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J. Biol. Chem., Vol. 281, Issue 25, 16849-16860, June 23, 2006

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Metabolism of Myeloperoxidase-derived 2-Chlorohexadecanal^*

From the Department of Biochemistry and Molecular Biology, St. Louis University Health Sciences Center, St. Louis, Missouri 63104

Numerous studies have suggested relationships between myeloperoxidase (MPO), inflammation, and atherosclerosis. MPO-derived reactive chlorinating species attack membrane plasmalogens releasing -chloro fatty aldehydes including 2-chlorohexadecanal (2-ClHDA), which have been found to accumulate in activated neutrophils, activated monocytes, infarcted myocardium and human atheromas. The present study employed synthetically prepared 2-Cl-[³H]-HDA as well as stable isotope-labeled 2-ClHDA to elucidate the metabolism of 2-ClHDA. The results herein demonstrate that human coronary artery endothelial cells oxidize and reduce 2-ClHDA to its respective chlorinated fatty acid (-ClFA) and chlorinated fatty alcohol (-ClFOH). Within the first hour of incubations of human coronary artery endothelial cells with 2-Cl-[³H]-HDA, the label was incorporated into the -ClFOH and -ClFA pools. After 1 h, the radiolabel was predominantly found in the -ClFOH pool. Cell-derived -ClFOH and -ClFA were also released into the cell culture medium. Additionally, chlorinated fatty acid was incorporated into complex endothelial cell glycerolipids, including monoglycerides, triglycerides, phosphatidylcholine, and phosphatidylethanolamine. The oxidation and reduction of 2-ClHDA to -ClFA and -ClFOH, respectively, was further supported by mass spectrometric analyses of human coronary artery endothelial cells incubated with either 2-ClHDA or stable isotope-labeled 2-ClHDA (2-Cl-[d₄]-HDA). 2-ClHDA was also oxidized to -ClFA and reduced to -ClFOH in both control and phorbol 12-myristate 13-acetate-stimulated neutrophils. Taken together, these results show that a family of chlorinated lipidic metabolites is produced from -chloro fatty aldehydes derived from reactive chlorinating species targeting of plasmalogens. These metabolites are incorporated into complex lipids and their biological roles may provide new insights into MPO-mediated disease.

Received for publication, March 16, 2006

^* This research was supported by National Institutes of Health Grants HL74214 and RR19232 (to D. A. F.) and a predoctoral fellowship (to K. R. W.) and Grant-in-aid 0650044Z (to D. A. F.) from the American Heart Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104. Tel.: 314-977-9264; Fax: 314-977-9205; E-mail: fordda{at}slu.edu.

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