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J. Biol. Chem., Vol. 280, Issue 16, 15682-15689, April 22, 2005

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Regulation of Vascular Smooth Muscle Proliferation by Heparin

INHIBITION OF CYCLIN-DEPENDENT KINASE 2 ACTIVITY BY p27^kip1*

Stephen Fasciano, Rekha C. Patel, Indhira Handy, and Chandrashekhar V. Patel

From the Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208

Uncontrolled proliferation of vascular smooth muscle cells (VSMCs) contribute to intimal hyperplasia during atherosclerosis and restenosis. Heparin is an antiproliferative agent for VSMCs and has been shown to block VSMC proliferation both in tissue culture systems and in animals. Despite the well documented antiproliferative actions of heparin, its cellular targets largely remain unknown. In an effort to characterize the mechanism of the antiproliferative property of heparin, we have analyzed the effect of heparin on cell cycle in VSMC. Our results indicate that the heparin-induced block in G₁ to S phase transition is imposed by p27^kip1-mediated inhibition of cyclin-dependent kinase 2 activity. Further analysis of p27^kip1 mRNA levels showed that the increase in p27^kip1 protein levels in heparin-treated VSMC occurs at posttranscriptional levels. We present evidence that heparin causes stabilization of p27^kip1 protein during G₁ phase and thereby prevents activation of cyclin-dependent kinase 2.

Received for publication, October 7, 2004 , and in revised form, February 23, 2005.

^* This work was supported by U. S. Public Health Service Grant R01 HL63359 (NHLBI, National Institutes of Health) (to R. C. P.).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 Supplemental Figs. 1 and 2.

To whom correspondence should be addressed: Dept. of Biological Sciences, University of South Carolina, 700 Sumter St., Columbia, SC 29208. Tel.: 803-777-1853; Fax: 803-777-4002; E-mail: patelr{at}sc.edu.

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