Pivotal Role of Regulator of G-protein Signaling 12 in Pathological Cardiac Hypertrophy.
Cardiac hypertrophy is a major predictor of heart failure and is regulated by diverse signaling pathways. As a typical multi-domain member of the regulator of G-protein signaling (RGS) family, RGS12 plays a regulatory role in various signaling pathways. However, the precise effect of RGS12 on cardiac hypertrophy remains largely unknown. In this study, we observed increased expression of RGS12 in the development of pathological cardiac hypertrophy and heart failure. We then generated genetically engineered mice and neonatal rat cardiomyocytes to investigate the effects of RGS12 during this pathological process. Four weeks after aortic banding, RGS12-deficient hearts showed decreased cardiomyocyte cross area (374.7±43.2 μm(2) versus 487.1±47.9 μm(2) in controls; P<0.05) with preserved fractional shortening (43.0±3.4% versus 28.4±2.2% in controls; P<0.05), whereas RGS12-overexpressing hearts exhibited increased cardiomyocyte cross area (582.4±46.7 μm(2) versus 474.8±40.0 μm(2) in controls; P<0.05) and reduced fractional shortening (20.8±4.1% versus 28.6±3.2% in controls; P<0.05). RGS12 also contributed to angiotensin II-induced hypertrophy in isolated cardiomyocytes. Mechanistically, our data indicated that the activation of MEK1/2-ERK1/2 signaling may be responsible for the prohypertrophic action of RGS12. In addition, the requirement of the MEK1/2-ERK1/2 signaling for RGS12-mediated cardiac hypertrophy was confirmed in rescue experiments using the MEK1/2-specific inhibitor U0126. In conclusion, our findings provide a novel diagnostic and therapeutic target for pathological cardiac hypertrophy and heart failure.
From the Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu, PR China (J.H., L.C., Y.Y., C.T., J.D., C.F., G.M.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China (H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, PR China (H.L.).
Jia
J
Huang
From the Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu, PR China (J.H., L.C., Y.Y., C.T., J.D., C.F., G.M.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China (H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, PR China (H.L.).
Lijuan
L
Chen
From the Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu, PR China (J.H., L.C., Y.Y., C.T., J.D., C.F., G.M.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China (H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, PR China (H.L.).
Yuyu
Y
Yao
From the Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu, PR China (J.H., L.C., Y.Y., C.T., J.D., C.F., G.M.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China (H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, PR China (H.L.).
Chengchun
C
Tang
From the Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu, PR China (J.H., L.C., Y.Y., C.T., J.D., C.F., G.M.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China (H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, PR China (H.L.).
Jiandong
J
Ding
From the Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu, PR China (J.H., L.C., Y.Y., C.T., J.D., C.F., G.M.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China (H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, PR China (H.L.).
Cong
C
Fu
From the Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu, PR China (J.H., L.C., Y.Y., C.T., J.D., C.F., G.M.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China (H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, PR China (H.L.).
Hongliang
H
Li
From the Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu, PR China (J.H., L.C., Y.Y., C.T., J.D., C.F., G.M.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China (H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, PR China (H.L.). magenshan@hotmail.com.
Genshan
G
Ma
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D020710:RGS Proteins / Q000235:genetics*; D051381:Rats; D012380:Role; D015398:Signal Transduction; D015854:Up-Regulation
D020710:RGS Proteins; C508173:RGS12 protein, mouse; D019204:GTP-Binding Proteins
amino acids; angiotensin II; dilated cardiomyopathy; heart failure; signal transduction