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Papers In Press, published online ahead of print April 1, 2004
J. Lipid Res., doi:10.1194/jlr.M300376-JLR200

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Journal of Lipid Research, Vol. 45, 626-634, April 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Protein-bound 4-hydroxy-2-hexenal as a marker of oxidized n-3 polyunsaturated fatty acids

Satoshi Yamada^*, Tadashi Funada^*, Noriyuki Shibata, Makio Kobayashi, Yoshichika Kawai, Emi Tatsuda, Atsunori Furuhata and Koji Uchida^1,

^* Tsukuba Research Laboratory, NOF Corporation, Tsukuba 300-2635, Japan
Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan
Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan

¹ To whom correspondence should be addressed. e-mail: uchidak{at}agr.nagoya-u.ac.jp

In the present study, to investigate the contribution of n-3 PUFAs in the oxidative modification of protein in vivo, we characterize the covalent binding of 4-hydroxy-2-hexenal (HHE), a potent cytotoxic aldehyde originating from the peroxidation of n-3 PUFAs, to protein and describe the production of this aldehyde in oxidatively modified LDL and in human atherosclerotic lesions. Upon incubation with BSA, HHE was rapidly incorporated into the protein and generated the protein-linked carbonyl derivative, a potential marker of oxidatively modified proteins under oxidative stress. To detect the protein-bound HHE in vivo, we raised monoclonal antibody HHE53 (MAb HHE53) directed to the HHE-modified protein and identified the Michael addition-type HHE-histidine adduct as the major epitope. This antibody reacted with copper-oxidized LDL, suggesting that HHE was produced during the oxidative modification of LDL. In addition, we demonstrated that the materials immunoreactive to MAb HHE53 indeed constituted the atherosclerotic lesions, in which intense positivity was associated primarily with macrophage-derived foam cells.

The results of this study suggest that the reaction between oxidized n-3 PUFAs and protein might represent a process common to the formation of degenerative proteins during aging and its related diseases.

Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HHE, 4-hydroxy-2-hexenal; HNE, 4-hydroxy-2-nonenal; KLH, keyhole limpet hemocyanin; LC-MS, liquid chromatography-mass spectrometry; MAb, monoclonal antibody; TBARS, 2-thiobarbituric acid-reactive substance

Supplementary key words reactive aldehydes • oxidatively modified proteins • oxidized low density lipoprotein • atherosclerosis

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