Effects of rapamycin on growth factor-stimulated vascular smooth muscle cell DNA synthesis. Inhibition of basic fibroblast growth factor and platelet-derived growth factor action and antagonism of rapamycin by FK506.
Rapamycin (RPM) is a potent and effective immunosuppressant which we have shown previously to inhibit intimal thickening in rat allograft and balloon-injured arteries. In this report, we have examined the effects of RPM on growth factor-induced vascular smooth muscle cell (VSMC) DNA synthesis. RPM potently inhibited platelet-derived growth factor (PDGF) (IC50 = 5 x 10(-9) M) and basic fibroblast growth factor (bFGF) (IC50 = 8 x 10(-10) M)-induced VSMC DNA synthesis. In contrast, only the highest concentrations of FK506 and CsA significantly altered PDGF- or bFGF-induced VSMC DNA synthesis. Addition of RPM (10(-9) M) at as late as 46 hr after growth factor addition still effectively suppressed bFGF- or PDGF-induced DNA synthesis by 76% and 54%, respectively. The extent of the antagonism of RPM's inhibition of bFGF-induced VSMC DNA synthesis by FK506 was inversely proportional to RPM concentration and directly proportional to FK506 concentration.
Cao
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W
Department of Cardiothoracic Surgery, School of Medicine, Stanford University, California 94305-5247.
Mohacsi
P
P
Shorthouse
R
R
Pratt
R
R
Morris
R E
RE
D000818:Animals; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011090:Polyenes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology
D010982:Platelet-Derived Growth Factor; D011090:Polyenes; D016222:Fibroblast Growth Factor 2; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus