Rapamycin: signaling in vascular smooth muscle.
Rapamycin (sirolimus) was initially developed as an antibiotic, then as an immunosuppressant, and recently has been identified as one of the most promising novel agents for prevention of coronary artery stent restenosis. The story of how rapamycin was developed for the prevention of stent restenosis involves the discovery of its antiproliferative and antimigratory actions in vascular smooth muscle and ultimately the demonstration that it inhibits neointimal hyperplasia in a large animal model of restenosis. Rapamycin upregulates the cyclin-dependent kinase inhibitor p27(kip1), resulting in cell-cycle arrest at the G1 to S transition. Rapamycin also inhibits other important cellular functions, including protein translation. The precise mechanisms underlying rapamycin's actions have not been fully elucidated. However, its ability to potently inhibit vascular smooth muscle cell migration and proliferation has been the basis for developing rapamycin-eluting coronary artery stents that have reduced in-stent restenosis from about 30% to less than 5% in large clinical trials.
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Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA. arm42@columbia.edu
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000493:pharmacokinetics / Q000494:pharmacology*; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism
D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus