Changing ratios of omega-6 to omega-3 fatty acids can differentially modulate polychlorinated biphenyl

Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs) can cause endothelial cell (EC) activation by inducing pro-inflammatory signaling pathways. Our previous studies indicated that linoleic acid (LA, 18:2), a major omega 6 unsaturated fatty acid in the American diet, can potentiate PCB77 mediated inflammatory responses in EC. In addition, omega-3 fatty acids (such as alpha linolenic acid, ALA and 18:3) are known for their anti inflammatory properties. We tested the hypothesis that mechanisms of PCB induced endothelial cell activation and inflammation can be modified by different ratios of omega 6 to omega 3 fatty acids. EC were pretreated with LA, ALA, or different ratios of these fatty acids, followed by exposure to PCB77. PCB77 induced oxidative stress and activation of the oxidative stress sensitive transcription factor nuclear factor alpha B (NFaB) were markedly increased in the presence of LA and diminished by increasing the relative amount of ALA to LA. Similar protective effects by increasing ALA were observed by measuring NFaB responsive genes, such as vascular cell adhesion molecule 1 (VCAM1) and cyclooxygenase 2 (COX2). COX2 catalyzes the rate limiting step of the biosynthesis of prostaglandin E2 (PGE2). PCB77 exposure also increased PGE2 levels, which were down-regulated with relative increasing amounts of ALA to LA. The present studies suggest that NFaB is a critical player in the regulation of PCB induced inflammatory markers as modulated by omega 6 and omega 3 fatty acids. (Authors abstract)

Substantial evidence from epidemiological studies suggests that cardiovascular diseases are linked to environmental pollution which may also precipitate lipid peroxidation and led to a persistent state of oxidative stress. In addition, dysfunction of endothelial cells is a critical underlying cause of the initiation of cardiovascular diseases such as atherosclerosis. Severe endothelial cell activation and injury can lead to necrotic and apoptotic cytotoxicity, and ultimately to disruption of endothelial integrity. Oxidative stress-induced transcription factors, such as nuclear factor aB (NF-aB) regulate inflammatory cytokine and adhesion molecule production, and play a critical role in the induction of inflammatory responses. Binding sites for NF aB and related transcription factors were identified in the promoter regions of a variety of inflammatory genes such as interleukin 6 (IL6), vascular cell adhesion molecule-1 (VCAM1) or cyclooxygenase 2 (COX2), all of which are upregulated during PCB toxicity. Specific fatty acids rich in plant oils, such as linoleic acid can amplify PCB toxicity in vascular endothelial cells and may enhance the cellular availability of PCBs. In contrast to omega 6 fatty acids, omega-3 fatty acids can influence cardiovascular disease pathology by beneficially modulating inflammation. The current study was designed to test the hypothesis that PCB induced endothelial cell inflammation can be enhanced by omega 6 fatty acids and antagonized by omega 3 fatty acid with a focus upon those acids which are most commonly consumed in the average U.S. diet. Data from the present study confirm that endothelial exposure to PCB77 provides a pro oxidative cellular environment, sufficient to induce oxidative stress sensitive transcription factors such as NF aB and associated inflammatory events characteristic of early events in the pathology of atherosclerosis. Using an established cell culture model, the data clearly demonstrate that increasing the relative amount of ALA over linoleic acid LA protects against PCB mediated endothelial activation. The data support the hypothesis that the lipid milieu within the vascular endothelium can either up regulate or down regulate inflammatory events induced by PCB77. LA stimulated NF aB transcriptional activation the most and markedly enhanced mRNA levels of TNFa, monocyte chemoattractant protein 1 (MCP1) and adhesion molecules such as VCAM1. A relative increase in ALA over LA markedly reduced inflammatory markers induced by exposure to PCB77. In the present study, it was demonstrated that inhibition of NF aB markedly reduced both PCB and linoleic acid mediated endothelial inflammation.  Protective mechanisms of omega 3 fatty acids such as ALA on down regulation of PCB induced vascular inflammation are not well understood. One inhibitory mechanism may be a relative decrease in substrate availability for the pro inflammatory eicosanoid PGE2 formation during cellular enrichment with ALA. In summary, the current study demonstrates that diet derived lipids can modulate PCB77 stimulated activation of endothelial cells by affecting oxidative stress sensitive signaling pathways including activation of NF aB and up regulation of inflammatory genes. The authors indicate that whether an increase in the consumption of omega 3s such as ALA can be used therapeutically against inflammation that is mediated in part by environmental pollutants warrants further study. (Editors comments)