RAPAMYCIN-FKBP INHIBITS CELL-CYCLE REGULATORS OF PROLIFERATION IN VASCULAR SMOOTH-MUSCLE CELLS

Multiple growth factors can stimulate quiescent vascular smooth muscle cells to exit from G0 and reenter the cell cycle. The macrolide antib iotic rapamycin, bound to its cytosolic receptor FKBP, is an immunosup pressant and a potent inhibitor of cellular proliferation. In the pres ent study, the antiproliferative effects of rapamycin on human and rat vascular smooth muscle cells were examined and compared with the effe cts of a related immunosuppressant, FK520. In vascular smooth muscle c ells, rapamycin, at concentrations as low as 1 ng/mL, inhibited DNA sy nthesis and cell growth. FK520, an analogue of the immunosuppressant F K506, is structurally related to rapamycin and binds to FKBP but did n ot inhibit vascular smooth muscle cell growth. Molar excesses of FK520 blocked the antiproliferative effects of rapamycin, indicating that t he effects of rapamycin required binding to FKBP. Rapamycin-FKBP inhib ited retinoblastoma protein phosphorylation at the G1/S transition. Th is inhibition of retinoblastoma protein phosphorylation was associated with a decrease in p33(cdk2) kinase activity. These observations sugg est that rapamycin, but not FK520, inhibits vascular smooth muscle cel l proliferation by reducing cell-cycle kinase activity.