title: A Disintegrin and Metalloprotease-17 Regulates Pressure Overload-Induced Myocardial Hypertrophy and Dysfunction Through Proteolytic Processing of Integrin β1.
abstract: A disintegrin and metalloprotease-17 (ADAM17) belongs to a family of transmembrane enzymes, and it can mediate ectodomain shedding of several membrane-bound molecules. ADAM17 levels are elevated in patients with hypertrophic and dilated cardiomyopathy; however, its direct role in hypertrophic cardiomyopathy is unknown. Cardiomyocyte-specific ADAM17 knockdown mice (ADAM17(flox/flox)/αMHC-Cre; ADAM17(f/f)/Cre) and littermates with intact ADAM17 levels (ADAM17(f/f)) were subjected to cardiac pressure-overload by transverse aortic constriction. Cardiac function/architecture was assessed by echocardiography at 2 and 5 weeks post transverse aortic constriction. ADAM17 knockdown enhanced myocardial hypertrophy, fibrosis, more severe left ventricular dilation, and systolic dysfunction at 5 weeks post transverse aortic constriction. Pressure overload-induced upregulation of integrin β1 was much greater with ADAM17 knockdown, concomitant with the greater activation of the focal adhesion kinase pathway, suggesting that integrin β1 could be a substrate for ADAM17. ADAM17 knockdown did not alter other cardiomyocyte integrins, integrin α5 or α7, and HB-EGF (heparin-bound epidermal growth factor), another potential substrate for ADAM17, remained unaltered after pressure overload. ADAM17-mediated cleavage of integrin β1 was confirmed by an in vitro assay. Intriguingly, ADAM17 knockdown did not affect the myocardial hypertrophy induced by a subpressor dose of angiotensin II, which occurs independent from the integrin β1-mediated pathway. ADAM17-knockdown enhanced the hypertrophic response to cyclic mechanical stretching in neonatal rat cardiomyocytes. This study reports a novel cardioprotective function for ADAM17 in pressure overload cardiomyopathy, where loss of ADAM17 promotes hypertrophy by reducing the cleavage of cardiac integrin β1, a novel substrate for ADAM17. This function of ADAM17 is selective for pressure overload-induced myocardial hypertrophy and dysfunction, and not agonist-induced hypertrophy.
authors.affiliation: From the Departments of Physiology (D.F., A.T., M.S., X.W., Z.K.), Biochemistry (C.F.-P.), Medicine, Faculty of Medicine and Dentistry (R.B., V.P., G.Y.O.), and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (V.S., J.M.S.); and Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada (D.F., A.T., M.S., V.S., R.B., V.P., X.W., C.F.-P., J.M.S., G.Y.O., Z.K.).
authors.forename: Dong
authors.initials: D
authors.lastname: Fan
authors.affiliation: From the Departments of Physiology (D.F., A.T., M.S., X.W., Z.K.), Biochemistry (C.F.-P.), Medicine, Faculty of Medicine and Dentistry (R.B., V.P., G.Y.O.), and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (V.S., J.M.S.); and Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada (D.F., A.T., M.S., V.S., R.B., V.P., X.W., C.F.-P., J.M.S., G.Y.O., Z.K.).
authors.forename: Abhijit
authors.initials: A
authors.lastname: Takawale
authors.affiliation: From the Departments of Physiology (D.F., A.T., M.S., X.W., Z.K.), Biochemistry (C.F.-P.), Medicine, Faculty of Medicine and Dentistry (R.B., V.P., G.Y.O.), and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (V.S., J.M.S.); and Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada (D.F., A.T., M.S., V.S., R.B., V.P., X.W., C.F.-P., J.M.S., G.Y.O., Z.K.).
authors.forename: Mengcheng
authors.initials: M
authors.lastname: Shen
authors.affiliation: From the Departments of Physiology (D.F., A.T., M.S., X.W., Z.K.), Biochemistry (C.F.-P.), Medicine, Faculty of Medicine and Dentistry (R.B., V.P., G.Y.O.), and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (V.S., J.M.S.); and Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada (D.F., A.T., M.S., V.S., R.B., V.P., X.W., C.F.-P., J.M.S., G.Y.O., Z.K.).
authors.forename: Victor
authors.initials: V
authors.lastname: Samokhvalov
authors.affiliation: From the Departments of Physiology (D.F., A.T., M.S., X.W., Z.K.), Biochemistry (C.F.-P.), Medicine, Faculty of Medicine and Dentistry (R.B., V.P., G.Y.O.), and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (V.S., J.M.S.); and Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada (D.F., A.T., M.S., V.S., R.B., V.P., X.W., C.F.-P., J.M.S., G.Y.O., Z.K.).
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.affiliation: From the Departments of Physiology (D.F., A.T., M.S., X.W., Z.K.), Biochemistry (C.F.-P.), Medicine, Faculty of Medicine and Dentistry (R.B., V.P., G.Y.O.), and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (V.S., J.M.S.); and Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada (D.F., A.T., M.S., V.S., R.B., V.P., X.W., C.F.-P., J.M.S., G.Y.O., Z.K.).
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Patel
authors.affiliation: From the Departments of Physiology (D.F., A.T., M.S., X.W., Z.K.), Biochemistry (C.F.-P.), Medicine, Faculty of Medicine and Dentistry (R.B., V.P., G.Y.O.), and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (V.S., J.M.S.); and Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada (D.F., A.T., M.S., V.S., R.B., V.P., X.W., C.F.-P., J.M.S., G.Y.O., Z.K.).
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Departments of Physiology (D.F., A.T., M.S., X.W., Z.K.), Biochemistry (C.F.-P.), Medicine, Faculty of Medicine and Dentistry (R.B., V.P., G.Y.O.), and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (V.S., J.M.S.); and Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada (D.F., A.T., M.S., V.S., R.B., V.P., X.W., C.F.-P., J.M.S., G.Y.O., Z.K.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Patron
authors.affiliation: From the Departments of Physiology (D.F., A.T., M.S., X.W., Z.K.), Biochemistry (C.F.-P.), Medicine, Faculty of Medicine and Dentistry (R.B., V.P., G.Y.O.), and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (V.S., J.M.S.); and Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada (D.F., A.T., M.S., V.S., R.B., V.P., X.W., C.F.-P., J.M.S., G.Y.O., Z.K.).
authors.forename: John M
authors.initials: JM
authors.lastname: Seubert
authors.affiliation: From the Departments of Physiology (D.F., A.T., M.S., X.W., Z.K.), Biochemistry (C.F.-P.), Medicine, Faculty of Medicine and Dentistry (R.B., V.P., G.Y.O.), and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (V.S., J.M.S.); and Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada (D.F., A.T., M.S., V.S., R.B., V.P., X.W., C.F.-P., J.M.S., G.Y.O., Z.K.).
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: From the Departments of Physiology (D.F., A.T., M.S., X.W., Z.K.), Biochemistry (C.F.-P.), Medicine, Faculty of Medicine and Dentistry (R.B., V.P., G.Y.O.), and Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (V.S., J.M.S.); and Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada (D.F., A.T., M.S., V.S., R.B., V.P., X.W., C.F.-P., J.M.S., G.Y.O., Z.K.). z.kassiri@ualberta.ca.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019483:Disintegrins / Q000378:metabolism; D015150:Echocardiography, Doppler; D006973:Hypertension / Q000139:chemically induced / Q000150:complications*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D059748:Proteolysis; D011897:Random Allocation; D051381:Rats; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D019483:Disintegrins; D000804:Angiotensin II; D000072198:ADAM17 Protein
keywords: angiotensin II; dilated cardiomyopathy; disintegrin; hypertrophy; upregulation