Heparin Responses in Vascular Smooth Muscle Cells Involve cGMP-Dependent Protein Kinase (PKG)

Published data provide strong evidence that heparin treatment of proliferating vascular smooth muscle cells results in decreased signaling through the ERK pathway and decreases in cell proliferation. In addition, these changes have been shown to be mimicked by antibodies that block heparin binding t...

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Bibliographic Details
Published in:	Journal of cellular physiology Vol. 229; no. 12; pp. 2142 - 2152
Main Authors:	Gilotti, Albert C., Nimlamool, Wutigri, Pugh, Raymond, Slee, Joshua B., Barthol, Trista C., Miller, Elizabeth A., Lowe-Krentz, Linda J.
Format:	Journal Article
Language:	English
Published:	United States Blackwell Publishing Ltd 01-12-2014 Wiley Subscription Services, Inc
Subjects:	Animals Cell Proliferation - drug effects Cyclic GMP - administration & dosage Cyclic GMP - analogs & derivatives Cyclic GMP - metabolism Cyclic GMP-Dependent Protein Kinases - genetics Cyclic GMP-Dependent Protein Kinases - metabolism Gene Expression Regulation - drug effects Heparin - administration & dosage Heparin - metabolism MAP Kinase Signaling System - drug effects Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - metabolism Phosphorylation - drug effects Rats Receptors, Cell Surface - metabolism Thionucleotides - administration & dosage
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Summary:	Published data provide strong evidence that heparin treatment of proliferating vascular smooth muscle cells results in decreased signaling through the ERK pathway and decreases in cell proliferation. In addition, these changes have been shown to be mimicked by antibodies that block heparin binding to the cell surface. Here, we provide evidence that the activity of protein kinase G is required for these heparin effects. Specifically, a chemical inhibitor of protein kinase G, Rp‐8‐pCPT‐cGMS, eliminates heparin and anti‐heparin receptor antibody effects on bromodeoxyuridine incorporation into growth factor‐stimulated cells. In addition, protein kinase G inhibitors decrease heparin effects on ERK activity, phosphorylation of the transcription factor Elk‐1, and heparin‐induced MKP‐1 synthesis. Although transient, the levels of cGMP increase in heparin treated cells. Finally, knock down of protein kinase G also significantly decreases heparin effects in growth factor‐activated vascular smooth muscle cells. Together, these data indicate that heparin effects on vascular smooth muscle cell proliferation depend, at least in part, on signaling through protein kinase G. J. Cell. Physiol. 229: 2142–2152, 2014. © 2014 Wiley Periodicals, Inc.
Bibliography:	ark:/67375/WNG-S4L26KPG-Z ArticleID:JCP24677 Public Health Service - No. HL54269 istex:75C53FA09F251BCFED643AA7027A80EC436C7C28 Current address: Toxological Sciences, Merck Research Laboratories, Building K-15, Block F – 2516, 2000 Galloping Hill Road, Kenilworth, NJ 07033 Current address: Penn State University, 403 Wartik Laboratory, University Park, PA 16802 Current address: Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104 and The University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104
ISSN:	0021-9541 1097-4652
DOI:	10.1002/jcp.24677