Short-term local delivery of an inhibitor of ras farnesyltransferase prevents neointima formation in vivo after porcine coronary balloon angioplasty

Background-Mitogenic stimuli present at the site of coronary arterial ballo on injury contribute to the progression and development of a restenotic les ion, many signaling through a common pathway involving the small G protein p21(ras). Our aim was to demonstrate in biochemical studies that farnesyl p rotein transferase inhibitor III (FPTIII) is an inhibitor of p21(ras) proce ssing and that when it is given locally in vivo at the site of coronary bal loon injury in a porcine model, it can inhibit neointima formation. Methods and Results-FPTIII (I to 25 mu mol/L) concentration-dependently red uced p21(ras) levels in porcine coronary artery smooth muscle cell membrane s. FPTIII also prevented p42/p44 MAPK activation and DNA synthesis in respo nse to platelet-derived growth factor in these cells at a concentration of 25 mu mol/L. Application of 25 mu mol/L FPTIII locally for 15 minutes to ba lloon-injured porcine coronary arteries in vivo prevented neointima. format ion assessed at 4 weeks, reduced proteoglycan deposition, and inhibited adv entitial hypertrophy. Coronary arteries from FPTIII-treated pigs had no det erioration in contraction or in endothelium-dependent relaxation. Conclusions-The study demonstrates in the pig that short-term local deliver y of inhibitors of p21(ras)-dependent mitogenic signal transduction prevent s restenosis after balloon angioplasty.