LAUSR

&NA; Atherosclerosis is currently understood to be mainly the consequence of a complicated inflammatory process at the different stages of plaque development. Among the several inflammatory molecules involved, up‐regulation of the functional cyclooxygenase 2/membrane‐bound prostaglandin E synthase 1 (COX‐2/mPGES‐1) axis plays a key role in plaque development. Excessive production of oxidized lipids, following low‐density lipoprotein (LDL) oxidation, is a characteristic feature of atherosclerosis. Among the oxidized lipids of LDLs, the oxysterol 27‐hydroxycholesterol (27‐OH) and the aldehyde 4‐hydroxynonenal (HNE) substantially accumulate in the atherosclerotic plaque, contributing to its progression and instability through a variety of processes. This study shows that 27‐OH and HNE promote up‐regulation of both the inducible enzymes COX‐2 and mPGES‐1, leading to increased production of prostaglandin (PG) E2 and inducible nitric oxide synthase, and the subsequent release of nitric oxide in human promonocytic U937 cells. The study also examined the potential involvement of the functionally coupled COX‐2/mPGES‐1 in enhancing the production of certain pro‐inflammatory cytokines and of matrix metalloproteinase 9 by U937 cells. This enhancement is presumably due to the induction of PGE2 synthesis, as a result of the up‐regulation of the COX‐2/mPGES‐1, stimulated by the two oxidized lipids, 27‐OH and HNE. Induction of PGE2 synthesis might thus be a mechanism of plaque instability and eventual rupture, contributing to matrix metalloproteinase production by activated macrophages. Graphical abstract Figure. No caption available. Highlights27‐OH and HNE stimulate inflammation by COX‐2/mPGES‐1 axis and PGE2 release.27‐OH and HNE induce NO production through iNOS up‐regulation.Inflammation promoted by 27‐OH and HNE may be involved in plaque instability.Inhibition of inflammation induced by 27‐OH and HNE reduces MMP‐9 up‐regulation.