Heparin inhibits c-fos and c-myc mRNA expression in vascular smooth muscle cells.
Heparin is a potent inhibitor of vascular smooth muscle cell (VSMC) growth. In this paper we show that heparin suppressed the induction of c-fos and c-myc mRNA in rat and calf VSMC. This effect of heparin is closely associated with its growth-inhibitory activity, as shown by isolating and characterizing a strain of rat VSMC that was resistant to heparin's antiproliferative effect; heparin did not suppress c-fos mRNA induction in these cells. Moreover, neither a nonantiproliferative heparin fragment or other glycosaminoglycans that lack growth-inhibitory activity repressed c-fos or c-myc mRNA levels. The effect of heparin on c-fos mRNA induction was selective for specific mitogens, as heparin inhibited c-fos mRNA induction in phorbol 12-myristate 13-acetate (TPA) stimulated but not epidermal growth factor (EGF) stimulated VSMC. The effect of heparin on gene expression is independent of ongoing protein synthesis, and inhibition of c-fos mRNA is at the transcriptional level. These results suggest that heparin may selectively inhibit a protein kinase C-dependent pathway for protooncogene induction and that this may be one mechanism used by heparin to inhibit cell proliferation.
Pukac
L A
LA
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115.
Castellot
J J
JJ
Wright
T C
TC
Caleb
B L
BL
Karnovsky
M J
MJ
D000818:Animals; D002455:Cell Division / Q000502:physiology; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000235:genetics*; D006025:Glycosaminoglycans / Q000502:physiology; D006131:Growth Inhibitors; D006493:Heparin / Q000502:physiology*; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D011519:Proto-Oncogenes / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains
D006025:Glycosaminoglycans; D006131:Growth Inhibitors; D012333:RNA, Messenger; D006493:Heparin; D011493:Protein Kinase C