Identification of α-Chloro Fatty Aldehydes and Unsaturated Lysophosphatidylcholine Molecular Species in Human Atherosclerotic Lesions
Open accessAbstract
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 α-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 α-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 present studies demonstrate that plasmalogens are attacked by MPO-derived reactive chlorinating species within human atheroma. The resultant species formed, α-chloro fatty aldehydes and unsaturated lysophospholipids, possess proatherogenic properties, as shown by induction of P-selectin surface expression in primary human coronary artery endothelial cells.
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Unsaturated lipids serve as major HOCl-targets under physiological conditions.
“Consistent with chlorination-associated electrophilic stress, unsaturated lipids serve as major HOCl-targets under physiological conditions ( Figure 3B ) (92–99).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [96]
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- Authors
- Thukkani, A. K., McHowat, J., Hsu, F.-F., Brennan, M.-L., Hazen, S. L., & Ford, D. A.
- Affiliations
- Cleveland Clinic (US)
- Venue
- Circulation
- Published
- 2003-12-23
- Volume
- 108
- Issue
- 25
- Pages
- 3128-3133
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2141759373
- Cited by
- 194
- References
- 31
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 6 · 2020: 11 · 2019: 3 · 2018: 8 · 2017: 13 · 2016: 9 · 2015: 8 · 2014: 10 · 2013: 12 · 2012: 9
- FWCI
- 3.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association (0340042N)
- Cleveland Clinic
- Cleveland Clinic Foundation
- National Institutes of Health (5p41rr000954-34)
- National Heart, Lung, and Blood Institute (R01-HL-42665-11, HL 62526, R01HL068588, HL 70621, R01HL042665, R01HL062526, R01HL070621, HL68588)
- National Center for Research Resources (RR 00954, M01RR018390)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- myeloperoxidase, atherosclerosis, plasmalogens, lipid oxidation, P-selectin, coronary artery endothelial cells, atherosclerotic plaque, linoleic acid, arachidonic acid, docosahexaenoic acid
- MeSH terms
- Aldehydes, Animals, Aorta, Arteriosclerosis, Cells, Cultured, Endothelium, Vascular, Fatty Acids, Fatty Acids, Unsaturated, Humans, Hydrocarbons, Chlorinated, Lysophosphatidylcholines, Plasmalogens, P-Selectin, Mice
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