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Papers In Press, published online ahead of print September 8, 2004
Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601
Corresponding Author: uchidak{at}agr.nagoya-u.ac.jp
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 the 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 the 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, the intraperitoneal administration of HNE resulted in an increase in cell numbers in the peritoneal cavity, which 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 the COX-2 induction and found that HNE did not stimulate the induction of nitric oxide synthase and activation of NF-kB 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, which plays a role in stimulation of the inflammatory response and contributes to the progression of atherogenesis.
J. Biol. Chem, 10.1074/jbc.M409935200
Submitted on August 30, 2004
Revised on September 7, 2004
Accepted on September 8, 2004
A lipid peroxidation-derived inflammatory mediator: Identification of 4-hydroxy-2-nonenal as a potential inducer of cyclooxygenase-2 in macrophages
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