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) (IC 50 =5×10 -9 M) and basic fibroblast growth factor (bFGF) (IC 50 =8×10 -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