Abstract
Numerous studies have suggested relationships between myeloperoxidase (MPO), inflammation, and atherosclerosis. MPO-derived reactive chlorinating species attack membrane plasmalogens releasing alpha-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 (alpha-ClFA) and chlorinated fatty alcohol (alpha-ClFOH). Within the first hour of incubations of human coronary artery endothelial cells with 2-Cl-[3H]-HDA, the label was incorporated into the alpha-ClFOH and alpha-ClFA pools. After 1 h, the radiolabel was predominantly found in the alpha-ClFOH pool. Cell-derived alpha-ClFOH and alpha-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 alpha-ClFA and alpha-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 alpha-ClFA and reduced to alpha-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 alpha-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.
Highlights
Tion of the reactive chlorinating species (RCS), hypochlorous acid (HOCl), which is a bactericidal agent [4]
The accumulation of ␣-chloro fatty aldehyde in atherosclerotic lesions and in infarcted myocardium, coupled with the potential role this lipid may have on cardiovascular function, underscore the importance of determining the mechanisms responsible for ␣-chloro fatty aldehyde catabolism
The results demonstrate that both endothelial cells and neutrophils oxidize and reduce 2-ClHDA to its respective chlorinated fatty acid and chlorinated fatty alcohol, which are subsequently incorporated into complex glycerolipids
Summary
Tion of the reactive chlorinating species (RCS), hypochlorous acid (HOCl), which is a bactericidal agent [4]. At the end of each chase interval, radiolabeled lipid metabolites of 2-Cl-[3H]-HDA associated with the HCAEC, as well as the cell culture medium, were prepared for analyses (see above).
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