Suppression of cholesteryl ester accumulation in cultured human monocyte-derived macrophages by lipoxygenase inhibitors

Abstract

Atherosclerotic lesions and xanthomas are characterized by the occurrence of cholesteryl ester (CE)-laden foam cells, which partly originate from macrophages. Little is known about the role of cyclo-oxygenase or lipoxygenase metabolites of arachidonic acid in the development of foam cells. In this study we investigated the influence of prostaglandins and inhibitors of the cyclo-oxygenase or the lipoxygenase pathway on CE accumulation in cultured human monocyte-derived macrophages. Accumulation of CE was achieved by incubation of the cells with acetylated low density lipoprotein (AcLDL). The stable prostacyclin analogue ZK 36 374 and prostaglandin E2 showed no effect on cellular CE storage. Similarly, the cyclo-oxygenase inhibitor indomethacin failed to influence AcLDL-induced CE accumulation. By contrast, however, the inhibitors of lipoxygenase activity nordihydroguaiaretic acid (NDGA) and BW 755 C markedly suppressed the accumulation of CE in monocyte-derived macrophages. The inhibitory effect of NDGA was dose-dependent. Incubation of the cells with the anti-oxidant vitamin E gave no significant reduction of CE accumulation. Our results indicate that inhibition of the lipoxygenase pathway of arachidonic acid metabolism in cultured monocyte-derived macrophages effectively decreases the rate of experimentally-induced CE accumulation.