Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit.

Abstract

It has been postulated that low density lipoprotein (LDL) becomes fully atherogenic only if it first undergoes oxidative modification. The oxidatively modified form, but not native LDL, is recognized by the acetyl-LDL or "scavenger" receptor and could, therefore, be taken up rapidly by tissue macrophages to generate the fatty-streak lesion of atherosclerosis. However, there is thus far very little direct evidence for oxidative modification in vivo. The studies reported here take advantage of the fact that probucol is an effective antioxidant transported in lipoproteins, including LDL, and blocks the oxidative modification of LDL in vitro. We now show that the rate of degradation of LDL in the macrophage-rich fatty-streak lesions of the LDL receptor-deficient rabbit treated with probucol (1% by weight in the diet) is reduced to about one-half of that in the lesions of receptor-deficient rabbits not given probucol (but matched for plasma cholesterol levels). In contrast, the rates of degradation in the nonlesioned areas of the aorta were no different in probucol-treated and control animals. Most of the LDL degradation in fatty-streak lesions takes place in macrophages, whereas in nonlesioned aorta, which contains very few macrophages, the degradation is almost exclusively in endothelial cells and smooth muscle cells. Thus, the results are compatible with the postulate that the native LDL taken up and degraded by foam cells in the developing fatty-streak lesions was in part first converted to a form recognized by the scavenger receptor (by oxidative or analogous modification). Finally, and most importantly, we show that treatment with probucol significantly reduced the rate of development of fatty-streak lesions even though plasma cholesterol levels were no lower than lovastatin-treated (control) rabbits.