A SPECIFIC 15-LIPOXYGENASE INHIBITOR LIMITS THE PROGRESSION AND MONOCYTE-MACROPHAGE ENRICHMENT OF HYPERCHOLESTEROLEMIA-INDUCED ATHEROSCLEROSIS IN THE RABBIT

Oxidant signalling and lipoprotein oxidation may play important roles in atherosclerotic lesion development. Given coincident localization o f 15-lipoxygenase (15-LO), stereospecific products of 15-LO and epitop es of modified LDL in atherosclerotic lesions, we hypothesized that in hibition of 15-LO by PD146176, an inhibitor of 15-LO with an IC50 in c ells or isolated enzyme of 0.5-0.8 mu M, may limit atherosclerotic les ion development through regulation of monocyte-macrophage enrichment. Rabbits exposed to chronic endothelial denudation of the iliac-femoral artery were meal-fed a 0.25% cholesterol (C), 3% peanut oil (PNO), 3% coconut oil (CNO) diet twice daily with and without 175 mg/kg PD14617 6 for 12 weeks. In a second study, atherosclerotic lesions were pre-es tablished in rabbits through chronic endothelial denudation and meal-f ed a 0.5% C, 3% PNO, 3% CNO diet for 9 weeks and a 0% C/fat diet for 6 weeks prior to an 8 week administration of PD146176 at 175 mg/kg, q.d . Plasma total and lipoprotein cholesterol exposure were similar in co ntrol and PD146176-treated animals in both studies but PD146176 increa sed plasma triglyceride exposure 2- to 4-fold. Plasma PD146176 concent rations ranged from 99 to 214 ng/ml at 2 h post-dose. In the progressi on study, the iliac-femoral monocyte-macrophage area was reduced 71%, cross-sectional lesion area was unchanged and cholesteryl ester (CE) c ontent was reduced 63%. In the regression study, size and macrophage c ontent of iliac-femoral, fibrous plaque-like lesions were decreased 34 %, CE content was reduced 19% and gross extent of thoracic aortic lesi ons were reduced 41%. We conclude that PD146176 can limit monocyte-mac rophage enrichment of atherosclerotic lesions and can attenuate develo pment of fibrofoamy and fibrous plaque lesions in the absence of chang es in plasma total or lipoprotein cholesterol concentrations. (C) 1998 Warner Lambert Company. Published by Elsevier Science Ireland Ltd.