Metabolic profiling of murine plasma reveals eicosapentaenoic acid metabolites protecting against endothelial activation and atherosclerosis
Metabolic profiling of murine plasma reveals eicosapentaenoic acid metabolites protecting against endothelial activation and atherosclerosis
复制标题
小鼠血浆的代谢分析揭示了二十碳五烯酸代谢物可防止内皮活化和动脉粥样硬化。
DOI：
10.1111/bph.13971
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发表时间：
2018-04-01
影响因子：
7.3
通讯作者：
Zhu, Yi
中科院分区：
文献类型：
--
作者：
Liu, Yajin;Fang, Xuan;Zhu, Yi
背景和目的动脉粥样硬化是由于低密度脂蛋白（LDL）滞留在动脉血管敏感部位引起的适应不良的炎症反应。-3多不饱和脂肪酸（-3）在动脉粥样硬化中具有保护作用;然而，它们的分子机制在很大程度上仍然未知。本研究采用代谢组学方法揭示动脉粥样硬化的代谢产物的-3和调查的潜在mechanism.Experimental ApproachWe评估的发展动脉粥样硬化的LDL受体缺陷小鼠（LDLR-/-）喂养西方型饮食（WTD）加-3，也LDLR-/-和脂肪-1转基因（LDLR-/--脂肪-1（tg））小鼠喂养WTD。使用无偏系统代谢组学分析，通过LC-MS/MS筛选血浆中-3的谱。我们还研究了二十碳五烯酸（EPA）的代谢产物对内皮细胞activationinvitro.Key Results-3饮食和脂肪-1转基因降低单核细胞浸润，抑制促炎基因的表达，并显着衰减动脉粥样硬化斑块的形成和增强斑块的稳定性在LDLR-/-小鼠的影响。来自EPA的细胞色素P450途径的18-羟基-二十碳五烯酸（18-HEPE）和17，18-环氧-二十碳四烯酸（17，18-EEQ）的含量在来自-3-处理的LDLR-/-和LDLR-/--fat-1（tg）小鼠的血浆中显著高于WTD-喂养的LDLR-/-小鼠。在体外内皮细胞，18-HEPE或17，18-EEQ降低炎症基因表达诱导的TNF通过NF-B信号转导，从而抑制单核细胞粘附到内皮cells.Conclusions and ImplicationsEPA保护动脉粥样硬化的发展arteroprone小鼠通过代谢产物18-HEPE和/或17，18-EEQ，减少内皮细胞活化。这些化合物可能对动脉粥样硬化有治疗意义。链接文章这篇文章是聚焦心血管疾病中的小分子的主题部分的一部分。要查看本节中的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc
\ Background and PurposeAtherosclerosis results from a maladaptive inflammatory response initiated by the intramural retention of LDL in susceptible areas of the arterial vasculature. The -3 polyunsaturated fatty acids (-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 -3 and investigate the underlying mechanisms.Experimental ApproachWe evaluated the development of atherosclerosis in LDL receptor-deficient mice (LDLR-/-) fed a Western-type diet (WTD) plus -3 and also LDLR-/- and fat-1 transgenic (LDLR-/--fat-1(tg)) mice fed a WTD. The profiles of -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 ResultsThe -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 -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 TNF via NF-B signalling and thereby inhibited monocyte adhesion to endothelial cells.Conclusions and ImplicationsEPA 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 ArticlesThis 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