5,6-delta-DHTL 是花生四烯酸的稳定代谢物，是一种潜在的 EDHF，可介导微血管扩张。,Free Radical Biology and Medicine

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5,6-delta-DHTL 是花生四烯酸的稳定代谢物，是一种潜在的 EDHF，可介导微血管扩张。
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2016 Dec 19 , DOI: 10.1016/j.freeradbiomed.2016.12.022
Reut Levi-Rosenzvig ₁ , Andreas M Beyer ₂ , Joseph Hockenberry ₃ , Rotem Shelly Ben-Shushan ₄ , Dimitry Chuyun ₅ , Shahar Atiya ₁ , Snait Tamir ₁ , David D Gutterman ₃ , Andrea Szuchman-Sapir ₁

Affiliation

目的：在内皮细胞衍生的超极化因子 (EDHF) 中，最突出的是细胞色素 P450 (CYP) 环氧合酶衍生的花生四烯酸代谢物 - 环氧二十碳三烯酸 (EET)，它们在微循环中被称为血管扩张剂。在 EET 异构体中，5,6-EET 在水溶液中快速内酯化为更稳定的 5,6-delta DHTL（5,6-二羟基三烯内酯）异构体。目前尚不清楚这种代谢转化是否保持其血管扩张潜力以及作用机制是什么。因此，本研究的目的是研究内酯异构体 5,6-delta DHTL 诱导小动脉扩张的能力并探索内皮 Ca2+ 反应机制。方法和结果：在孤立的人体微血管中，5,6-delta DHTL 诱导剂量依赖性血管舒张，这被内皮层的机械剥脱所抑制。在存在 L-NAME（NOS 抑制剂）或 NO 清除剂 cPTIO 的情况下，这种 5,6-delta DHTL 依赖性扩张部分减少（减少 19.7%，这在统计学上没有显着性意义）。在人内皮细胞中，5,6-delta DHTL 以剂量依赖性方式诱导细胞内 Ca2+([Ca2+]i) 增加。[Ca2+]i 的这种增加与 5,6-EET 异构体诱导的增加相似，并且显着高于通过施用水解二羟基异构体 5,6-DHET 观察到的增加。旨在研究作用机制的进一步实验表明，5,6-delta DHTL 介导的（[Ca2+]i 升高被 IP3 和兰尼碱拮抗剂降低，但不是被 TRPV4 膜通道的拮抗剂降低。类似于它们对动脉的扩张反应，本研究表明，5,6-delta DHTL 是一种潜在的 EDHF，它通过涉及内皮依赖性 Ca2+ 进入的机制扩张微血管，需要内皮超极化。这些结果表明存在额外的含有内酯的代谢物，这些代谢物可以来源于 PUFA 代谢，并且可以作为新的 EDHF 发挥作用。本研究表明，5,6-delta DHTL 是一种潜在的 EDHF，它通过涉及内皮依赖性 Ca2+ 进入的机制扩张微血管，需要内皮超极化。这些结果表明存在额外的含有内酯的代谢物，这些代谢物可以来源于 PUFA 代谢，并且可以作为新的 EDHF 发挥作用。

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5,6-delta-DHTL, a stable metabolite of arachidonic acid, is a potential EDHF that mediates microvascular dilation.

OBJECTIVE: Prominent among the endothelium-derived hyperpolarizing factors (EDHFs) are the Cytochrome P450 (CYP) epoxygenase-derived arachidonic acid metabolites-the epoxyeicosatrienoic acids (EETs), that are known as vasodilators in the microcirculation. Among the EET isomers, 5,6-EET undergoes rapid lactonization in aqueous solution to the more stable 5,6-delta DHTL (5,6-dihydroxytrienoic lactone) isomer. It is unclear whether this metabolic transformation maintains its vasodilator potential and what is the mechanism of action. Thus, the aim of this study was to investigate the capacity of the lactone isomer, 5,6- delta DHTL, to induce dilation of arterioles and explore the endothelial Ca2+ response mechanism. APPROACH AND RESULTS: In isolated human microvessels 5,6- delta DHTL induced a dose dependent vasodilation, that was inhibited by mechanical denudation of the endothelial layer. This 5,6- delta DHTL -dependent dilation was partially reduced in the presence of L-NAME (NOS inhibitor) or the NO-scavenger, cPTIO (by 19.7%, which was not statistically significantly). In human endothelial cells, 5,6- delta DHTL induced an increase in intracellular Ca2+([Ca2+]i) in a dose dependent manner. This increase in [Ca2+]i was similar to that induced by the 5,6-EET isomer, and significantly higher than observed by administering the hydrolytic dihydroxy isomer, 5,6-DHET. Further experiments aimed to investigate the mechanism of action revealed, that the 5,6-delta DHTL-mediated ([Ca2+]i elevation was reduced by IP3 and ryanodine antagonists, but not by antagonists to the TRPV4 membrane channel. Similar to their effect on the dilation response in the arteries, NO inhibitors reduced the 5,6-delta DHTL-mediated ([Ca2+]i elevation by 20%. Subsequent 5,6-delta DHTL -dependent K+ ion efflux from endothelial cells, was abolished by the inhibition of small and intermediate conductance KCa. CONCLUSIONS: The present study shows that 5,6-delta DHTL is a potential EDHF, that dilates microvessels through a mechanism that involves endothelial dependent Ca2+ entry, requiring endothelial hyperpolarization. These results suggest the existence of additional lactone-containing metabolites that can be derived from the PUFA metabolism and which may function as novel EDHFs.

更新日期：2017-01-31

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