Endothelin-1, but not Ang II, activates MAP kinases through c-Src-independent Ras-Raf-dependent pathways in vascular smooth muscle cells

Yogi, A., Callera, G.E., Montezano, A.C., Aranha, A.B., Tostes, R.C., Schiffrin, E.L. and Touyz, R.M. (2007) Endothelin-1, but not Ang II, activates MAP kinases through c-Src-independent Ras-Raf-dependent pathways in vascular smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 27(9), pp. 1960-1967. (doi: 10.1161/ATVBAHA.107.146746)

Abstract

<b>Objective—</b> Endothelin-1 (ET-1) and angiotensin II (Ang II) activate common signaling pathways to promote changes in vascular reactivity, remodeling, inflammation, and oxidative stress. Here we sought to determine whether upstream regulators of mitogen-activated protein kinases (MAPKs) are differentially regulated by ET-1 and Ang II focusing on the role of c-Src and the small GTPase Ras.<p></p> <b>Methods and Results—</b> Mesenteric vascular smooth muscle cells (VSMCs) from mice with different disruption levels in the c-Src gene (c-Src+/− and c-Src−/−) and wild-type (c-Src+/+) were used. ET-1 and Ang II induced extracellular signal-regulated kinase (ERK) 1/2, SAPK/JNK, and p38MAPK phosphorylation in c-Src+/+ VSMCs. In VSMCs from c-Src+/− and c-Src−/−, Ang II effects were blunted, whereas c-Src deficiency had no effect in ET-1–induced MAPK activation. Ang II but not ET-1 induced c-Src phosphorylation in c-Src+/+ VSMCs. Activation of c-Raf, an effector of Ras, was significantly increased by ET-1 and Ang II in c-Src+/+ VSMCs. Ang II but not ET-1–mediated c-Raf phosphorylation was inhibited by c-Src deficiency. Knockdown of Ras by siRNA inhibited both ET-1 and Ang II–induced MAPK phosphorylation.<p></p> <b>Conclusions—</b> Our data indicate differential regulation of MAPKs by distinct G protein–coupled receptors. Whereas Ang II has an obligatory need for c-Src, ET-1 mediates its actions through a c-Src–independent Ras-Raf–dependent pathway for MAPK activation. These findings suggest that Ang II and ET-1 can activate similar signaling pathways through unrelated mechanisms. MAP kinases are an important point of convergence for Ang II and ET-1.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Montezano, Dr Augusto and Touyz, Professor Rhian
• Authors: Yogi, A., Callera, G.E., Montezano, A.C., Aranha, A.B., Tostes, R.C., Schiffrin, E.L., and Touyz, R.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Arteriosclerosis, Thrombosis, and Vascular Biology
• Publisher: American Heart Association
• ISSN: 1079-5642
• ISSN (Online): 1524-4636
• Published Online: 14 June 2007