The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport
Open accessAbstract
Although oxidatively damaged lipoproteins are implicated in vascular injury, there is little information regarding the role of high-density lipoprotein (HDL) oxidation in atherogenesis. One potential pathway involves hypochlorous acid (HOCl) produced by myeloperoxidase (MPO), a heme protein secreted by phagocytes. We previously showed that 3-chlorotyrosine is a specific product of HOCl. Therefore, to explore the role of oxidized HDL in the pathogenesis of vascular disease, we used MS to quantify 3-chlorotyrosine in HDL isolated from plasma and atherosclerotic tissue. HDL from human aortic atherosclerotic intima had an 8-fold higher level of 3-chlorotyrosine than plasma HDL. Tandem MS analysis identified MPO as a component of lesion HDL, suggesting that the two interact in the artery wall. Moreover, immunohistochemical studies found that specific epitopes derived from HOCl colocalized with apolipoprotein A-I, the major protein of HDL. These observations strongly support the hypothesis that MPO promotes HDL oxidation in the human artery wall. Levels of 3-chlorotyrosine were elevated in HDL isolated from the blood of humans with established coronary artery disease, suggesting that circulating levels of oxidized HDL represent a unique marker for clinically significant atherosclerosis. HDL or lipid-free apolipoprotein A-I exposed to HOCl was less able to remove cholesterol from cultured cells by a pathway requiring the cell membrane transporter ATP-binding cassette transporter A1. The detection of 3-chlorotyrosine in HDL isolated from vascular lesions raises the possibility that MPO, by virtue of its ability to form HOCl, may promote atherogenesis by counteracting the established antiatherogenic effects of HDL and the ATP-binding cassette transporter A1 pathway.
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In the context of atherosclerosis, HOCl has been shown to oxidize both high and low density lipoproteins.
“In the context of atherosclerosis, HOCl has been shown to oxidize both high and low density lipoproteins (90, 470, 881, 1042).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [90]
Chlorinated proteins and lipids are present in atherosclerotic plaques.
“Furthermore, chlorinated proteins and lipids are present in atherosclerotic plaques (90, 415, 621).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [90]
MPO-derived oxidant 3-Cl-Tyr occurs in high-density lipoprotein (HDL) and is a good biomarker of cardiovascular diseases.
“MPO-derived oxidant 3-Cl-Tyr is occurring in high-density lipoprotein (HDL) and therefore is a good biomarker of cardiovascular diseases (Bergt et al. 2004)”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Bergt et al. 2004
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- Authors
- Bergt, C., Pennathur, S., Fu, X., Byun, J., O'Brien, K., McDonald, T. O., Singh, P., Anantharamaiah, G. M., Chait, A., Brunzell, J., Geary, R. L., Oram, J. F., & Heinecke, J. W.
- Affiliations
- University of Washington (US)
- Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; and Division of Surgical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-08-23
- Volume
- 101
- Issue
- 35
- Pages
- 13032-13037
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC516512
- OpenAlex
- W2134551277
- Cited by
- 454
- References
- 50
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 8 · 2023: 13 · 2022: 10 · 2021: 9 · 2020: 18 · 2019: 12 · 2018: 15 · 2017: 18 · 2016: 18 · 2015: 20 · 2014: 20 · 2013: 29 · 2012: 23
- FWCI
- 12.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Donald W. Reynolds Foundation
- University of Washington
- National Institutes of Health (HL 18645, ES-07033)
- National Institute on Aging (AG021191, R01AG021191)
- National Heart, Lung, and Blood Institute (HL-18645, HL75381, P50HL073996, P01HL030086, HL-34343, HL-55362, HL-073996, HL-64344, HL030086, P01HL034343, R01HL064344, P01HL018645, R01HL075381, R01HL055362)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 02456, P01DK002456)
- National Institute of Environmental Health Sciences (ES-07033, P30ES007033)
- 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 › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- myeloperoxidase, hypochlorous acid, HDL oxidation, 3-chlorotyrosine, atherosclerosis, ABCA1, cholesterol efflux, apolipoprotein A-I, coronary artery disease, aortic intima, atherogenesis
- MeSH terms
- Amino Acid Sequence, Arteries, Arteriosclerosis, Chromatography, Liquid, Humans, Hypochlorous Acid, Cholesterol, HDL, Molecular Sequence Data, Peroxidase, Mass Spectrometry, Tyrosine, Apolipoprotein A-I, ATP-Binding Cassette Transporters, ATP Binding Cassette Transporter 1
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