Loading…
A Lipid Peroxidation-derived Inflammatory Mediator
Cyclooxygenases (COXs) catalyze the conversion of arachidonic acid to eicosanoids, which mediate a variety of biological actions involved in vascular pathophysiology. In the present study, we investigated the role of lipid peroxidation products in the up-regulation of COX-2, an inducible isoform res...
Saved in:
Published in: | The Journal of biological chemistry 2004-11, Vol.279 (46), p.48389-48396 |
---|---|
Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | Cyclooxygenases (COXs) catalyze the conversion of arachidonic acid to eicosanoids, which mediate a variety of biological actions
involved in vascular pathophysiology. In the present study, we investigated the role of lipid peroxidation products in the
up-regulation of COX-2, an inducible isoform responsible for high levels of prostaglandin production during inflammation and
immune responses. COX-2 was found to colocalize with 4-hydroxy-2-nonenal (HNE), a major lipid peroxidation-derived aldehyde,
in foamy macrophages within human atheromatous lesions, suggesting that COX-2 expression may be associated with the accumulation
of lipid peroxidation products within macrophages. To test the hypothesis that lipid peroxidation products might be involved
in the regulation of prostanoid biosynthesis, we conducted a screen of oxidized fatty acid metabolites and found that, among
the compounds tested, only HNE showed inducibility of the COX-2 protein in RAW264.7 macrophages. In addition, intraperitoneal
administration of HNE resulted in an increase in cell numbers in the peritoneal cavity that was associated with significant
increases in the peritoneal and tissue levels of COX-2 in mice. To understand the possible signaling mechanism underlying
the inducing effect of HNE on COX-2 up-regulation, we examined the phosphorylation events that may lead to COX-2 induction
and found that HNE did not stimulate the induction of nitric oxide synthase and activation of NF-κB but significantly activated
p38 mitogen-activated protein kinase and its upstream kinase in RAW264.7 macrophages. Tyrosine kinases, such as the epidermal
growth factor-like and Src family tyrosine kinases, appeared to mediate the stabilization of COX-2 mRNA via the p38 mitogen-activated
protein kinase pathway. These findings suggest that HNE accumulated in macrophages/foam cells may represent an inflammatory
mediator that plays a role in stimulation of the inflammatory response and contributes to the progression of atherogenesis. |
---|---|
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M409935200 |