HEPARIN INHIBITS PHORBOL ESTER-INDUCED ORNITHINE DECARBOXYLASE GENE-EXPRESSION IN ENDOTHELIAL-CELLS

Glycosaminoglycans regulate angiogenesis by affecting the availability of different growth factors for the endothelial cell (EC), However, l ittle is known about the molecular and functional consequences resulti ng from direct interaction of these polyclectrolytes with the EC, Here me show that heparin markedly inhibited serum-stimulated DNA synthesi s and ornithine decarboxylase (ODC) mRNA expression in human endotheli al cells (HEC), About 50% of the serum effect on DNA synthesis and ODC gene expression was prevented by the selective protein kinase C (PI(C ) inhibitor chelerythrine or by PKC down-regulation, Heparin was ineff ective in counteracting that part of the effect of serum that,vas resi stant to PKC inhibition or down-regulation. In serum-free cultured HEC , heparin completely abolished the increase in DNA synthesis and ODC m RNA expression elicited by a number of PKC activators, Cell exposure t o difluoromethylornithine, an irreversible inhibitor of ODC enzyme, dr amatically antagonised both serum- and phorbol 12-myristate 13-acetate (PMA)-stimulated DNA synthesis, These results suggest that inhibition of PKC-mediated ODC gene expression by glycosaminoglycans mag represe nt an important mechanism in the regulation of HEC proliferation. (C) 1998 Federation of European Biochemical Societies.