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Rapamycin inhibits vascular smooth muscle cell migration
1Cardiovascular Institute, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Abstract:
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.
Insights
Rapamycin, an antibiotic, effectively inhibits vascular smooth muscle cell migration. This finding is crucial for understanding and treating conditions like restenosis and arteriopathy.
Area of Science:
- Vascular Biology
- Pharmacology
Background:
- Abnormal vascular smooth muscle cell (SMC) proliferation and migration are key factors in restenosis and arteriopathy.
- Rapamycin previously showed inhibition of SMC proliferation, unlike FK506.
Purpose of the Study:
- To investigate the effects of rapamycin on SMC migration in vitro and in vivo.
- To compare rapamycin's effect on SMC migration with FK506.
Main Methods:
- In vitro assays using a modified Boyden chamber to assess PDGF-induced SMC migration.
- In vivo studies using a porcine aortic SMC explant model.
- Administration of rapamycin orally to pigs.
Main Results:
- Rapamycin significantly inhibited PDGF-induced SMC migration in cultured rat and human cells (P < 0.0001).
- FK506 did not significantly affect SMC migration.
- Oral administration of rapamycin significantly inhibited porcine aortic SMC migration (P < 0.0001).
Conclusions:
- Rapamycin is a potent inhibitor of vascular smooth muscle cell migration.
- Beyond its immunosuppressive and antiproliferative properties, rapamycin also impacts SMC migration, suggesting therapeutic potential for vascular diseases.
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