J Sun1, S O Marx, H J Chen, M Poon, A R Marks, L E Rabbani. 1. 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.
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.
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.
Authors: Yann Gouëffic; Susan Potter-Perigo; Christina K Chan; Pamela Y Johnson; Kathleen Braun; Steven P Evanko; Thomas N Wight Journal: Atherosclerosis Date: 2006-12-14 Impact factor: 5.162