Anti-inflammatory ω-3 endocannabinoid epoxides
Anti-inflammatory ω-3 endocannabinoid epoxides
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DOI：
10.1073/pnas.1610325114
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发表时间：
2017-07-25
影响因子：
11.1
通讯作者：
Das, Aditi
中科院分区：
文献类型：
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作者：
McDougle, Daniel R.;Watson, Josephine E.;Das, Aditi
临床研究表明，富含omega-3多不饱和脂肪酸（PUFAs）的饮食具有有益的抗炎作用，部分原因是它们转化为生物活性代谢物。在这里，我们报道了一种以前未知的由omega-3 pufa衍生的脂质代谢产物的内源性产生，这种代谢产物起源于内源性大麻素和细胞色素P450 （CYP）环氧化酶代谢途径之间的相互作用。omega-3内源性大麻素环氧化合物分别由二十二碳六烯酸（DHA）和二十碳五烯酸（EPA）衍生而成环氧二十碳四烯酸-乙醇酰胺（EEQ-EA）和环氧二十碳五烯酸-乙醇酰胺（EDP-EA）。通过靶向脂质组学方法确定，EEQ-EAs和EDP-EAs均内源性存在于大鼠大脑和外周器官中。这些代谢物是由活化的BV-2小胶质细胞和人CYP2J2直接环氧化omega-3内源性大麻素、二十二碳己烯醇乙醇酰胺（DHEA）和二十碳五烯醇乙醇酰胺（EPEA）直接产生的。神经炎症研究表明，末端环氧化合物17,18- eeq -EA和19,20- edp -EA剂量依赖性地减少促炎IL-6细胞因子，同时增加抗炎IL-10细胞因子，部分是通过大麻素受体-2激活。此外，omega-3内源性大麻素环氧化合物17,18- eeq - ea和19,20- edp - ea对人微血管内皮细胞（HMVEC）具有抗血管生成作用，对牛冠状动脉具有血管扩张作用，并相互调节洗涤后的人血小板聚集。综上所述，omega-3内源性大麻素环氧化合物的生理作用是通过内源性大麻素和环氧类大麻素信号通路介导的。总之，omega-3内源性大麻素环氧化物的浓度与其他内源性大麻素相当，预计在体内炎症过程中发挥关键作用；因此，它们的鉴定可能有助于神经炎症和脑血管疾病治疗方法的发展。
Clinical studies suggest that diets rich in omega-3 polyunsaturated fatty acids (PUFAs) provide beneficial anti-inflammatory effects, in part through their conversion to bioactive metabolites. Here we report on the endogenous production of a previously unknown class of omega-3 PUFA-derived lipid metabolites that originate from the crosstalk between endocannabinoid and cytochrome P450 (CYP) epoxygenase metabolic pathways. The omega-3 endocannabinoid epoxides are derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to form epoxyeicosatetraenoic acid-ethanolamide (EEQ-EA) and epoxydocosapentaenoic acid-ethanolamide (EDP-EA), respectively. Both EEQ-EAs and EDP-EAs are endogenously present in rat brain and peripheral organs as determined via targeted lipidomics methods. These metabolites were directly produced by direct epoxygenation of the omega-3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by activated BV-2 microglial cells, and by human CYP2J2. Neuroinflammation studies revealed that the terminal epoxides 17,18-EEQ- EA and 19,20-EDP-EA dose-dependently abated proinflammatory IL-6 cytokines while increasing anti-inflammatory IL-10 cytokines, in part through cannabinoid receptor-2 activation. Furthermore the omega-3 endocannabinoid epoxides 17,18-EEQ-EA and 19,20-EDP-EA exerted antiangiogenic effects in human microvascular endothelial cells (HMVEC) and vasodilatory actions on bovine coronary arteries and reciprocally regulated platelet aggregation in washed human platelets. Taken together, the omega-3 endocannabinoid epoxides' physiological effects are mediated through both endocannabinoid and epoxyeicosanoid signaling pathways. In summary, the omega-3 endocannabinoid epoxides are found at concentrations comparable to those of other endocannabinoids and are expected to play critical roles during inflammation in vivo; thus their identification may aid in the development of therapeutics for neuroinflammatory and cerebrovascular diseases.