Marx S O, Jayaraman T, Go L O, Marks A R
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029.
Circ Res. 1995 Mar;76(3):412-7. doi: 10.1161/01.res.76.3.412.
Multiple growth factors can stimulate quiescent vascular smooth muscle cells to exit from G0 and reenter the cell cycle. The macrolide antibiotic rapamycin, bound to its cytosolic receptor FKBP, is an immunosuppressant and a potent inhibitor of cellular proliferation. In the present study, the antiproliferative effects of rapamycin on human and rat vascular smooth muscle cells were examined and compared with the effects of a related immunosuppressant, FK520. In vascular smooth muscle cells, rapamycin, at concentrations as low as 1 ng/mL, inhibited DNA synthesis and cell growth. FK520, an analogue of the immunosuppressant FK506, is structurally related to rapamycin and binds to FKBP but did not inhibit vascular smooth muscle cell growth. Molar excesses of FK520 blocked the antiproliferative effects of rapamycin, indicating that the effects of rapamycin required binding to FKBP. Rapamycin-FKBP inhibited retinoblastoma protein phosphorylation at the G1/S transition. This inhibition of retinoblastoma protein phosphorylation was associated with a decrease in p33cdk2 kinase activity. These observations suggest that rapamycin, but not FK520, inhibits vascular smooth muscle cell proliferation by reducing cell-cycle kinase activity.
多种生长因子可刺激静止的血管平滑肌细胞退出G0期并重新进入细胞周期。与胞质受体FKBP结合的大环内酯类抗生素雷帕霉素是一种免疫抑制剂，也是细胞增殖的有效抑制剂。在本研究中，检测了雷帕霉素对人及大鼠血管平滑肌细胞的抗增殖作用，并与相关免疫抑制剂FK520的作用进行了比较。在血管平滑肌细胞中，低至1 ng/mL的雷帕霉素就能抑制DNA合成和细胞生长。FK520是免疫抑制剂FK506的类似物，与雷帕霉素结构相关且能与FKBP结合，但不抑制血管平滑肌细胞生长。过量的FK520可阻断雷帕霉素的抗增殖作用，这表明雷帕霉素的作用需要与FKBP结合。雷帕霉素-FKBP在G1/S期转换时抑制视网膜母细胞瘤蛋白的磷酸化。这种对视网膜母细胞瘤蛋白磷酸化的抑制与p33cdk2激酶活性的降低有关。这些观察结果表明，雷帕霉素而非FK520通过降低细胞周期激酶活性来抑制血管平滑肌细胞增殖。
