Metabolism of Myeloperoxidase-derived 2-Chlorohexadecanal

• Published in: The Journal of biological chemistry 2006-06, Vol.281 (25), p.16849-16860
• Main Authors: Wildsmith, Kristin R., Albert, Carolyn J., Anbukumar, Dhanalakshmi S., Ford, David A.
• Format: Article
• Language: English
• Subjects: Aldehydes - chemistry; Aldehydes - metabolism; Coronary Vessels - drug effects; Endothelium, Vascular - drug effects; Fatty Acids - metabolism; Heart - drug effects; Humans; Lipids - chemistry; Models, Chemical; Myocardium - pathology; Neutrophils - drug effects; Neutrophils - metabolism; Oxygen - metabolism; Peroxidase - metabolism; Phosphatidylcholines - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M602505200

Numerous studies have suggested relationships between myeloperoxidase (MPO), inflammation, and atherosclerosis. MPO-derived reactive chlorinating species attack membrane plasmalogens releasing α-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 (α-ClFA) and chlorinated fatty alcohol (α-ClFOH). Within the first hour of incubations of human coronary artery endothelial cells with 2-Cl-[3H]-HDA, the label was incorporated into the α-ClFOH and α-ClFA pools. After 1 h, the radiolabel was predominantly found in the α-ClFOH pool. Cell-derived α-ClFOH and α-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 α-ClFA and α-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 α-ClFA and reduced to α-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 α-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.