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 balloon injury contribute to the progression and development of a restenotic lesion, many signaling through a common pathway involving the small G protein p21(ras). Our aim was to demonstrate in biochemical studies that farnesyl protein transferase inhibitor III (FPTIII) is an inhibitor of p21(ras) 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.


RESULTS
FPTIII (1 to 25 micromol/L) concentration-dependently reduced p21(ras) 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 micromol/L. Application of 25 micromol/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.


CONCLUSIONS
The study demonstrates in the pig that short-term local delivery of inhibitors of p21(ras)-dependent mitogenic signal transduction prevents restenosis after balloon angioplasty.
Work
L M
LM
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland, UK.
McPhaden
A R
AR
Pyne
N J
NJ
Pyne
S
S
Wadsworth
R M
RM
Wainwright
C L
CL
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D011183:Postoperative Complications / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014652:Vascular Diseases / Q000209:etiology / Q000517:prevention & control
C436083:2-(2-oxo-2-((3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy)aminoethyl)phosphonic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester sodium; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase