Rapamycin inhibits vascular smooth muscle cell migration
Rapamycin inhibits vascular smooth muscle cell migration
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DOI：
10.1172/jci119038
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发表时间：
1996-11-15
影响因子：
15.9
通讯作者：
Marks, AR
中科院分区：
文献类型：
--
作者：
Poon, M;Marx, SO;Marks, AR
异常的血管平滑肌细胞（SMC）增殖和迁移导致经皮冠状动脉成形术后再狭窄的发生以及心脏移植后动脉病变的加速。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和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 增殖（Marx, S.O., T. Jayaraman, L.O. Go, 和 A.R. Marks. 1995. Circ. Res. 362:801）。在本研究中，使用改良的博伊登室在体外测定雷帕霉素对 SMC 迁移的影响，并使用猪主动脉 SMC 外植体模型在体内测定雷帕霉素对 SMC 迁移的影响。在培养的大鼠和人 SMC 中，用雷帕霉素 (2 ng/ml) 预处理 48 小时可抑制 PDGF 诱导的迁移（PDGF BE 同二聚体；20 ng/ml）（n = 10；P < 0.0001），而 FK506 对迁移没有显着影响。与对照组相比，口服雷帕霉素（每天 1 mg/kg，持续 7 d）显着抑制猪主动脉 SMC 迁移（n = 15；P < 0.0001）。因此，雷帕霉素除了是一种有效的免疫抑制剂和抗增殖剂之外，还可以抑制 SMC 迁移。
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 BE 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.