Poon M, Marx S O, Gallo R, Badimon J J, Taubman M B, Marks A R
Cardiovascular Institute, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
J Clin Invest. 1996 Nov 15;98(10):2277-83. doi: 10.1172/JCI119038.
Abnormal vascular smooth muscle cell (SMC) proliferation and migration contribute to the development of restenosis after percutaneous transluminal coronary angioplasty and accelerated arteriopathy after cardiac transplantation. Previously, we reported that the macrolide antibiotic rapamycin, but not the related compound FK506, inhibits both human and rat aortic SMC proliferation in vitro by inhibiting cell cycle-dependent kinases and delaying phosphorylation of retinoblastoma protein (Marx, S.O., T. Jayaraman, L.O. Go, and A.R. Marks. 1995. Circ. Res. 362:801). In the present study the effects of rapamycin on SMC migration were assayed in vitro using a modified Boyden chamber and in vivo using a porcine aortic SMC explant model. Pretreatment with rapamycin (2 ng/ml) for 48 h inhibited PDGF-induced migration (PDGF BB homodimer; 20 ng/ml) in cultured rat and human SMC (n = 10; P < 0.0001), whereas FK506 had no significant effect on migration. Rapamycin administered orally (1 mg/kg per d for 7 d) significantly inhibited porcine aortic SMC migration compared with control (n = 15; P < 0.0001). Thus, in addition to being a potent immunosuppressant and antiproliferative, rapamycin also inhibits SMC migration.
异常的血管平滑肌细胞（SMC）增殖和迁移会导致经皮腔内冠状动脉成形术后再狭窄的发展以及心脏移植后加速性动脉病变。此前，我们报道过，大环内酯类抗生素雷帕霉素而非相关化合物FK506，通过抑制细胞周期依赖性激酶并延迟视网膜母细胞瘤蛋白的磷酸化，在体外抑制人和大鼠主动脉SMC的增殖（马克思，S.O.，T. 贾亚拉曼，L.O. 戈，以及A.R. 马克斯。1995年。《循环研究》362:801）。在本研究中，使用改良的博伊登小室在体外以及使用猪主动脉SMC外植体模型在体内测定雷帕霉素对SMC迁移的影响。用雷帕霉素（2纳克/毫升）预处理48小时可抑制培养的大鼠和人SMC中血小板衍生生长因子（PDGF）诱导的迁移（PDGF BB同二聚体；20纳克/毫升）（n = 10；P < 0.0001），而FK506对迁移没有显著影响。与对照组相比，口服雷帕霉素（每天1毫克/千克，共7天）可显著抑制猪主动脉SMC迁移（n = 15；P < 0.0001）。因此，除了是一种强效免疫抑制剂和抗增殖剂外，雷帕霉素还能抑制SMC迁移。
