| First Author | Liu Y | Year | 2018 |
| Journal | Br J Pharmacol | Volume | 175 |
| Issue | 8 | Pages | 1190-1204 |
| PubMed ID | 28771708 | Mgi Jnum | J:289924 |
| Mgi Id | MGI:6433238 | Doi | 10.1111/bph.13971 |
| Citation | Liu Y, et al. (2018) Metabolic profiling of murine plasma reveals eicosapentaenoic acid metabolites protecting against endothelial activation and atherosclerosis. Br J Pharmacol 175(8):1190-1204 |
| abstractText | 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 omega-3 polyunsaturated fatty acids (omega-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 omega-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 omega-3 and also LDLR(-/-) and fat-1 transgenic (LDLR(-/-) -fat-1(tg) ) mice fed a WTD. The profiles of omega-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 omega-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 omega-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 TNFalpha via NF-kappaB 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. |
