S. Eligini et al., Oxidized low density lipoprotein suppresses expression of inducible cyclooxygenase in human macrophages, ART THROM V, 19(7), 1999, pp. 1719-1725
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.