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(American Journal of Pathology. 2002;161:1893-1901.)
© 2002 American Society for Investigative Pathology

Heparin Inhibits Phosphorylation and Autonomous Activity of Ca²⁺/Calmodulin-Dependent Protein Kinase II in Vascular Smooth Muscle Cells

Ketu Mishra-Gorur^*, Harold A. Singer and John J. Castellot, Jr^*

From the Program in Cell, Molecular and Developmental Biology,^* Sackler School of Biomedical Sciences, Tufts University, Boston, Massachusetts; the Center for Cardiovascular Sciences, Albany Medical College, Albany, New York; and the Department of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, Massachusetts

Vascular smooth muscle cell (VSMC) hyperproliferation is a characteristic feature of both atherosclerosis and restenosis seen after vascular surgery. A number of studies have shown that heparin inhibits VSMC proliferation in vivo and in culture. To test our hypothesis that heparin mediates its antiproliferative effect by altering Ca²⁺ regulated pathways involved in mitogenic signaling in VSMC, we analyzed the effect of heparin on multifunctional Ca²⁺/calmodulin dependent protein kinase II (CaM kinase II) which is abundantly expressed in VSMC. Using activity assays, radioactive labeling, and immunoprecipitation it was found that heparin inhibits the overall phosphorylation of the -subunit of CaM kinase II which is consistent with inhibition of autophosphorylation-dependent, Ca²⁺/calmodulin-independent CaM kinase II activity. This effect was less evident in heparin-resistant cells, consistent with a role for CaM kinase II in mediating the antiproliferative effect of heparin. Finally, the effects of pharmacological inhibitors of phosphatases like okadaic acid, calyculin, and tautomycin suggest that heparin inhibits CaM kinase II phosphorylation by activating protein phosphatases 1 and 2A. These findings support the hypothesis that alterations in calcium-mediated mitogenic signaling pathways may be involved in the antiproliferative mechanism of action of heparin.

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