| First Author | Fan D | Year | 2016 |
| Journal | Hypertension | Volume | 68 |
| Issue | 4 | Pages | 937-48 |
| PubMed ID | 27550917 | Mgi Jnum | J:308118 |
| Mgi Id | MGI:6726657 | Doi | 10.1161/HYPERTENSIONAHA.116.07566 |
| Citation | Fan D, et al. (2016) A Disintegrin and Metalloprotease-17 Regulates Pressure Overload-Induced Myocardial Hypertrophy and Dysfunction Through Proteolytic Processing of Integrin beta1. Hypertension 68(4):937-48 |
| abstractText | 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)/alphaMHC-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 beta1 was much greater with ADAM17 knockdown, concomitant with the greater activation of the focal adhesion kinase pathway, suggesting that integrin beta1 could be a substrate for ADAM17. ADAM17 knockdown did not alter other cardiomyocyte integrins, integrin alpha5 or alpha7, and HB-EGF (heparin-bound epidermal growth factor), another potential substrate for ADAM17, remained unaltered after pressure overload. ADAM17-mediated cleavage of integrin beta1 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 beta1-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 beta1, a novel substrate for ADAM17. This function of ADAM17 is selective for pressure overload-induced myocardial hypertrophy and dysfunction, and not agonist-induced hypertrophy. |
