UC San Diego

Oxidation of LDL plays all important role in atherogenesis. The lag-time in the formation of conjugated dienes provides a sensitive measure of the resistance of plasma LDL to oxidation and is widely assumed to be an indicator of atherogenic risk. To test this assumption, we investigated whether different antioxidants yielding similar lag-times result in similar reduction of atherosclerosis. A 6-months intervention study was carried out in three groups of 10 LDL receptor-deficient rabbits each. Because previous studies indicated that antioxidants that reduce atherosclerosis resulted in very long lag-times, the first group was treated with an antioxidant combination containing 1,000 IU vitamin E, 0.05% probucol analogue (BM15.0639), and 0.025% probucol. The lag-times achieved throughout the intervention period by this combination (952 +/- 39 min) were matched in a second group (829 +/- 46 min) treated with a variable dose of probucol (0.0575-0.11%, average 0.091%). A third, untreated group served as a control. Plasma cholesterol levels of all groups were matched. Even though both treatments yielded similar antioxidant protection of plasma LDL, 0.091% probucol reduced aortic atherosclerosis by 51.7% compared to the untreated group (P < 0.005), whereas the antioxidant combination failed to reduce lesion formation. Thus, the lag-time is clearly not correlated with the antiatherogenic efficacy of different antioxidants. However, a weak correlation was found within the group treated with probucol only. Our results suggest that the degree of antioxidant protection of plasma LDL may not be a good indicator of the atherogenic risk, in general, and that probucol reduces atherogenesis by mechanisms not shared by all antioxidants.