Abstract 1703: Involvement of Adam17 in Neointima Formation after Vascular Injury; Potential Role of Tyrosine Phosphorylation on its Activity
Angiotensin II (AngII) and its G protein-coupled receptor, AngII type-1 receptor (AT1), play critical roles in mediating cardiovascular diseases such as hypertension and atherosclerosis. It is widely believed that AngII promotes these diseases by inducing vascular remodeling that involves hypertrophy and hyperplasia of vascular smooth muscle cells (VSMCs). We and others have shown that the EGF receptor transactivation pathway is the key signaling mechanism by which AngII induces VSMC growth. Recently, we have further reported that production of HB-EGF via a metalloprotease, ADAM17, leads to EGF receptor transactivation by AngII in vitro. Here, we hypothesised that tyrosine phosphorylation of ADAM17 is essential for ADAM17 activation by the AT1 receptor in VSMCs, and that ADAM17 is a critical target of intervention for prevention of vascular remodeling in vivo. Our result revealed that not only a forced expression of dominant-negative (dn) ADAM17-E406A by adenovirus but also the tyrosine phosphorylation incapable ADAM17-Y702F mutant markedly inhibited AngII-induced EGF receptor transactivation compared to the stimulated control in vector-infected VSMCs. The neointimal cells appeared 14 days after balloon injury are strongly positive for ADAM17 immunostaining. Moreover, we observed marked inhibition of intimal hyperplasia in dnADAM17 adenovirus treated carotid artery after the balloon injury. We also confirmed marked expression of dnADAM17 in the artery after the virus infection. Taken together, these results suggest the involvement of ADAM17 in neointima formation. ADAM17 may be activated at the lesion by an upstream tyrosine kinase in response to AngII and other hormonal factors.
This research has received full or partial funding support from the American Heart Association, AHA National Center.