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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1439.)
© 2002 American Heart Association, Inc.

Vascular Biology

Contribution of Double-Stranded RNA-Activated Protein Kinase Toward Antiproliferative Actions of Heparin on Vascular Smooth Muscle Cells

Rekha C. Patel; Indhira Handy; Chandrashekhar V. Patel

From the Department of Biological Sciences (R.C.P., I.H.) and the Department of Developmental Biology and Anatomy (C.V.P.), School of Medicine, University of South Carolina, Columbia.

Correspondence to Rekha C. Patel, Department of Biological Sciences, University of South Carolina, 700 Sumter St, Columbia, SC 29208. E-mail patelr{at}sc.edu

Objective— The proliferation of vascular smooth muscle cells (VSMCs) in blood vessels after endothelial injury contributes to the onset of atherosclerosis. Heparin is a potent antiproliferative agent for VSMCs in vivo and in vitro. Although heparin has shown promise in suppressing VSMC proliferation after invasive procedures in laboratory animals, the mechanism of its antiproliferative actions is largely unknown. Here, we present evidence for the first time that the antiproliferative action of heparin is in part mediated by its ability to activate double-stranded RNA-activated protein kinase (PKR), an interferon-induced protein kinase.

Methods and Results— We have analyzed the VSMC proliferation by cell-cycle analysis and correlated it to the kinase activity of PKR in the presence of heparin. Heparin treatment of VSMCs results in activation of PKR by direct binding and results in a block in G₁- to S-phase transition. PKR-null cells are largely insensitive to the antiproliferative actions of heparin, and inhibition of PKR in VSMCs results in a partial abrogation of the antiproliferative effects of heparin.

Conclusions— These results invoke the involvement of novel PKR-dependent regulatory pathways in mediating the antiproliferative actions of heparin.

Key Words: vascular smooth muscle cell proliferation • heparin • RNA-activated protein kinase • cell cycle • interferon

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