Contribution of double-stranded RNA-activated protein kinase toward antiproliferative actions of heparin on vascular smooth muscle cells.
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.


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.
Patel
Rekha C
RC
Department of Biological Sciences, School of Medicine, University of South Carolina, Columbia 29208, USA. patelr@sc.edu
Handy
Indhira
I
Patel
Chandrashekhar V
CV
D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000502:physiology*
D006131:Growth Inhibitors; D006493:Heparin; D019892:eIF-2 Kinase