title: Exacerbating Pressure Overload-Induced Cardiac Hypertrophy: Novel Role of Adaptor Molecule Src Homology 2-B3.
abstract: The adaptor protein Src homology 2-B3 (SH2B3), which belongs to a subfamily of Src homology 2 proteins, is a broad inhibitor of growth factors and cytokine signaling in hematopoietic cells. However, the role of SH2B3 in nonhematopoietic systems, particularly cardiomyocytes, has not been defined. In this study, we observed noticeable increase in SH2B3 protein expression during pathological cardiac remodeling in both humans and rodents. Follow-up in vitro gain- and loss-of-function studies suggested that SH2B3 promotes the cardiomyocyte hypertrophy response. Consistent with the cell phenotype, SH2B3 knockout (SH2B3(-/-)) mice exhibited attenuated cardiac remodeling with preserved cardiac function after chronic pressure overload. Conversely, cardiac-specific SH2B3 overexpression aggravated pressure overload-triggered cardiac hypertrophy, fibrosis, and dysfunction. Mechanistically, SH2B3 accelerates and exacerbates cardiac remodeling through the activation of focal adhesion kinase, which, in turn, activates the prohypertrophic downstream phosphoinositide 3-kinase-AKT-mammalian target of rapamycin/glycogen synthase kinase 3β signaling pathway. Finally, we generated a novel SH2B3 knockout rat line and further confirmed the protective effects of SH2B3 deficiency on cardiac remodeling across species. Collectively, our data indicate that SH2B3 functions as a novel and effective modulator of cardiac remodeling and failure.
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.Z., J.F., X.W.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.).
authors.forename: Xuehai
authors.initials: X
authors.lastname: Zhu
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.Z., J.F., X.W.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.).
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.Z., J.F., X.W.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.).
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.Z., J.F., X.W.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.).
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.Z., J.F., X.W.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.).
authors.forename: Guang-Nian
authors.initials: GN
authors.lastname: Zhao
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.Z., J.F., X.W.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.).
authors.forename: Xueyong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.Z., J.F., X.W.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.).
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.Z., J.F., X.W.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.). lihl@whu.edu.cn xiangwee@126.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wei
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.Z., J.F., X.W.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.). lihl@whu.edu.cn xiangwee@126.com.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C490082:Shb protein, rat
keywords: LNK protein, mouse; TALEN; aortic banding; cardiomegaly; knockout rats