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

Zuzana Majkova, Joseph Layne, Manjula Sunkara, Andrew J. Morris, Michal J Toborek, Bernhard Hennig

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)41-49
Number of pages9
JournalToxicology and Applied Pharmacology
Volume251
Issue number1
DOIs
StatePublished - Feb 15 2011
Externally publishedYes

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Neuroprostanes
Polychlorinated Biphenyls
Endothelial cells
Omega-3 Fatty Acids
Endothelial Cells
Chemical activation
Chemokine CCL2
Oxidation
Toxicity
Atherosclerosis
NF-E2-Related Factor 2
Eicosapentaenoic Acid
Electrospray Ionization Mass Spectrometry
Docosahexaenoic Acids
Fish Oils
Vascular Endothelium
Nutrition
Metabolites
Tandem Mass Spectrometry
Superoxides

Keywords

  • Docosahexaenoic acid (DHA)
  • Endothelial cells
  • Monocyte chemoattractant protein-1 (MCP-1)
  • NF-E2-related factor-2 (Nrf2)
  • Oxidative stress
  • Polychlorinated biphenyls (PCBs)

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Omega-3 fatty acid oxidation products prevent vascular endothelial cell activation by coplanar polychlorinated biphenyls. / Majkova, Zuzana; Layne, Joseph; Sunkara, Manjula; Morris, Andrew J.; Toborek, Michal J; Hennig, Bernhard.

In: Toxicology and Applied Pharmacology, Vol. 251, No. 1, 15.02.2011, p. 41-49.

Research output: Contribution to journalArticle

Majkova, Zuzana ; Layne, Joseph ; Sunkara, Manjula ; Morris, Andrew J. ; Toborek, Michal J ; Hennig, Bernhard. / Omega-3 fatty acid oxidation products prevent vascular endothelial cell activation by coplanar polychlorinated biphenyls. In: Toxicology and Applied Pharmacology. 2011 ; Vol. 251, No. 1. pp. 41-49.
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