Cyclic GMP‐mediates NO‐induced attenuation of endothelin‐1 signaling and hypertrophic response in vascular smooth muscle cells (VSMC).

Abstract

Nitric oxide (NO) has been shown to antagonize the mitogenic and hypertrophic responses of growth factors and vasoactive peptides such as endothelin-1 (ET-1) inVSMCs. However, the mechanism by which NO exerts its anti-mitogenic and anti-hypertrophic effect remains unknown. Therefore, the aim of this study was to determine if NO generation would modify ET-1-induced signaling pathways involved in cellular growth, proliferation and hypertrophy in VSMC. Treatment of VSMCs with SNAP, a NO donor, attenuated the ET-1-enhanced phosphorylation of several key components of growth promoting and hypertrophic signaling pathways such as ERK1/2, PKB and Pyk2. Since, NO mediates its effect principally through a cyclic GMP/soluble guanylate cyclase (GC) pathway, we investigated the role of these molecules in NO action. 8-Br-cGMP, a non-metabolizable and cell permeable analogue of cGMP, exhibited a similar effect as SNAP and inhibited ET-1-induced ERK1/2, PKB and Pyk2 phosphorylation. Furthermore, ODQ, an inhibitor of soluble GC activity, reversed the inhibitory effect of NO on ET-1-induced responses. SNAP also decreased the protein synthesis induced by ET-1. Taken together, these data demonstrate that NO, in a cGMP-dependent manner, attenuated ET-1-induced phosphorylation of ERK1/2, PKB and Pyk2 and also antagonized the hypertrophic effects of ET-1. It may be suggested that NO-induced generation of cyclic GMP contributes to the inhibition of ET-1-induced mitogenic and hypertrophic response s in VSMCs. (Supported by a grant from Canadian Institutes of Health Research)