Abstract 557: Pharmacological Inhibition of ADAM17 by a Human-Cross Reactive Antibody and Selective Inhibitor JG26 Prevents Vascular Fibrosis Induced by Angiotensin II in vivo and in vitro

Abstract

In cultured vascular smooth muscle cells (VSMCs), we have shown that a metalloprotease, ADAM17, mediates EGF receptor (EGFR) transactivation induced by angiotensin II (AngII). We have also shown that in mice with AngII infusion, EGFR inhibitor erlotinib prevents vessel remodeling independently from hypertension. In the present study, we hypothesized that pharmacological inhibition of ADAM17 prevents AngII-induced vascular fibrosis in vivo and in vitro. A novel human-cross reactive ADAM17 inhibitory antibody, A9(B8), (10 mg/kg ip on day 1 and 7) was utilized in C57Bl/6 mice with AngII infusion (1000 ng/kg/min for 2 weeks). A novel ADAM17 inhibitor JG26 (1 μM) was utilized in cultured rat aortic VSMCs stimulated with 100 nM AngII. A9(B8) but not control IgG treatment attenuated perivascular fibrosis and vascular hypertrophy in mouse coronary arteries (assessed by Sirius Red staining) infused with AngII. A9(B8) also attenuated cardiac hypertrophy (assessed by echocardiogram and heart body weight ratio) but not hypertension in mice with AngII infusion. In VSMCs, 30 min pretreatment of JG26 inhibited AngII-induced extracellular collagen accumulation at 48 h (assessed by a Sirius Red quantification kit). JG26 also inhibited AngII-induced EGFR transactivation (2 and 10 min) and ERK activation (10 min) in VSMCs. We conclude that inhibition of ADAM17 is an effective approach to attenuate pathophysiological cardiovascular remodeling in an AngII-dependent model of hypertension. These data highlight ADAM17 as a novel therapeutic target to prevent end-organ damage associated with hypertension.