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J. Biol. Chem., Vol. 280, Issue 33, 29864-29873, August 19, 2005

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Forkhead Transcription Factors Inhibit Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia^*

Md. Ruhul Abid, Kiichiro Yano, Shaodong Guo, Virendra I. Patel, Gautam Shrikhande, Katherine C. Spokes, Christiane Ferran, and William C. Aird¶

From the Center for Vascular Biology Research, Department of Medicine, Divisions of Molecular and Vascular Medicine and Vascular Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Vascular smooth muscle cell (VSMC) proliferation and migration contribute significantly to atherosclerosis, postangioplasty restenosis, and transplant vasculopathy. Forkhead transcription factors belonging to the FoxO subfamily have been shown to inhibit growth and cell cycle progression in a variety of cell types. We hypothesized that forkhead proteins may play a role in VSMC biology. Under in vitro conditions, platelet-derived growth factor (PDGF)-BB, tumor necrosis factor-, and insulin-like growth factor 1 stimulated phosphorylation of FoxO in human coronary artery smooth muscle cells via MEK1/2 and/or phosphatidylinositol 3-kinase-dependent signaling pathways. PDGF-BB, tumor necrosis factor-, and insulin-like growth factor 1 treatment resulted in the nuclear exclusion of FoxO, whereas PDGF-BB alone down-regulated the FoxO target gene, p27^kip1, and enhanced cell survival and progression through the cell cycle. These effects were abrogated by overexpression of a constitutively active, phosphorylation-resistant mutant of the FoxO family member, TM-FKHRL1. The anti-proliferative effect of TM-FKHRL1 was partially reversed by small interfering RNA against p27^kip1. In a rat balloon carotid arterial injury model, adenovirus-mediated gene transfer of FKHRL1 caused an increase in the expression of p27^kip1 in the VSMC and inhibition of neointimal hyperplasia. These data suggest that FoxO activity inhibits VSMC proliferation and activation and that this signaling axis may represent a therapeutic target in vasculopathic disease states.

Received for publication, February 25, 2005 , and in revised form, May 18, 2005.

^* This work was supported in part by American Heart Association National Scientist Development Grant 0435284N (to M. R. A.); National Institutes of Health Grants HL60585, HL63609, HL65216, and HL36028 (to W. C. A.), T32 HL07734-08 (to C. F., V. I. P., and G. S.), and HL57791-04 (to C. F.); and a grant from the Roche Organ Transplantation Research Foundation (Basel, Switzerland) (to C. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two additional figures.

^¶ To whom correspondence should be addressed: Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, RW-663, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-1031; Fax: 617-667-1035; E-mail: waird{at}bidmc.harvard.edu.

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