title: SH2B1 is critical for the regulation of cardiac remodelling in response to pressure overload.
abstract: OBJECTIVE
  Src homology 2 (SH2) B adaptor protein 1 (SH2B1) is expressed in various tissues, including the heart. Previous studies have demonstrated that SH2B1 is involved in a variety of biological process, such as maintaining neuronal differentiation, regulating energy and glucose homeostasis, and promoting cell proliferation and motility. However, the role of SH2B1 in cardiac hypertrophy remains unclear. This study aimed at identifying the effects and the underlying mechanisms of SH2B1 in cardiac hypertrophy.
  
  
  RESULTS
  We performed gain- and loss-of-function studies using genetic approaches, and cardiac hypertrophy was evaluated through pathological, echocardiographic, haemodynamic, and molecular analyses. We found that SH2B1 expression was significantly increased in both failing human hearts and hypertrophic murine hearts. Mice overexpressing SH2B1 specifically in the heart displayed increased aortic banding (AB)-induced cardiac hypertrophy, fibrosis, ventricular dilation, and dysfunction compared with controls, whereas loss of SH2B1 produced the opposite phenotype. Consistently, similar results were observed in a global SH2B1-knockout rat model. Mechanistically, the pro-hypertrophic effects elicited by SH2B1 were associated with activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signalling cascade. Furthermore, rescue experiments revealed that pharmacological inactivation of JAK2 rescued pressure overload-induced cardiac abnormalities in transgenic mice with cardiac-specific SH2B1 overexpression.
  
  
  CONCLUSIONS
  Taken together, our data demonstrate, for the first time, that SH2B1 is a key positive mediator of pathological cardiac hypertrophy, and that it primarily acts by regulating JAK2/STAT3 signalling.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan 430060, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan 430060, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan 430060, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan 430060, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan 430060, China.
authors.forename: Wanli
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan 430060, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Mei
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan 430060, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Wan
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan 430060, China.
authors.forename: Xiaoxiong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan 430060, China huangcongxin@vip.163.com.
authors.forename: Congxin
authors.initials: C
authors.lastname: Huang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011312:Pressure; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C518910:SH2B1 protein, human; C115327:Sh2bpsm1 protein, mouse
keywords: Cardiac hypertrophy; Fibrosis; JAK2; SH2B1