Short-Term Local Delivery of an Inhibitor of Ras Farnesyltransferase Prevents Neointima Formation In Vivo After Porcine Coronary Balloon Angioplasty

Abstract

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. Methods and Results-FPTIII (1 to 25 mol/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 mol/L. Application of 25 mol/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.

Rad GTPase Deficiency Leads to Cardiac Hypertrophy

“…10 The inhibition of Ras attenuates atherosclerosis in apolipoprotein E-deficient mice and neointimal formation in porcine coronary balloon angioplasty. 23 Furthermore, inhibition of Rac1 induces regression of coronary atherosclerosis in a pig model treated with interleukin-1␤. 24 Activation of RhoA is a critical component of hypertension, whereas oxyhemoglobin-induced Rho/ROK activation is a major causative component of cerebral vasospasm.…”

Angiotensin II-Induced Osteopontin Expression in Vascular Smooth Muscle Cells Involves Gq/11, Ras, ERK, Src and Ets-1

“…Thus, while Ang II also activates small G proteins, Rac, Rho, and other MAP kinases (e.g., JNK and p38MAPK) (21), the Ras-MEK1-ERK axis appears to be the primary mediator of Ang II-induced OPN expression. Interestingly, inhibition of Ras by dominant-negative Ras or pharmacological inhibitors attenuates atherosclerosis and neointimal formation after balloon injury (25)(26)(27). (28).…”

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

“…In the same in vivo models, prevention of posttranslational modifications and thereby, inhibition of Ras activity by FTIs or S-adenosylhomocysteine hydrolase inhibitors (433,540), or S-trans,trans-farnesylthiosalicylic acid (136) has the same inhibitory action on balloon injury-induced neointimal proliferation.…”