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PMID: 21130106 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Omega-3 fatty acid oxidation products prevent vascular endothelial cell activation by coplanar polychlorinated biphenyls.

Toxicology and applied pharmacology ·Vol. 251 ·No. 1 ·2011-02-15 ·Pages 41-9

Majkova Z, Layne J, Sunkara M, Morris AJ, Toborek M, Hennig B

Abstract

Coplanar polychlorinated biphenyls (PCBs) may facilitate development of atherosclerosis by stimulating pro-inflammatory pathways in the vascular endothelium. Nutrition, including fish oil-derived long-chain omega-3 fatty acids, such as docosahexaenoic acid (DHA, 22:6ω-3), can reduce inflammation and thus the risk of atherosclerosis. We tested the hypothesis that cyclopentenone metabolites produced by oxidation of DHA can protect against PCB-induced endothelial cell dysfunction. Oxidized DHA (oxDHA) was prepared by incubation of the fatty acid with the free radical generator 2,2-azo-bis(2-amidinopropane) dihydrochloride (AAPH). Cellular pretreatment with oxDHA prevented production of superoxide induced by PCB77, and subsequent activation of nuclear factor-κB (NF-κB). A₄/J₄-neuroprostanes (NPs) were identified and quantitated using HPLC ESI tandem mass spectrometry. Levels of these NPs were markedly increased after DHA oxidation with AAPH. The protective actions of oxDHA were reversed by treatment with sodium borohydride (NaBH₄), which concurrently abrogated A₄/J₄-NP formation. Up-regulation of monocyte chemoattractant protein-1 (MCP-1) by PCB77 was markedly reduced by oxDHA, but not by un-oxidized DHA. These protective effects were proportional to the abundance of A₄/J₄ NPs in the oxidized DHA sample. Treatment of cells with oxidized eicosapentaenoic acid (EPA, 20:5ω-3) also reduced MCP-1 expression, but less than oxDHA. Treatment with DHA-derived cyclopentenones also increased DNA binding of NF-E2-related factor-2 (Nrf2) and downstream expression of NAD(P)H:quinone oxidoreductase (NQO1), similarly to the Nrf-2 activator sulforaphane. Furthermore, sulforaphane prevented PCB77-induced MCP-1 expression, suggesting that activation of Nrf-2 mediates the observed protection against PCB77 toxicity. Our data implicate A₄/J₄-NPs as mediators of omega-3 fatty acid-mediated protection against the endothelial toxicity of coplanar PCBs.

MeSH Terms
Animals Antioxidants/metabolism Borohydrides/pharmacology Cells, Cultured Cyclopentanes/metabolism Cytoprotection Docosahexaenoic Acids/metabolism Eicosapentaenoic Acid/metabolism Endothelial Cells/drug effects,metabolism NAD(P)H Dehydrogenase (Quinone)/metabolism NF-E2-Related Factor 2/metabolism NF-kappa B/metabolism Neuroprostanes/metabolism Oxidation-Reduction Oxidative Stress/drug effects Polychlorinated Biphenyls/toxicity Superoxides/metabolism Swine Time Factors
Chemicals
Antioxidants Borohydrides Cyclopentanes NF-E2-Related Factor 2 NF-kappa B Neuroprostanes Superoxides Docosahexaenoic Acids sodium borohydride Eicosapentaenoic Acid Polychlorinated Biphenyls NAD(P)H Dehydrogenase (Quinone) cyclopentenone 3,4,3',4'-tetrachlorobiphenyl
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Majkova Zuzana
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0200, USA.
Layne Joseph
Sunkara Manjula
Morris Andrew J
Toborek Michal
Hennig Bernhard
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Article Info
Journal
Toxicology and applied pharmacology
Abbr.
Toxicol Appl Pharmacol
ISSN
1096-0333
DOI
10.1016/j.taap.2010.11.013
Published
2011-02-15
Epub
2010-00-01
Pages
41-9
Language
English
Region
United States
NLM ID
0416575
PMCID
PMC3026064
Subset
IM
Grants
NIGMS NIH HHS · GM50388 · United States
NCRR NIH HHS · P20 RR021954-03 · United States
NIEHS NIH HHS · P42 ES007380 · United States
NCRR NIH HHS · S10 RR024598 · United States
NIGMS NIH HHS · R01 GM050388 · United States
NIEHS NIH HHS · P42 ES007380-14 · United States
NCRR NIH HHS · P20RR021954 · United States
NIEHS NIH HHS · P42ES007380 · United States
NCRR NIH HHS · P20 RR021954 · United States
External Links
PubMed source DOI: 10.1016/j.taap.2010.11.013 PMC Full Text View journal details
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