This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 27/9/1960    most recent ATVBAHA.107.146746v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yogi, A. Articles by Touyz, R.M. Search for Related Content PubMed PubMed Citation Articles by Yogi, A. Articles by Touyz, R.M.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1960.)
© 2007 American Heart Association, Inc.

Vascular Biology

Endothelin-1, but not Ang II, Activates MAP Kinases Through c-Src–Independent Ras-Raf–Dependent Pathways in Vascular Smooth Muscle Cells

A. Yogi; G.E. Callera; A.C.I. Montezano; A.B. Aranha; R.C. Tostes; E.L. Schiffrin; R.M. Touyz

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.

Correspondence to Rhian M. Touyz, MD, PhD, Kidney Research Centre, University of Ottawa/Ottawa Health Research Institute, 451 Smyth Rd, Ottawa, ON, KIH 8M5. 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.

c-Src and Ras involvement in MAPK activation by ET-1 and Ang II was examined. ET-1, but not Ang II, induced MAPK phosphorylation in c-Src–deficient VSMCs. Ras knockdown by siRNA inhibited both Ang II– and ET-1–induced effects. Our findings demonstrate that whereas MAPK regulation by Ang II is c-Src–sensitive, ET-1–mediated actions involve c-Src–independent Ras-Raf–dependent pathways.

Key Words: MAPK • Src tyrosine kinases • Ras • c-Raf • signal transduction • G protein–coupled receptors

This article has been cited by other articles:

				T. Matsumoto, K. Ishida, N. Nakayama, T. Kobayashi, and K. Kamata Involvement of NO and MEK/ERK pathway in enhancement of endothelin-1-induced mesenteric artery contraction in later-stage type 2 diabetic Goto-Kakizaki rat Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1388 - H1397. [Abstract] [Full Text] [PDF]

				U. Sen, N. Tyagi, P. K. Patibandla, W. L. Dean, S. C. Tyagi, A. M. Roberts, and D. Lominadze Fibrinogen-induced endothelin-1 production from endothelial cells Am J Physiol Cell Physiol, April 1, 2009; 296(4): C840 - C847. [Abstract] [Full Text] [PDF]

				F. R. C. Giachini, S. M. Zemse, F. S. Carneiro, V. V. Lima, Z. N. Carneiro, G. E. Callera, A. Ergul, R. C. Webb, and R. C. Tostes Interleukin-10 attenuates vascular responses to endothelin-1 via effects on ERK1/2-dependent pathway Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H489 - H496. [Abstract] [Full Text] [PDF]

				M. Klein, R. T. Schermuly, P. Ellinghaus, H. Milting, B. Riedl, S. Nikolova, S. S. Pullamsetti, N. Weissmann, E. Dony, R. Savai, et al. Combined Tyrosine and Serine/Threonine Kinase Inhibition by Sorafenib Prevents Progression of Experimental Pulmonary Hypertension and Myocardial Remodeling Circulation, November 11, 2008; 118(20): 2081 - 2090. [Abstract] [Full Text] [PDF]

				V. Bugaj, O. Pochynyuk, E. Mironova, A. Vandewalle, J. L. Medina, and J. D. Stockand Regulation of the epithelial Na+ channel by endothelin-1 in rat collecting duct Am J Physiol Renal Physiol, October 1, 2008; 295(4): F1063 - F1070. [Abstract] [Full Text] [PDF]

				R. Lu, A. Alioua, Y. Kumar, P. Kundu, M. Eghbali, N. V. Weisstaub, J. A. Gingrich, E. Stefani, and L. Toro c-Src tyrosine kinase, a critical component for 5-HT2A receptor-mediated contraction in rat aorta J. Physiol., August 15, 2008; 586(16): 3855 - 3869. [Abstract] [Full Text] [PDF]

				A.C. Montezano, G.E. Callera, A. Yogi, Y. He, R.C. Tostes, G. He, E.L. Schiffrin, and R.M. Touyz Aldosterone and Angiotensin II Synergistically Stimulate Migration in Vascular Smooth Muscle Cells Through c-Src-Regulated Redox-Sensitive RhoA Pathways Arterioscler Thromb Vasc Biol, August 1, 2008; 28(8): 1511 - 1518. [Abstract] [Full Text] [PDF]