Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 251, Issue 1, Pages 41-49Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2010.11.013
Keywords
Polychlorinated biphenyls (PCBs); Endothelial cells; Docosahexaenoic acid (DHA); Monocyte chemoattractant protein-1 (MCP-1); NF-E2-related factor-2 (Nrf2); Oxidative stress
Categories
Funding
- NIH/NIEHS [P42ES007380 NIH GM50388, P20RR021954]
- University of Kentucky Agricultural Experiment Station
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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, 22:6 omega-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-kappa B (NF-kappa B). A(4)/J(4)-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 A(4)/J(4)-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 A(4)/J(4) NPs in the oxidized DHA sample. Treatment of cells with oxidized eicosapentaenoic acid (EPA, 20:5 omega-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 A(4)/J(4)-NP5 as mediators of omega-3 fatty acid-mediated protection against the endothelial toxicity of coplanar PCBs. (C) 2010 Elsevier Inc. All rights reserved.
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