Endothelin-1, but Not Ang Ii, Activates Map Kinases Through C-src Independent Ras-raf Dependent Pathways in Vascular Smooth Muscle Cells.
From: Kidney Research Centre, University of Ottawa/Ottawa Health Research Institute, 451 Smyth Rd, Ottawa, ON, KIH 8M5.
Arteriosclerosis, thrombosis, and vascular biology
- Publish Date: Sep 2007
- ISSN: 1524-4636
- Volume: 27
- Issue: 9
- Pages: 1960-7
- Medium: Internet
- Language: English
- Citation (JAMA): Yogi A, Callera G E, Montezano A C I, et al. Endothelin-1, but Not Ang Ii, Activates Map Kinases Through C-src Independent Ras-raf Dependent Pathways in Vascular Smooth Muscle Cells.. Arterioscler. Thromb. Vasc. Biol. Sep 2007;27:1960-7
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.
Mesh Headings (Keywords): Angiotensin II, Animals, Cells, Cultured, Endothelin-1, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinases, Monomeric GTP-Binding Proteins, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Protein-Tyrosine Kinases
Check for Full Text / PubMed Unique Identifier (PMID): 17569879
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