p27（Kip1）在血管平滑肌细胞迁移中的作用。

Role for p27(Kip1) in Vascular Smooth Muscle Cell Migration.

作者信息

Sun J, Marx S O, Chen H J, Poon M, Marks A R, Rabbani L E

机构信息

Cardiology Division, Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, Mount Sinai School of Medicine, New York, NY, USA.

出版信息

Circulation. 2001 Jun 19;103(24):2967-72. doi: 10.1161/01.cir.103.24.2967.

DOI:10.1161/01.cir.103.24.2967

PMID:11413088

Abstract

BACKGROUND

Rapamycin is a potent inhibitor of smooth muscle cell (SMC) proliferation and migration. Rapamycin-mediated inhibition of SMC proliferation is associated with upregulation of the cyclin-dependent kinase inhibitor p27(Kip1). Previously, we showed that mixed embryonic fibroblasts obtained from p27(Kip1)(-/-) mice were relatively rapamycin-resistant, suggesting that p27(Kip1) plays an integral role in modulating the antiproliferative effects of rapamycin. We hypothesized that the antimigratory effect of rapamycin may also be mediated by p27(Kip1).

METHODS AND RESULTS

Rapamycin (1 to 10 nmol/L) inhibited basic fibroblast growth factor-induced migration of wild-type (WT) but not p27(Kip1)(-/-) SMCs in a dose-dependent manner (P<0.05) in a modified Boyden chamber. The effects of rapamycin on aortic SMC explant migration were also studied with WT, p27(+/-), and p27(-/-) mice. Rapamycin 4 mg. kg(-1). d(-1) IP for 5 days inhibited SMC migration by 90% in the WT and p27(Kip1)(+/-) (P<0.05) but not p27(Kip1)(-/-) animals.

CONCLUSIONS

Lack of p27(Kip1) reduces rapamycin-mediated inhibition of SMC migration. These novel findings suggest a role for p27(Kip1) in the signaling pathway(s) that regulates SMC migration.

摘要

背景

雷帕霉素是平滑肌细胞（SMC）增殖和迁移的有效抑制剂。雷帕霉素介导的SMC增殖抑制与细胞周期蛋白依赖性激酶抑制剂p27（Kip1）的上调有关。此前，我们发现从p27（Kip1）（-/-）小鼠获得的混合胚胎成纤维细胞对雷帕霉素相对耐药，提示p27（Kip1）在调节雷帕霉素的抗增殖作用中起重要作用。我们推测雷帕霉素的抗迁移作用也可能由p27（Kip1）介导。

方法与结果

在改良的博伊登小室中，雷帕霉素（1至10 nmol/L）以剂量依赖性方式抑制碱性成纤维细胞生长因子诱导的野生型（WT）SMC迁移，但对p27（Kip1）（-/-）SMC无此作用（P<0.05）。我们还研究了雷帕霉素对WT、p27（+/-）和p27（-/-）小鼠主动脉SMC外植体迁移的影响。雷帕霉素4 mg·kg（-1）·d（-1）腹腔注射5天，可使WT和p27（Kip1）（+/-）小鼠的SMC迁移抑制90%（P<0.05），但对p27（KipI）（-/-）小鼠无此作用。