MACROPHAGES, LIPID OXIDATION, CEROID ACCUMULATION AND ALPHA-TOCOPHEROL DEPLETION IN HUMAN ATHEROSCLEROTIC LESIONS

Necropsy samples of atherosclerotic lesions of different histological stages have been analysed. Ceroid was present in all the lesions, with in lipid-laden macrophage foam cells and extracellularly in the athero matous core of advanced lesions. Mean levels of 7 beta-hydroxycholeste rol, 26-hydrbxycholesterol and hydroxyoctadecadienoic acids were all s ignificantly greater in lesions than in normal intima. Levels of hydro xycholesterols were very low or undetectable in normal intima. Fatty s treaks showed the highest ratio of 7 beta-hydroxycholesterol to choles terol, and the lowest ratio of linoleate to oleate, suggesting that th is type of lesion experiences the greatest free radical activity. Leve ls of 26-hydroxycholestrol, a product of the cytochrome P-450 enzyme s terol 26-hydroxylase, and the ratio of 26-hydroxycholesterol to choles terol were significantly higher in advanced lesions than in intermedia te lesions or fatty streaks. The ratio of alpha-tocopherol to choleste rol levels varied widely in normal intima but was consistently low in lesions, especially those rich in macrophage foam cells, suggesting th at oxidative activity in the lesion may lead to significant oxidation of the lesion constituents only after alpha-tocopherol has been deplet ed. Macrophage death was a characteristic feature of advanced lesions, with apoptotic bodies present, and occasionally, intact apoptotic cel ls were seen in lesions. These striking correlations between macrophag es, lipid oxidation, alpha-tocopherol depletion, ceroid accumulation, and macrophage death in advanced lesions, strongly support a role for oxidative damage in atherosclerosis, and lend credence to the idea tha t alpha-tocopherol dietary supplementation may slow the progression of atherosclerosis in humans.