on June 14, 2007
Published online before print June 14, 2007, doi: 10.1161/ATVBAHA.107.146746
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Submitted on January 8, 2007
Accepted on May 23, 2007
Endothelin-1, but not Ang II, Activates MAP Kinases Through c-Src-Independent Ras-Raf-Dependent Pathways in Vascular Smooth Muscle Cells
A. Yogi ;
From the Kidney Research Centre (A.Y., G.E.C., A.C.I.M., A.B.A., R.M.T.), Ottawa Health Research Institute, University of Ottawa, Ontario, Canada; the Department of Pharmacology (A.Y., R.C.T.), Institute of Biomedical Sciences-USP, Sao Paulo, Brazil; and Lady Davis Institute for Medical Research (E.L.S.), Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Canada.
* To whom correspondence should be addressed. E-mail: rtouyz{at}uottawa.ca.
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.
Key words: MAPK • Src tyrosine kinases • Ras • c-Raf • signal transduction • G protein-coupled receptors
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