title: Heparin responses in vascular smooth muscle cells involve cGMP-dependent protein kinase (PKG).
abstract: 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.
authors.affiliation: Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Gilotti
authors.forename: Wutigri
authors.initials: W
authors.lastname: Nimlamool
authors.forename: Raymond
authors.initials: R
authors.lastname: Pugh
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Slee
authors.forename: Trista C
authors.initials: TC
authors.lastname: Barthol
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Miller
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Lowe-Krentz
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006493:Heparin / Q000008:administration & dosage / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D013873:Thionucleotides / Q000008:administration & dosage
chemical_list: C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D011956:Receptors, Cell Surface; D013873:Thionucleotides; C037680:heparin receptor; D006493:Heparin; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP