A lipid-derived endogenous inducer of COX-2: a bridge between inflammation and oxidative stress.
Several lines of evidence indicate that the oxidative modification of protein and the subsequent accumulation of the modified proteins have been found in cells during aging, oxidative stress, and in various pathological states including premature diseases, muscular dystrophy, rheumatoid arthritis, and atherosclerosis. The important agents that give rise to the modification of a protein may be represented by reactive aldehydic intermediates, such as ketoaldehydes, 2-alkenals and 4-hydroxy-2-alkenals. These reactive aldehydes are considered important mediators of cell damage due to their ability to covalently modify biomolecules, which can disrupt important cellular functions and can cause mutations. Furthermore, the adduction of aldehydes to apolipoprotein B in low-density lipoproteins (LDL) has been strongly implicated in the mechanism by which LDL is converted to an atherogenic form that is taken up by macrophages, leading to the formation of foam cells. During the search for an endogenous inducer of cyclooxygenase-2 (COX-2), an inducible isoform responsible for high levels of prostaglandin production during inflammation and immune responses, 4-hydroxy-2-noennal (HNE), one of the most representative lipid peroxidation product, has been identified as the potential inducer of COX-2. In addition, the following study on the molecular mechanism of the COX-2 induction by HNE has unequivocally established that a serum component, which is eventually identified to be denatured LDL, is essential for COX-2 induction. Here I review current understanding of the mechanisms by which HNE in cooperation with the serum component activates gene expression of COX-2.
Uchida
Koji
K
Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan. uchidak@agr.nagoya-u.ac.jp
D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D050197:Atherosclerosis / Q000201:enzymology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D018384:Oxidative Stress
D000447:Aldehydes; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D051546:Cyclooxygenase 2; C027576:4-hydroxy-2-nonenal