Document Detail

Heparin inhibits phosphorylation and autonomous activity of Ca(2+)/calmodulin-dependent protein kinase II in vascular smooth muscle cells.
MedLine Citation:
PMID:  12414535     Owner:  NLM     Status:  MEDLINE    
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 Ca(2+) regulated pathways involved in mitogenic signaling in VSMC, we analyzed the effect of heparin on multifunctional Ca(2+)/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 delta-subunit of CaM kinase II which is consistent with inhibition of autophosphorylation-dependent, Ca(2+)/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.
Ketu Mishra-Gorur; Harold A Singer; John J Castellot
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The American journal of pathology     Volume:  161     ISSN:  0002-9440     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2002 Nov 
Date Detail:
Created Date:  2002-11-04     Completed Date:  2002-11-22     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1893-901     Citation Subset:  AIM; IM    
Program in Cell, Molecular and Developmental Biology, Sackler School of Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
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MeSH Terms
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
Cells, Cultured
Enzyme Inhibitors / pharmacology*
Growth Inhibitors / pharmacology*
Heparin / pharmacology*
Ionomycin / antagonists & inhibitors
Muscle, Smooth, Vascular / drug effects,  enzymology*
Phosphoprotein Phosphatases / metabolism
Phosphorylation / drug effects
Rats, Sprague-Dawley
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Growth Inhibitors; 56092-81-0/Ionomycin; 9005-49-6/Heparin; EC Protein Kinase Type 2; EC Protein Kinases; EC Phosphatases

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