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

By A. Yogi, G.E. Callera, A.C. Montezano, A.B. Aranha, R.C. Tostes, E.L. Schiffrin and R.M. Touyz

Abstract

Objective— 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. Methods and Results— 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. Conclusions— 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

Publisher: 'Ovid Technologies (Wolters Kluwer Health)'
Year: 2007
DOI identifier: 10.1161/ATVBAHA.107.146746
OAI identifier: oai:eprints.gla.ac.uk:62403
Provided by: Enlighten
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