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• W2744977423 abstract "Background and Purpose Atherosclerosis results from a maladaptive inflammatory response initiated by the intramural retention of LDL in susceptible areas of the arterial vasculature. The ω‐3 polyunsaturated fatty acids (ω‐3) have protective effects in atherosclerosis; however, their molecular mechanism is still largely unknown. The present study used a metabolomic approach to reveal the atheroprotective metabolites of ω‐3 and investigate the underlying mechanisms. Experimental Approach We evaluated the development of atherosclerosis in LDL receptor‐deficient mice (LDLR −/− ) fed a Western‐type diet (WTD) plus ω‐3 and also LDLR −/− and fat‐1 transgenic (LDLR −/− ‐ fat‐1 tg ) mice fed a WTD. The profiles of ω‐3 in the plasma were screened by LC–MS/MS using unbiased systematic metabolomics analysis. We also studied the effect of metabolites of eicosapentaenoic acid (EPA) on endothelial activation in vitro . Key Results The ω‐3 diet and fat‐1 transgene decreased monocyte infiltration, inhibited the expression of pro‐inflammatory genes and significantly attenuated atherosclerotic plaque formation and enhanced plaque stability in LDLR −/− mice. The content of 18‐hydroxy‐eicosapentaenoic acid (18‐HEPE) and 17,18‐epoxy‐eicosatetraenoic acid (17,18‐EEQ), from the cytochrome P450 pathway of EPA, was significantly higher in plasma from both ω‐3‐treated LDLR −/− and LDLR −/− ‐ fat‐1 tg mice as compared with WTD‐fed LDLR −/− mice. In vitro in endothelial cells, 18‐HEPE or 17,18‐EEQ decreased inflammatory gene expression induced by TNFα via NF‐κB signalling and thereby inhibited monocyte adhesion to endothelial cells. Conclusions and Implications EPA protected against the development of atherosclerosis in atheroprone mice via the metabolites 18‐HEPE and/or 17,18‐EEQ, which reduced endothelial activation. These compounds may have therapeutic implications in atherosclerosis. Linked Articles This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc" @default.
• W2744977423 created "2017-08-17" @default.
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• W2744977423 date "2017-09-05" @default.
• W2744977423 modified "2023-10-17" @default.
• W2744977423 title "Metabolic profiling of murine plasma reveals eicosapentaenoic acid metabolites protecting against endothelial activation and atherosclerosis" @default.
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• W2744977423 doi "https://doi.org/10.1111/bph.13971" @default.
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