Suppression by mycophenolate mofetil of the neointimal thickening caused by vascular injury in a rat arterial stenosis model.
Injury of the rat carotid artery by gentle perfusion of air causes vascular thickening, similar to that seen in the clinic setting in humans after percutaneous angioplasty or bypass surgery to repair injured or diseased blood vessels. In the animal model as well as in patients, this stenosis appears to be the result of smooth muscle cell migration and proliferation. Various cell types in the lesion area may contribute by producing inflammatory cytokines, adhesion molecules and growth factors. In the present study, mycophenolate mofetil (MMF), an inosine monophosphate dehydrogenase inhibitor with antiproliferative and immunosuppressive properties, was tested for its ability to inhibit this process. With a daily oral dose of 30 mg MMF/kg started 6 days before injury to one carotid artery by air perfusion, MMF reduced cross-sectional areas of total vessel wall (intima-media) thickness by 17% to 25% and of neointimal thickness by 48% to 60% at 14 days after injury in four tests (P < .001 when MMF- and vehicle-treated groups were compared for these thickened areas, n = 29 or 30). In addition, intima/media ratios ranged from 0.26 +/- 0.03 to 0.46 +/- 0.04 for MMF-treated vs. 0.55 +/- 0.05 to 0.93 +/- 0.08 for vehicle-treated animals in the four different tests (P < .001). Starting MMF treatment at either 14 or 0 days before arterial injury made no difference in the degree of reduction, suggesting that any biological process that might be altered by MMF is not one that requires much time to become established. Intima/media ratios were 0.31 +/- 0.04 or 0.34 +/- 0.04 for MMF-treated vs. 0.55 +/- 0.05 or 0.65 +/- 0.07 for vehicle-treated animals (P < .001 for day 14 or 0, respectively, n = 30). Thus, MMF reduced the vascular thickening after carotid artery injury in rats, suggesting that this class of compound may be able to control the pathological processes that lead to restenosis.
Fraser-Smith
E B
EB
Syntex Discovery Research, Division of Roche Holdings, Palo Alto, California, USA.
Rosete
J D
JD
Schatzman
R C
RC
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000503:physiopathology; D020212:Carotid Artery Injuries; D016893:Carotid Stenosis / Q000188:drug therapy*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid