INHIBITION OF HYPERCHOLESTEROLEMIA-INDUCED ATHEROSCLEROSIS IN THE NONHUMAN PRIMATE BY PROBUCOL .1. IS THE EXTENT OF ATHEROSCLEROSIS RELATEDTO RESISTANCE OF LDL TO OXIDATION

Lipoprotein oxidation is believed to play an important role in atherog enesis. To investigate whether inhibition of oxidation of low density lipoprotein (LDL) would alter atherogenesis in the nonhuman primate, w e administered probucol, a potent antioxidant, to Macaca nemestrina fe d a high-fat, high-cholesterol diet. Probucol was administered to half of the 16 monkeys 14 wk after starting the hypercholesterolemic diet, and was given daily until they were sacrificed after 11 mos. To evalu ate the antioxidant effect of probucol, the resistance of isolated pla sma LDL to in vitro oxidation was evaluated. Probucol significantly in creased the resistance of LDL to oxidative modification, as shown by a n increase in the Lag time required for conjugated diene formation. Le sions in the probucol-treated animals appeared less mature, and increa sed accumulation of lipid was observed in smooth muscle cells. Compari son of all control and probucol-treated monkeys demonstrated that inti mal lesion areas in the thoracic aortas of the probucol-treated monkey s were reduced by 43% (P < 0.0001), but no significant difference in l esion area was found in the abdominal aortas or in the iliac arteries. However, the lag phase of conjugated diene formation was not prolonge d in 2 of the 8 probucol-treated animals. A plot of intimal lesion siz e versus lag phase of all 16 animals showed a trend that lesion size w as inversely related to oxidation resistance for all anatomic sites. T he strong inverse relationship between intimal lesion size and resista nce of LDL to oxidation supports a role for lipoprotein oxidation in t he development and progression of lesions of atherosclerosis. The poss ibility that some of the effect is due to other biological properties of probucol cannot be ruled out.