Year of Publication

2007

Document Type

Dissertation

College

Graduate School

Department

Nutritional Sciences

First Advisor

Bernhard Hennig

Abstract

Endothelial activation is considered to be an early and critical event in the pathology of atherogenesis which can be modified by environmental factors such as diet, pollutants, and lifestyle habits. Dietary andamp;ugrave;-6 and andamp;ugrave;-3 fatty acids have been reported to either amplify or diminish inflammatory responses related to atherosclerosis development. However, the interactions of andamp;ugrave;-6 and andamp;ugrave;-3 fatty acids with inflammatory cytokines or organic pollutants on endothelial cell activation are not well understood. The studies presented in this dissertation tested the hypothesis that andamp;ugrave;-6 and andamp;ugrave;-3 fatty acids alone, or in varying ratios can differently modulate pro-atherogenic mediators and inflammatory responses that are initiated by tumor necrosis factor- andamp;aacute; (TNF-andamp;aacute;) or polychlorinated biphenyls (PCBs) in endothelial cells. Exposure to TNF-andamp;aacute; induced oxidative stress, p38 MAPK, NF-andamp;ecirc;B, COX-2 and PGE2, which was amplified by pre-enrichment with linoleic acid but blocked or reduced by andamp;aacute;-linolenic acid. Furthermore, TNF-andamp;aacute;-induced caveolin-1 up-regulation and the co-localization of TNF receptor-1 with caveolin-1 was markedly increased in the presence of linoleic acid and diminished by andamp;aacute;-linolenic acid. Silencing of the caveolin-1 gene completely blocked TNF-andamp;aacute;-induced production of COX-2 and PGE2 and significantly reduced the amplified response of linoleic acid plus TNF-andamp;aacute;. These data suggest that omega-6 and omega-3 fatty acids can differentially modulate TNF-andamp;aacute;-induced inflammatory stimuli and that caveolae and its fatty acid composition play a regulatory role in these observed metabolic events. Besides cytokines, lipophilic environmental contaminants such as PCBs can also trigger inflammatory events in endothelial cells. Our data suggest that increasing the relative amount of andamp;aacute;-linolenic acid to linoleic acid can markedly decrease oxidative stress and NF-andamp;ecirc;B-responsive genes. The inhibitor study revealed that the modulation effect of andamp;ugrave;-6 and andamp;ugrave;-3 fatty acids on PCB toxicity was mainly through the oxidative stress sensitive transcription factor, NF-andamp;ecirc;B. In conclusion, our studies demonstrate that different dietary fats can selectively modulate vascular cytotoxicity caused by TNF-andamp;aacute; as well as by persistent organic pollutants such as PCBs. We also demonstrated the important relevance of substituting dietary andamp;ugrave;-3 fatty acids such as andamp;aacute;-linolenic acid for andamp;ugrave;-6 fatty acid such as linoleic acid in reducing cardiovascular diseases.

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