Oxidized low density lipoprotein suppresses expression of inducible cyclooxygenase in human macrophages

Atherogenesis involves several aspects of chronic inflammation and wound he aling. Indeed, the atheroma is considered a special case of tissue response to injury. Injurious stimuli may include lipoproteins trapped within lesio ns where protein and lipid moieties have undergone chemical modifications. We have studied the effect of oxidized low density lipoproteins (ox-LDL) on inducible cyclooxygenase (Cox-2) in human monocyte-derived macrophages exp osed to bacterial lipopolysaccharide (LPS). Levels of both Cox-2 and consti tutive cyclooxygenase (Cox-1) were assessed using Western blot analysis. Pr ior incubation of macrophages with ox-LDL resulted in a strong inhibition o f Cox-2 induced by LPS, without effect on Cox-1. The inhibitory effect was dependent on ox-LDL concentration and its onset was early in time (already detectable 1 hour after macrophage exposure to ox-LDL). Native LDL, and oth er forms of modified LDL, were without effect. The inhibition was dependent on endocytosis of ox-LDL and could be reproduced using the lipid extract f rom ox-LDL. Lysophosphatidylcholine, 7 beta-hydroxycholesterol, and 7-oxoch olesterol failed to mimic the inhibition, but oxidized arachidonic acid-con taining phospholipids, produced by autoxidation of 1-palmitoyl-2-arachidono yl-sn-glycero-3-phosphocholine, markedly inhibited Cox-2, The observation t hat ox-LDL downregulates Cox-2 in human macrophages may explain the fact th at, within atheromata, the transformation of macrophages into foam cells re sults in attenuation of the inflammatory response, thus contributing to pro gression of atherogenesis.