Open AccessEndothelin-1, but not Ang II, Activates MAP Kinases Through c-Src–Independent Ras-Raf–Dependent Pathways in Vascular Smooth Muscle Cells
Author(s) -
Álvaro Yogi,
Gláucia E. Callera,
Augusto C. Montezano,
Anna B. Aranha,
Rita C. Tostes,
Ernesto L. Schiffrin,
Rhian M. Touyz
Publication year - 2007
Publication title -
arteriosclerosis, thrombosis, and vascular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.007
H-Index - 270
eISSN - 1524-4636
pISSN - 1079-5642
DOI - 10.1161/atvbaha.107.146746
Subject(s) - proto oncogene tyrosine protein kinase src , vascular smooth muscle , angiotensin ii , phosphorylation , mapk/erk pathway , kinase , signal transduction , microbiology and biotechnology , chemistry , tyrosine protein kinase csk , p38 mitogen activated protein kinases , sh3 domain , biology , medicine , receptor , endocrinology , biochemistry , smooth muscle
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.