HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 289/5/C1286    most recent 00448.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (18) Citing Articles via Google Scholar Google Scholar Articles by Woolfolk, E. A. Articles by Motley, E. D. Search for Related Content PubMed PubMed Citation Articles by Woolfolk, E. A. Articles by Motley, E. D.

RECEPTORS AND SIGNAL TRANSDUCTION

Angiotensin II-induced activation of p21-activated kinase 1 requires Ca²⁺ and protein kinase C in vascular smooth muscle cells

¹Department of Physiology, Meharry Medical College, Nashville, Tennessee; ²Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania; ³Department of Biochemistry and Molecular Pathophysiology, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan; and ⁴Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada

Submitted 10 September 2004 ; accepted in final form 13 July 2005

ANG II promotes remodeling of vascular smooth muscle cells (VSMCs) in cardiovascular diseases. It has been shown to activate p21-activated kinase (PAK)1, 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 PKC activation are required for ANG II-induced PAK1 phosphorylation. Rottlerin, a PKC inhibitor, significantly blocked ANG II-induced PAK1 phosphorylation. Further support for this notion was provided through infection of VSMCs with 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 because a Ca²⁺ ionophore rapidly induced PKC phosphorylation at Tyr311 and Ca²⁺-dependent PAK1 phosphorylation was blocked by rottlerin. In addition, dnPYK-2, dnRac, and antioxidants inhibited ANG II-induced PAK1 phosphorylation, suggesting that PYK-2, Rac, and reactive oxygen species are involved in the upstream signaling. Finally, dnPAK1 markedly inhibited ANG II-induced protein synthesis in VSMCs. These data provide a novel signaling pathway by which ANG II may contribute to vascular remodeling.

vascular remodeling; signal transduction

This article has been cited by other articles:

				D. D. Tang and Y. Anfinogenova Physiologic Properties and Regulation of the Actin Cytoskeleton in Vascular Smooth Muscle Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2008; 13(2): 130 - 140. [Abstract] [PDF]

				D. D. Tang Intermediate filaments in smooth muscle Am J Physiol Cell Physiol, April 1, 2008; 294(4): C869 - C878. [Abstract] [Full Text] [PDF]

				H. Nakashima, G. D. Frank, H. Shirai, A. Hinoki, S. Higuchi, H. Ohtsu, K. Eguchi, A. Sanjay, M. E. Reyland, P. J. Dempsey, et al. Novel Role of Protein Kinase C-{delta} Tyr311 Phosphorylation in Vascular Smooth Muscle Cell Hypertrophy by Angiotensin II Hypertension, February 1, 2008; 51(2): 232 - 238. [Abstract] [Full Text] [PDF]

				H. Ohtsu, H. Suzuki, H. Nakashima, S. Dhobale, G. D. Frank, E. D. Motley, and S. Eguchi Angiotensin II Signal Transduction Through Small GTP-Binding Proteins: Mechanism and Significance in Vascular Smooth Muscle Cells Hypertension, October 1, 2006; 48(4): 534 - 540. [Full Text] [PDF]

				H. Ohtsu, P. J. Dempsey, G. D. Frank, E. Brailoiu, S. Higuchi, H. Suzuki, H. Nakashima, K. Eguchi, and S. Eguchi ADAM17 Mediates Epidermal Growth Factor Receptor Transactivation and Vascular Smooth Muscle Cell Hypertrophy Induced by Angiotensin II Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): e133 - e137. [Abstract] [Full Text] [PDF]