This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 98/10/1254    most recent 01.RES.0000221214.37803.79v1 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 PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vendrov, A. E. Articles by Runge, M. S. Search for Related Content PubMed PubMed Citation Articles by Vendrov, A. E. Articles by Runge, M. S. Related Collections Thrombin Oxidant stress Mechanism of atherosclerosis/growth factors Cell signalling/signal transduction Gene expression Gene regulation Smooth muscle proliferation and differentiation

(Circulation Research. 2006;98:1254.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Thrombin and NAD(P)H Oxidase–Mediated Regulation of CD44 and BMP4-Id Pathway in VSMC, Restenosis, and Atherosclerosis

Aleksandr E. Vendrov, Nageswara R. Madamanchi, Zeenat S. Hakim, Mauricio Rojas, Marschall S. Runge

From the Carolina Cardiovascular Biology Center, Department of Medicine, University of North Carolina at Chapel Hill.

Correspondence to Marschall S. Runge, 3033 OCB, UNC-CH, Chapel Hill, NC 27599-7055. E-mail mrunge{at}med.unc.edu

To characterize novel signaling pathways that underlie NAD(P)H oxidase–mediated signaling in atherosclerosis, we first examined differences in thrombin-induced gene expression between wild-type and p47phox^–/– (NAD[P]H oxidase–deficient) VSMC. Of the 9000 genes analyzed by cDNA microarray method at the G₁/S transition point, 76 genes were similarly and significantly modulated in both the cell types, whereas another 22 genes that encompass various functional groups were regulated in NAD(P)H oxidase–dependent manner. Among these 22 genes, thrombin-induced NAD(P)H oxidase–mediated regulation of Klf15, Igbp1, Ak4, Adamts5, Ech1, Serp1, Sec61a2, Aox1, Aoh1, Fxyd5, Rai14, and Serpinh1 was shown for the first time in VSMC. The role of NAD(P)H oxidase in the regulation of a subset of these genes (CD44, BMP4, Id1, and Id3) was confirmed using modulators of reactive oxygen species (ROS) generation, a ROS scavenger and in gain-of-function experiments. We then characterized regulation of these genes in restenosis and atherosclerosis. In both apoE^–/– mice and in a mouse vascular injury model, these genes are regulated in NAD(P)H oxidase–dependent manner during vascular lesion formation. Based on these findings, we propose that NAD(P)H oxidase–dependent gene expression in general, and the CD44 and BMP4-Id signaling pathway in particular, is important in restenosis and atherosclerosis.

Key Words: vascular smooth muscle cells • reactive oxygen species • microarray • redox regulation

This article has been cited by other articles:

				J. Kim, L. Zhang, K. Peppel, J.-H. Wu, D. A. Zidar, L. Brian, S. M. DeWire, S. T. Exum, R. J. Lefkowitz, and N. J. Freedman {beta}-Arrestins Regulate Atherosclerosis and Neointimal Hyperplasia by Controlling Smooth Muscle Cell Proliferation and Migration Circ. Res., July 3, 2008; 103(1): 70 - 79. [Abstract] [Full Text] [PDF]

				S. Hagita, M. Osaka, K. Shimokado, and M. Yoshida Oxidative Stress in Mononuclear Cells Plays a Dominant Role in Their Adhesion to Mouse Femoral Artery After Injury Hypertension, March 1, 2008; 51(3): 797 - 802. [Abstract] [Full Text] [PDF]

				A. E. Vendrov, Z. S. Hakim, N. R. Madamanchi, M. Rojas, C. Madamanchi, and M. S. Runge Atherosclerosis Is Attenuated by Limiting Superoxide Generation in Both Macrophages and Vessel Wall Cells Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2714 - 2721. [Abstract] [Full Text] [PDF]

				A. S. Martin, P. Du, A. Dikalova, B. Lassegue, M. Aleman, M. C. Gongora, K. Brown, G. Joseph, D. G. Harrison, W. R. Taylor, et al. Reactive oxygen species-selective regulation of aortic inflammatory gene expression in Type 2 diabetes Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2073 - H2082. [Abstract] [Full Text] [PDF]