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

Work, L.M. , McPhaden, A.R., Pyne, N.J., Pyne, S., Wadsworth, R.M. and Wainwright, C.L. (2001) Short-term local delivery of an inhibitor of ras farnesyltransferase prevents neointima formation in vivo after porcine coronary balloon angioplasty. Circulation, 104(13), pp. 1538-1543. (doi: 10.1161/​hc3801.095661)

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Publisher's URL: http://dx.doi.org/10.1161/​hc3801.095661

Abstract

<b>Background</b> Mitogenic stimuli present at the site of coronary arterial balloon injury contribute to the progression and development of a restenotic lesion, many signaling through a common pathway involving the small G protein p21<sup>ras</sup>. Our aim was to demonstrate in biochemical studies that farnesyl protein transferase inhibitor III (FPTIII) is an inhibitor of p21<sup>ras</sup> processing and that when it is given locally in vivo at the site of coronary balloon injury in a porcine model, it can inhibit neointima formation.<p></p> <b>Methods and Results</b> FPTIII (1 to 25 μmol/L) concentration-dependently reduced p21<sup>ras</sup> levels in porcine coronary artery smooth muscle cell membranes. FPTIII also prevented p42/p44 MAPK activation and DNA synthesis in response to platelet-derived growth factor in these cells at a concentration of 25 μmol/L. Application of 25 μmol/L FPTIII locally for 15 minutes to balloon-injured porcine coronary arteries in vivo prevented neointima formation assessed at 4 weeks, reduced proteoglycan deposition, and inhibited adventitial hypertrophy. Coronary arteries from FPTIII-treated pigs had no deterioration in contraction or in endothelium-dependent relaxation.<p></p> <b>Conclusions</b> The study demonstrates in the pig that short-term local delivery of inhibitors of p21<sup>ras</sup>-dependent mitogenic signal transduction prevents restenosis after balloon angioplasty.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Work, Dr Lorraine
Authors: Work, L.M., McPhaden, A.R., Pyne, N.J., Pyne, S., Wadsworth, R.M., and Wainwright, C.L.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Circulation
ISSN:0009-7322
ISSN (Online):1524-4539

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