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 microM, 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.
Hawker
J R
JR
Microcirculation Research Institute, College of Medicine, Texas A & M University Health Science Center, College Station 77843.
Granger
H J
HJ
D000818:Animals; D002417:Cattle; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism*; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D019833:Genistein; D007529:Isoflavones / Q000494:pharmacology; D007700:Kinetics; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D002934:Cinnamates; D007529:Isoflavones; D014443:Tyrosine; D005346:Fibroblast Growth Factors; C067472:methyl 2,5-dihydroxycinnamate; D004247:DNA; D019833:Genistein; D011505:Protein-Tyrosine Kinases