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

Journal Article · Tue Feb 15 04:00:00 EST 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.11.013· OSTI ID:21535236

Majkova, Zuzana ^[1]; Layne, Joseph ^[2]; Sunkara, Manjula; Morris, Andrew J ^[3]; Toborek, Michal ^[4]; Hennig, Bernhard ^[1]

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1. Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0200 (United States)
2. Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40536-0200 (United States)
3. Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, KY 40536-0509 (United States)
4. Department of Neurosurgery, University of Kentucky, Lexington, KY 40536-0200 (United States)

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{sub 4}/J{sub 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 (NaBH{sub 4}), which concurrently abrogated A{sub 4}/J{sub 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{sub 4}/J{sub 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{sub 4}/J{sub 4}-NPs as mediators of omega-3 fatty acid-mediated protection against the endothelial toxicity of coplanar PCBs.

• OSTI ID: 21535236
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 251; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AROMATICS
ARTERIOSCLEROSIS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CARBOXYLIC ACIDS
CARDIOVASCULAR DISEASES
CHLORINATED AROMATIC HYDROCARBONS
CHROMATOGRAPHY
DISEASES
DNA
HALOGENATED AROMATIC HYDROCARBONS
HAZARDS
HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY
HYPOTHESIS
LEUKOCYTES
LIQUID COLUMN CHROMATOGRAPHY
MASS SPECTROSCOPY
MATERIALS
METABOLITES
MONOCYTES
NUCLEIC ACIDS
ORGANIC ACIDS
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
POLYCHLORINATED BIPHENYLS
RADICALS
SAFETY
SEPARATION PROCESSES
SPECTROSCOPY
TOXICITY
VASCULAR DISEASES