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Hypertension. 2016 Oct;68(4):937-48. doi: 10.1161/HYPERTENSIONAHA.116.07566. Epub 2016 Aug 22.

A Disintegrin and Metalloprotease-17 Regulates Pressure Overload-Induced Myocardial Hypertrophy and Dysfunction Through Proteolytic Processing of Integrin β1.

Author information

1
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.).
2
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.

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.

KEYWORDS:

angiotensin II; dilated cardiomyopathy; disintegrin; hypertrophy; upregulation

[Indexed for MEDLINE]

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