title: Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis.
abstract: A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that Gab-cKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti- and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure.
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yin
authors.affiliation: Center for Heart Lung Innovation/Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Deng
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: F Q
authors.initials: FQ
authors.lastname: Jin
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Mastrangelo
authors.affiliation: Center for Heart Lung Innovation/Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Luo
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Z G
authors.initials: ZG
authors.lastname: Jin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; C490897:Gab1 protein, mouse; D010750:Phosphoproteins