Identification of α-Chloro Fatty Aldehydes and Unsaturated Lysophosphatidylcholine Molecular Species in Human Atherosclerotic Lesions

Abstract

Background-A role for myeloperoxidase (MPO) as a mediator of coronary artery disease and acute coronary syndromes has recently received considerable attention. Although active MPO and hypochlorite-modified proteins and peptides have been detected in human atherosclerotic lesions, detection of novel chlorinated oxidized lipid species with proatherogenic properties in vivo has not yet been reported. In this study we show that MPO-generated reactive chlorinating species promote selective oxidative cleavage of plasmalogens, liberating ␣-chloro fatty aldehydes and unsaturated lysophosphatidylcholine in human atherosclerotic lesions. Methods and Results-Stable isotope dilution gas chromatography-mass spectrometry methods were used to identify and quantitate the ␣-chloro fatty aldehyde, 2-chlorohexadecanal, in atherosclerotic versus normal human aorta. Compared with normal aorta, 2-chlorohexadecanal levels were elevated more than 1400-fold in atherosclerotic tissues. Parallel electrospray ionization mass spectrometry studies confirmed 34-and 20-fold increases in the plasmalogen cooxidation products, unsaturated lysophosphatidylcholine molecular species containing linoleic and arachidonic acid, respectively, within atherosclerotic compared with normal aorta. Unsaturated lysophosphatidylcholine containing docosahexaenoic acid was also detected in atherosclerotic but not in normal aorta. Exposure of primary human coronary artery endothelial cells to plasmalogen-derived lysophosphatidylcholine molecular species produced marked increases in P-selectin surface expression. Conclusions-The

Mouse brain plasmalogens are targets for hypochlorous acid-mediated modification in vitro and in vivo

“…In addition protein-derived chloramines are able to initiate secondary plasmalogen modification: The most potent are histidine chloramine analogues (with reaction kinetics only 5-to 30-fold slower than HOCl), whereas N-acetyllysine and taurine chloramines are less effective (approx 10 5 -fold slower than HOCl [42,43] We have detected substantial amounts of 2-ClHDA (2 μg/g wet brain containing approx 80% water resulting in a concentration of approx 10 μM) only in endotoxin-injected mice. These 2-ClHDA concentrations are in a range comparable to that reported for a rat model of myocardial infarction (approx 1 μM [21]) and for human atherosclerotic lesion material (approx 10 μM [7]). This provides clear evidence that MPO-dependent plasmalogen modification is a neuroinflammatory event.…”

“…2B), with quantitative modification occurring at oxidant:lipid mass ratios ranging from 50:100 to 500:100. The corresponding remnant lyso-compounds (formed upon HOCl attack of the vinyl ether bond and subsequent abstraction of 2-chloroaldehydes from the sn-1 position; [7]) are detectable at oxidant:lipid ratios between 1:100 and 50:100 in a transient manner (Fig. 2C).…”

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

“…Attack by this oxidant leads to cleavage of the vinyl ether by a 2-electron mechanisms to yield an D-chlorofatty aldehyde and a lysolipid [77]. D-chlorohexadecanal and D-chlorooctadecanal have both been detected as plasmalogen oxidation products in activated neutrophils [78], and have been found to be elevated significantly in atherosclerotic lesions in cardiovascular disease [79], and in mouse brain following systemic injection of endotoxin [80]. The formation and biological effects of these α-halogenated aldehydes have been reviewed recently [81], but as yet their reactivity is not very well established compared to the other lipid oxidation products described here.…”

The roles of myeloperoxidase in coronary artery disease and its potential implication in plaque rupture

“…HOCl reacts at much slower rates with double bonds, aromatic rings (including Tyr and Trp), fatty acid side chains and nucleobases (reviewed in reference [47]). Reactions with Tyr residues yield 3-chlorotyrosine, a specific biomarker for HOCl identified in human atherosclerotic lesions [48], together with chlorinated lipids [49,50]. The antioxidants ascorbate and urate react with HOCl with second-order rate constants of 6 × 10 6 and 2 × 10 5 M −1 s −1 , respectively [45,51].…”