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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 27; no. 9; pp. 1960 - 1967
• Main Authors: Yogi, A, Callera, G E, Montezano, A C.I, Aranha, A B, Tostes, R C, Schiffrin, E L, Touyz, R M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.09.2007; Hagerstown, MD Lippincott
• Subjects: Angiotensin II - physiology; Animals; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cells, Cultured; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelin-1 - physiology; Fundamental and applied biological sciences. Psychology; MAP Kinase Signaling System - physiology; Medical sciences; Mice; Mitogen-Activated Protein Kinases - metabolism; Monomeric GTP-Binding Proteins - physiology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - enzymology; Myocytes, Smooth Muscle - metabolism; Protein-Tyrosine Kinases - physiology; src-Family Kinases; Vertebrates: cardiovascular system; G protein-coupled receptors; Enzyme; Ras; c-Raf; Transferases; Mitogen-activated protein kinase; Cardiovascular disease; Smooth muscle; Endothelin 1; Src tyrosine kinases; MAPK; Vascular disease; Signal transduction; Atherosclerosis; Protein-tyrosine kinase; G protein
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.107.146746

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.