The fatty acid oxidation product 15‐A_3t‐Isoprostane is a potent inhibitor of NFκB transcription and macrophage transformation

Abstract

Fatty acids such as eicosapentaenoic acid (EPA) have been shown to be beneficial for neurological function and human health. It is widely thought that oxidation products of EPA are responsible for biological activity, although the specific EPA peroxidation product(s) which exert these responses have not yet been identified. In this work we provide the first evidence that the synthesized representative cyclopentenone IsoP, 15-A3t-IsoP, serves as a potent inhibitor of lipopolysaccharide-stimulated macrophage activation. The anti-inflammatory activities of 15-A3t-IsoP were observed in response not only to lipopolysaccharide, but also to tumor necrosis factor alpha and IL-1b stimulation. Subsequently, this response blocked the ability of these compounds to stimulate nuclear factor kappa b (NFκB) activation and production of proinflammatory cytokines. The bioactivity of 15-A3t-IsoP was shown to be dependent upon an unsaturated carbonyl residue which transiently adducts to free thiols. Site directed mutagenesis of the redox sensitive C179 site of the Ikappa kinase beta subunit, blocked the biological activity of 15-A3t-IsoP and NFκB activation. The vasoprotective potential of 15-A3t-IsoP was underscored by the ability of this compound to block oxidized lipid accumulation, a critical step in foam cell transformation and atherosclerotic plaque formation. Taken together, these are the first data identifying the biological activity of a specific product of EPA peroxidation, which is formed in abundance in vivo. The clear mechanism linking 15-A3t-IsoP to redox control of NFκB transcription, and the compound's ability to block foam cell transformation suggest that 15-A3t-IsoP provides a unique and potent tool to provide vaso- and cytoprotection under conditions of oxidative stress.

Lipids promote survival, proliferation, and maintenance of differentiation of rat liver sinusoidal endothelial cells in vitro

“…Unsaturated FFAs have been found to be able to protect against oxidative stress by reducing lipid peroxidation and inhibiting the inflammatory pathway NF-B, which can lead to endothelial cell activation (9,11,15,39). Thus OA may prevent oxidative stress in LSEC that decreases ERK1/2 activity (38,48), thereby allowing cells to resume cell survival and proliferation after day 3.…”

Oxidation of Marine Omega-3 Supplements and Human Health

“…Interestingly, in a study of liver tissue in culture, oxidized EPA inhibited the inflammatory NF- κ B pathway [34]. This may be mediated by n-3 derived isoprostanes, as these peroxides have been shown to be biologically active, inhibiting macrophage NF- κ B activation in tissue culture [35]; and affecting vascular and platelet function [10]. It is not yet clear whether these effects are important in vivo ; however, they provide evidence for a divergence of effects when n-3 LC-PUFAs are oxidized.…”

“…The effects of oxidation on the biological effects of these oils may be complex, there could be both beneficial [10, 34, 35] and harmful effects. Thus, long-term safety studies of marine oil are required, looking at appropriate disease outcomes and surrogates and relating these to the oxidative state.…”

Non-enzymatic cyclic oxygenated metabolites of adrenic, docosahexaenoic, eicosapentaenoic and α-linolenic acids; bioactivities and potential use as biomarkers

“…Altogether, the results reinforced the hypothesis that F 4 -NeuroPs could contribute to the anti-atherogenic effects of DHA. In parallel, several in vitro experiments showed that EPA and DHA-related isoprostanes (namely 15-A 3t -IsoP, J 3 -IsoP, A 4 /J 4 -NeuroP and 4-F 4t -NeuroP) possessed potent anti-inflammatory properties linked notably to the inhibition of the NFκB and/or Nrf-2 pathways [76][77][78][79]. However, contrasting outcome was found in supplementation of RTT patients with n-3 PUFA from fish oil in which plasma free F 4 -NeuroPs concentrations were lower when compared to controls.…”