The anti-inflammatory effects of eicosapentaenoic and docosahexaenoic acids found in fish in vivo and in vitro.

摘要

Cardiovascular disease (CVD) represents one of the leading causes of mortality in the U.S. being the number one killer of elderly. The main determinant for CVD is atherosclerosis, a condition characterized by a chronic low-grade inflammation in the arterial wall. It has been shown that consumption of fish, presumably through its content of n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has anti-atherogenic properties and protects against CVD. It is well accepted that, at least in part, these effects are due to the anti-inflammatory properties of EPA and DHA.; This project was conducted to elucidate the effects of EPA and DHA on markers of inflammation recognized as predictors of CVD and active players during atherogenesis. The central hypothesis was that EPA and DHA would attenuate the production of pro-inflammatory interleukins (IL-1beta, IL-6) and acute-phase reactants (C-reactive protein). To test this hypothesis, a comprehensive approach was taken. First, the effects of fish oil were assessed in a human supplementation study, and then the results obtained were further investigated in human cells relevant for the atherogenic process in vivo.; In healthy postmenopausal women, supplementation with two dietary relevant doses of fish oil for five weeks significantly decreased plasma IL-6 and serum C-reactive protein concentrations. Also, supplementation decreased the ex vivo production of IL-6 as measured in the supernatant of lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells.; Further, a mechanistic approach was used to explain these findings, whereby the anti-inflammatory effects of physiological doses of EPA and DHA were investigated in U937-derived macrophages enriched with these fatty acids and then stimulated with LPS. It was hypothesized that EPA and DHA would decrease IL-1beta, IL-6, and modified CRP (mCRP) production by preventing the activation of transcription factors involved in the regulation of these markers. Also, it was hypothesized that to a great extent the anti-inflammatory effects of EPA and DHA would be mediated via their enzymatically oxidized metabolites resulting from the action of 15-lipoxygenase. The results obtained supported these hypotheses and showed that 15-LO-derived oxidized EPA and DHA but not their unoxidized precursors are potent suppressors of IL-1beta, IL-6, and mCRP production. These effects were mediated by decreasing the activation of NF-kappaB, C/EBP-beta, and STAT-3 and were more apparent for oxidized EPA than for oxidized DHA.; The overall significance of this project is that it reinforces the beneficial properties of fish consumption and provides new insights in understanding how EPA and DHA modulate the dynamics of plaque formation. Moreover, the mechanistic findings reported here could be useful in designing more selective therapeutic approaches to prevent atherosclerosis and hence, CVD.