Rapamycin inhibits vascular smooth muscle cell migration.
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.
Poon
M
M
Cardiovascular Institute, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Marx
S O
SO
Gallo
R
R
Badimon
J J
JJ
Taubman
M B
MB
Marks
A R
AR
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000166:cytology; D001483:Base Sequence; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000166:cytology / Q000502:physiology*; D016366:Open Reading Frames; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D011090:Polyenes / Q000008:administration & dosage / Q000494:pharmacology*; D012313:RNA / Q000032:analysis; D051381:Rats; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D020123:Sirolimus; D013552:Swine; D016559:Tacrolimus / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D010982:Platelet-Derived Growth Factor; D011090:Polyenes; D012313:RNA; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D016559:Tacrolimus