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in Vascular Smooth Muscle Cells
1 Physiology, Meharry Medical College, Nashville, TN, USA
2 Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA, USA
3 Biochemistry and Molecular Pathophysiology, University of Occupational and Environmental Health, Japan, School of Medicine, Kitakyushu, Japan, Japan
4 Pharmacology, University of Neveda School of Medicine, Reno, NV, USA
* To whom correspondence should be addressed. E-mail: emotley{at}mmc.edu.
Angiotensin II (Ang II) promotes remodeling of vascular smooth muscle cells (VSMCs) in cardiovascular diseases. It has been shown to activate p21-activated kinase 1 (PAK1), a critical component of signaling pathways implicated in growth and migration. However, the detailed signaling mechanism by which Ang II induces PAK1 activation in VSMCs remains unclear. Therefore, we have examined the mechanism required for activation of PAK1 by Ang II in VSMCs. Ang II, through activation of the Ang II type-1 receptor, rapidly promotes phosphorylation of PAK1 in VSMCs via a pathway independent of transactivation of the epidermal growth factor receptor. Using selective agonists and inhibitors, we demonstrated that mobilization of intracellular Ca2+ and protein kinase C delta (PKC
) activation are required for Ang II-induced PAK1 phosphorylation. Rottlerin, a PKC inhibitor, significantly blocked Ang II-induced PAK1 phosphorylation. Further support of this notion is provided through infection of VSMCs with the adenovirus encoding a dominant-negative (dn) PKC which also markedly reduced phosphorylation of PAK1 by Ang II. In this pathway, Ca2+ acts upstream of PKC since a Ca2+ ionophore rapidly induced PKC phosphorylation at Tyr311 and Ca2+-dependent PAK1 phosphorylation was blocked by rottlerin. In addition, dnPYK2, dnRac, and antioxidants inhibited Ang II-induced PAK1 phosphorylation, suggesting that PYK2, Rac, and reactive oxygen species are involved in the upstream signaling. Finally, dnPAK1 markedly inhibited AngII-induced protein synthesis in VSMCs. These data provide a novel signaling pathway by which Ang II may contribute to vascular remodeling.
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