Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle

• Published in: Circulation (New York, N.Y.) N.Y.), 1999-04, Vol.99 (16), p.2164-2170
• Main Authors: GALLO, R, PADUREAN, A, BADIMON, J. J, JAYARAMAN, T, MARX, S, ROQUE, M, ADELMAN, S, CHESEBRO, J, FALLON, J, FUSTER, V, MARKS, A
• Format: Article
• Language: English
• Subjects: Angioplasty, Balloon, Coronary - adverse effects; Animals; Biological and medical sciences; Cell Cycle Proteins; Cell Division - drug effects; Cell Movement; Coronary Disease - etiology; Coronary Disease - metabolism; Coronary Disease - pathology; Coronary Vessels - drug effects; Coronary Vessels - injuries; Coronary Vessels - metabolism; Coronary Vessels - pathology; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases - antagonists & inhibitors; Diseases of the cardiovascular system; Humans; Medical sciences; Microtubule-Associated Proteins - metabolism; Phosphorylation; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Rats; Retinoblastoma Protein - metabolism; Sirolimus - pharmacology; Swine; Tumor Suppressor Proteins; Tunica Intima - drug effects; Tunica Intima - injuries; Tunica Intima - metabolism; Tunica Intima - pathology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.99.16.2164

Although percutaneous transluminal coronary angioplasty (PTCA) is a highly effective procedure to reduce the severity of stenotic coronary atherosclerotic disease, its long-term success is significantly limited by the high rate of restenosis. Several cellular and molecular mechanisms have been implicated in the development of restenosis post-PTCA, including vascular smooth muscle cell (VSMC) activation, migration, and proliferation. Recently, our group demonstrated that rapamycin, an immunosuppressant agent with antiproliferative properties, inhibits both rat and human VSMC proliferation and migration in vitro. In the present study, we investigated (1) whether rapamycin administration could reduce neointimal thickening in a porcine model of restenosis post-PTCA and (2) the mechanism by which rapamycin inhibits VSMCs in vivo. PTCA was performed on a porcine model at a balloon/vessel ratio of 1.7+/-0.2. Coronary arteries were analyzed for neointimal formation 4 weeks after PTCA. Intramuscular administration of rapamycin started 3 days before PTCA at a dose of 0.5 mg/kg and continued for 14 days at a dose of 0.25 mg/kg. Cyclin-dependent kinase inhibitor (CDKI) p27(kip1) protein levels and pRb phosphorylation within the vessel wall were determined by immunoblot analysis. PTCA in the control group was associated with the development of significant luminal stenosis 4 weeks after the coronary intervention. Luminal narrowing was a consequence of significant neointimal formation in the injured areas. Rapamycin administration was associated with a significant inhibition in coronary stenosis (63+/-3.4% versus 36+/-4.5%; P