TYROSINE KINASE INHIBITORS IMPAIR FIBROBLAST GROWTH-FACTOR SIGNALING IN CORONARY ENDOTHELIAL-CELLS

We examined the effect of various tyrosine kinase inhibitors on basic fibroblast growth factor (bFGF)-induced cell signaling and DNA synthesis in coronary venular endothelial cells (CVEC). Two tyrosine kinase inhibitors, genistein and methyl 2,5-dihydroxycinnamate, showed reversible, dose-dependent inhibition of bFGF-stimulated DNA synthesis in CVEC with half-maximal inhibitory concentrations of 12 and 3 mu M, respectively. Both compounds exhibited preferential inhibition of bFGF vs. serum-induced DNA synthesis. bFGF stimulated increased tyrosine phosphorylation of CVEC cellular proteins, including the FGF receptor, which were visible within 1 min of treatment. Concomitant with their effect on DNA synthesis, both compounds exhibited dose-dependent inhibition of tyrosine phosphorylation of intracellular substrates induced by bFGF. A 2-h pretreatment of quiescent CVEC with genistein blocked nuclear translocation but not cytoplasmic internalization of bFGF, whereas the same treatment with methyl 2,5-dihydroxycinnamate inhibited both processes. These results suggest that activation of bFGF receptor tyrosine kinase activity plays a role in nuclear translocation of bFGF and initiation of DNA synthesis in endothelial cells.