Structural Identification by Mass Spectrometry of Oxidized Phospholipids in Minimally Oxidized Low Density Lipoprotein That Induce Monocyte/Endothelial Interactions and Evidence for Their Presence in Vivo
Open accessAbstract
Entry of monocytes into the vessel wall is an important event in atherogenesis. Previous studies from our laboratory suggest that oxidized arachidonic acid-containing phospholipids present in mildly oxidized low density lipoproteins (MM-LDL) can activate endothelial cells to bind monocytes. In this study, biologically active oxidized arachidonic acid-containing phospholipids were produced by autoxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) and analyzed by liquid chromatography and electrospray ionization mass spectrometry in conjuction with biochemical derivatization techniques. We have now determined the molecular structure of two of three molecules present in MM-LDL and Ox-PAPC that induce monocyte-endothelial interactions. These lipids were identified as 1-palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine (m/z 594.3) and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (m/z 610.2). These two molecules were produced by unambiguous total synthesis and found to be identical by analytical techniques and bioactivity assays to those present in MM-LDL and Ox-PAPC. Evidence for the importance of all three oxidized phospholipids in vivo was suggested by their presence in fatty streak lesions from cholesterol-fed rabbits and by their immunoreactivity with natural antibodies present in ApoE null mice. Overall, these studies suggest that specific oxidized derivatives of arachidonic acid-containing phospholipids may be important initiators of atherogenesis.
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OxPLs in oxLDL activate endothelial cells and control endothelial barrier permeability, and oxPLs released from dying cells are captured by CD14 on dendritic cells, causing inflammasome-dependent phagocyte hyperactivation.
“the oxPLs present in oxLDL activate endothelial cells and control the endothelial barrier permeability52,53, and oxPLs released from dying cells are captured by the CD14 receptor on dendritic cells, with ensuing inflammasome-dependent phagocyte hyperactivation54.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [52]
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References 65 · Cited by 753
Research works printed but not linked: 3
- Working Group of Arteriosclerosis (1981) Report of the Working Group of Arteriosclerosis of the National Heart, Lung, and Blood Institute, Vol. 2, DHEW publication (NIH) 82-2035, Government Printing Office, Washington, D. C.
- Cushing, S. D., Berliner, J. A., Valente, A. J., Territo, M. C., Navab, M., Parhami, F., Gerrity, R., Schwartz, C. J., and Fogelman, A. M. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 5134 -5138
- Palinski, W., Miller, E., and Witztum, J. L. (1995) Proc. Natl. Acad. Sci.
- Authors
- Watson, A. D., Leitinger, N., Navab, M., Faull, K. F., Hörkkö, S., Witztum, J. L., Palinski, W., Schwenke, D., Salomon, R. G., Sha, W., Subbanagounder, G., Fogelman, A. M., & Berliner, J. A.
- Affiliations
- University of California, Los Angeles (US)
- University of California San Diego (US)
- Atrium Health Wake Forest Baptist (US)
- Case Western Reserve University (US)
- Corresponding author
- Watson, Andrew D.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-05
- Volume
- 272
- Issue
- 21
- Pages
- 13597-13607
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2137511741
- Cited by
- 753
- References
- 65
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 7 · 2023: 10 · 2022: 12 · 2021: 13 · 2020: 9 · 2019: 15 · 2018: 19 · 2017: 26 · 2016: 18 · 2015: 26 · 2014: 22 · 2013: 29 · 2012: 29
- FWCI
- 13.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5t32hl007386-15)
- National Heart, Lung, and Blood Institute (HL3 0568, HL 07386, P01HL030568)
- National Center for Research Resources (RR-865)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- oxidized phospholipids, monocyte-endothelial interaction, atherogenesis, autoxidation, total synthesis, fatty streaks, ApoE-null mice, natural antibodies, oxidized phosphatidylcholine
- MeSH terms
- Animals, Antibodies, Monoclonal, Arteriosclerosis, Borohydrides, Cell Adhesion, Chromatography, High Pressure Liquid, Endothelium, Vascular, Fluorobenzenes, Fluorocarbons, Hydroxylamines, Lipoproteins, LDL, Monocytes, Oxidation-Reduction, Phospholipid Ethers, Phospholipids, Rabbits, Mass Spectrometry, Mice
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