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: 287/6/L1314    most recent 00383.2003v1 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 (10) Citing Articles via Google Scholar Google Scholar Articles by Patil, S. Articles by Black, S. M. Search for Related Content PubMed PubMed Citation Articles by Patil, S. Articles by Black, S. M.

Important role for Rac1 in regulating reactive oxygen species generation and pulmonary arterial smooth muscle cell growth

¹Department of Pediatrics, Northwestern University, Chicago, Illinois 60611; and ²Department of Biomedical and Pharmaceutical Sciences and ³International Heart Institute of Montana, University of Montana, Missoula, Montana 59802

Submitted 10 November 2003 ; accepted in final form 4 August 2004

Vascular NADPH oxidases have been shown to be a major source of reactive oxygen species (ROS). Recent studies have also implicated ROS in the proliferation of vascular smooth muscle cells. However, the components required for activation of the NADPH oxidase complex have not been clearly elucidated. Here we demonstrate that ROS generation in ovine pulmonary arterial smooth muscle cells (PASMCs) requires the activation of Rac1, implicating this protein as an important subunit of the NADPH oxidase complex. Our results, using a geranylgeranyl transferase inhibitor (GGTI-287), demonstrated a dose-dependent inhibition of Rac1 activity and ROS production. This was associated with an inhibition of PASMC proliferation with an arrest at G₂/M. The inhibition of Rac1 by GGTI-287 led us to more specifically target Rac1 to investigate its role in the generation of ROS and cellular proliferation. To accomplish this, we utilized a dominant negative Rac1 (N17Rac1) and a constitutively active Rac1 (V12Rac1). These two forms of Rac1 were transiently expressed in PASMCs using adenovirus-mediated gene transfer. N17Rac1 expression resulted in decreased cellular Rac1 activity, whereas V12Rac1 infection showed increased activity. Compared with controls, the V12Rac1-expressing cells had higher levels of ROS production and increased proliferation, whereas the N17Rac1-expressing cells had decreased ROS generation and proliferation and cell cycle arrest at G₂/M. However, the inhibition of cell growth produced by N17Rac1 overexpression could be overcome if cells were co-incubated with the Cu,Zn superoxide dismutase inhibitor DETC. These results indicate the importance of Rac1 in ROS generation and proliferation of vascular smooth muscle cells.

vascular reduced nicotinamide adenine dinucleotide phosphate oxidase

This article has been cited by other articles:

				S. M. Black, J. M. DeVol, and S. Wedgwood Regulation of fibroblast growth factor-2 expression in pulmonary arterial smooth muscle cells involves increased reactive oxygen species generation Am J Physiol Cell Physiol, January 1, 2008; 294(1): C345 - C354. [Abstract] [Full Text] [PDF]

				S.-E. Chow, Y.-C. Hshu, J.-S. Wang, and J.-K. Chen Resveratrol attenuates oxLDL-stimulated NADPH oxidase activity and protects endothelial cells from oxidative functional damages J Appl Physiol, April 1, 2007; 102(4): 1520 - 1527. [Abstract] [Full Text] [PDF]

				K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF]

				M. Oelze, A. Warnholtz, J. Faulhaber, P. Wenzel, A. L. Kleschyov, M. Coldewey, U. Hink, O. Pongs, I. Fleming, S. Wassmann, et al. NADPH Oxidase Accounts for Enhanced Superoxide Production and Impaired Endothelium-Dependent Smooth Muscle Relaxation in BK{beta}1-/- Mice Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1753 - 1759. [Abstract] [Full Text] [PDF]

				A. C. Grobe, S. M. Wells, E. Benavidez, P. Oishi, A. Azakie, J. R. Fineman, and S. M. Black Increased oxidative stress in lambs with increased pulmonary blood flow and pulmonary hypertension: role of NADPH oxidase and endothelial NO synthase Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1069 - L1077. [Abstract] [Full Text] [PDF]

				A.-C. Ceacareanu, B. Ceacareanu, D. Zhuang, Y. Chang, R. M. Ray, L. Desai, K. E. Chapman, C. M. Waters, and A. Hassid Nitric oxide attenuates IGF-I-induced aortic smooth muscle cell motility by decreasing Rac1 activity: essential role of PTP-PEST and p130cas Am J Physiol Cell Physiol, April 1, 2006; 290(4): C1263 - C1270. [Abstract] [Full Text] [PDF]