Paradoxical enhancement of atherosclerosis by probucol treatment in apolipoprotein E-deficient mice.

Abstract

Dietary administration of probucol (0.5%, wt/wt) efficiently reduced total plasma cholesterol levels in apolipoprotein E-deficient mice (apoE Ϫ / Ϫ ) by 40%, with decreases in high density lipoprotein (HDL) and apoAI by 70 and 50%, respectively. Paradoxically, however, aortic atherosclerotic plaques in the probucol-treated apoE Ϫ / Ϫ mice formed more rapidly than in the untreated apoE Ϫ / Ϫ mice, and the lesions were two to four times larger and more mature regardless of sex, age, and genetic background ( P Ͻ 10 Ϫ 6 ). Histologically, lesions in probucol-treated mice contained increased fibrous materials and cells other than foam cells, and were commonly associated with focal inflammation and aneurysmal dilatation. Probucol treatment also accelerated lesion development in apoE ϩ / Ϫ mice fed an atherogenic diet, indicating that the adverse effect is not dependent on the complete absence of apoE. Furthermore, mice lacking apoE and apoAI have plasma lipoprotein profiles very similar to the probucol-treated apoE Ϫ / Ϫ mice, but do not have accelerated plaque development. Thus, the enhanced atherosclerosis in the probucol-treated animals is unlikely to be caused by the reduction of HDL and apoAI levels. Our data indicate that a reduction in plasma cholesterol caused by probucol does not necessarily lead to an antiatherogenic effect. ( J. Clin. Invest. 1997. 99:2858-2866.)

Site-Specific Antiatherogenic Effect of Probucol in Apolipoprotein E–Deficient Mice

“…Consistent with previ-ous findings, 25,35 lesions were found at all sites and covered large areas of the vessel, with the exception of the descending thoracic aorta, where lesions were smaller and located around the ostia of the branching intercostal arteries. Although a detailed compositional analysis was not made, the lesion morphology was grossly similar in all regions, with necrotic cores containing cholesterol crystals observed regularly at all sites.…”

“…Previous studies have reported that probucol enhances lesion formation in the aortic root of female and male apoEϪ/Ϫ mice fed normal chow. 25,26 Consistent with that finding, lesions at this site were larger in probucol than control male mice fed a high-fat chow (Table I), although this difference did not reach statistical significance. Lesion size in the aortic root varied in the probucol group (Table I) owing to 2 animals with no lesions at all (not shown), whereas all other drug-treated animals had larger lesions than the largest individual control mouse.…”

“…Lesion size in the aortic root varied in the probucol group (Table I) owing to 2 animals with no lesions at all (not shown), whereas all other drug-treated animals had larger lesions than the largest individual control mouse. Table I also shows that not only was the reported previously lesion-enhancing effect of probucol 25,26 confined to the aortic root region but also that probucol changed to become increasingly more antiatherogenic the more distal the site examined (Table I). At the abdominal aorta, probucol effectively prevented lesion formation.…”

“…20 It is also ineffective in reducing established lesions in mature, LDL receptor-deficient rabbits 21 and nonhuman primates. 14 Furthermore, probucol promotes atherosclerosis in the aortic origin in LDL receptor- [22][23][24] and apolipoprotein E-deficient (apoEϪ/Ϫ) mice 25,26 for reasons presently unknown.…”

Antiatherosclerotic Effect of Alacepril, an Angiotensin-Converting Enzyme Inhibitor, in Monkeys Fed a High-Cholesterol Diet.

“…For example, probucol, which inhibits the oxidative modification of LDL, prevented the development of atherosclerotic lesions in WHHL rabbits (17,18), but increased atherosclerotic lesions 2 to 4 times in apolipoprotein E-deficient mice as compared with control mice (19). These findings suggest that the effects of antioxidants on atherosclerosis may be species specific.…”