 5 per group) and representative heart images (bottom panel) from 4-week sham-operated and AngII-treated mice. Hearts were dissected from the euthanized mice, weighed and normalized to body weight.Cardiomyocyte size in left ventricle sections of the sham-operated or AngII-treated WT and KO mice. H&E staining was performed (top), and the mean cross-sectional area was calculated using ImageJ (bottom) (scale bar = 50 µm).The size of cardiomyocytes isolated from the hearts of WT and TR3-KO adult mice. The mice were treated with AngII for 4 weeks using implanted osmotic minipumps. The cardiomyocytes were isolated as described in the Supporting Information Methods. The cardiomyocytes were stained with an anti-α-actinin antibody (left), and the mean cardiomyocyte size was calculated using ImageJ (right).AngII upregulates TR3 expression through its own receptor. During the administration of AngII, the mice (n = 5 per group) received losartan (200 mg/L) or propranolol (100 mg/L) in their drinking water for 2 weeks. The left ventricles were removed, and the proteins were extracted for the analysis of TR3 expression by Western blotting.IVSd and LVPWd were measured in the same mice as in Fig 1F. In each panel shown above, the following symbols were used: ***p < 0.001, **p < 0.01, *p < 0.05 and NS: non-significant.
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fig01: TR3-mediated AngII-induced cardiac hypertrophy in miceIn the AngII-induced hypertrophy model, AngII was continuously provided for 4 weeks using an osmotic minipump. The same volume of 0.9% saline including 0.01 M acetic acid was substituted for AngII in sham-operated mice.AngII elevated TR3 protein levels. The left ventricles from individual hearts (n = 5 per group) were removed, and the proteins were extracted. The expression levels of TR3 were determined by Western blotting using a TR3 antibody followed by quantification (bottom: fold induction). Tubulin was used as a loading control.Echocardiographic analysis of WT mice and TR3-KO littermates (n = 15 per group). IVSd and LVPWd were measured weekly.The heart weight to body weight (mg/g) ratios (top panel) (n = 5 per group) and representative heart images (bottom panel) from 4-week sham-operated and AngII-treated mice. Hearts were dissected from the euthanized mice, weighed and normalized to body weight.Cardiomyocyte size in left ventricle sections of the sham-operated or AngII-treated WT and KO mice. H&E staining was performed (top), and the mean cross-sectional area was calculated using ImageJ (bottom) (scale bar = 50 µm).The size of cardiomyocytes isolated from the hearts of WT and TR3-KO adult mice. The mice were treated with AngII for 4 weeks using implanted osmotic minipumps. The cardiomyocytes were isolated as described in the Supporting Information Methods. The cardiomyocytes were stained with an anti-α-actinin antibody (left), and the mean cardiomyocyte size was calculated using ImageJ (right).AngII upregulates TR3 expression through its own receptor. During the administration of AngII, the mice (n = 5 per group) received losartan (200 mg/L) or propranolol (100 mg/L) in their drinking water for 2 weeks. The left ventricles were removed, and the proteins were extracted for the analysis of TR3 expression by Western blotting.IVSd and LVPWd were measured in the same mice as in Fig 1F. In each panel shown above, the following symbols were used: ***p < 0.001, **p < 0.01, *p < 0.05 and NS: non-significant.
Mentions: A recent study demonstrated increased TR3 expression in the transverse aorta constriction (TAC) mouse model, which can induce pathological cardiac hypertrophy (Cheng et al, 2011). Similar to TAC, AngII has been reported to cause pathological cardiac hypertrophy. Therefore, we investigated whether TR3 is involved in AngII-induced cardiac hypertrophy. To establish a model of AngII-induced cardiac hypertrophy, 12-week-old WT mice and age-matched TR3-knockout (TR3-KO) littermates were implanted with osmotic minipumps to administer AngII continuously for 4 weeks. TR3 expression in the WT mice and the BP of mice with both genotypes were upregulated within 4 weeks. However, the increase in BP by AngII was comparable between the WT and TR3-KO mice (Fig 1A and Supporting Information Fig S1A). These results suggest that TR3 expression, rather than BP, may cause the difference in phenotype between the WT and TR3-KO mice.

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