Vascular Endothelial Over-Expression of Human Soluble Epoxide Hydrolase (Tie2-sEH Tr) Attenuates Coronary Reactive Hyperemia in Mice: Role of Oxylipins and ω-Hydroxylases.
Vascular Endothelial Over-Expression of Human Soluble Epoxide Hydrolase (Tie2-sEH Tr) Attenuates Coronary Reactive Hyperemia in Mice: Role of Oxylipins and ω-Hydroxylases.
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DOI：
10.1371/journal.pone.0169584
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Nayeem MA
中科院分区：
文献类型：
--
作者：
Hanif A;Edin ML;Zeldin DC;Morisseau C;Falck JR;Nayeem MA
细胞色素 P450 将花生四烯酸 (AA) 代谢为两种具有相反生物效应的血管活性氧脂素：环氧二十碳三烯酸 (EET) 和 omega-(ω)-末端羟基二十碳四烯酸 (HETE)。 EET 具有许多有益的生理作用，包括血管舒张和防止缺血/再灌注损伤，而 ω 末端 HETE 会诱导血管收缩和血管功能障碍。我们评估了这些氧脂素对缺血后血管舒张（称为冠状动脉反应性充血（CRH））的影响。 CRH 可预防与短暂性脑缺血相关的潜在危害。 EET 被可溶性环氧化物水解酶 (sEH) 水解为二羟基二十碳三烯酸 (DHET) 后，其有益效果会降低。 ω-末端 HETE 由 ω-羟化酶家族成员形成。 sEH (Tie2-sEH Tr) 的内皮过度表达、它可能产生的氧脂素的变化、ω-羟化酶的药理学抑制、PPARγ 的激活以及 CRH 对短暂缺血的反应之间的关系尚不清楚。我们假设，通过调节氧脂质谱，内皮 sEH 过度表达的离体小鼠心脏中的 CRH 会减弱，而 ω-羟化酶的抑制和 PPARγ 的激活都会增强 CRH。与WT小鼠相比，Tie2-sEH Tr小鼠的CRH降低，包括还款量、还款持续时间和还款/债务比（P < 0.05），而抑制ω-羟化酶则增加了Tie2-sEH Tr小鼠的这些相同的CRH参数。用 t-AUCB 抑制 sEH 可逆转 Tie2-sEH Tr 小鼠中 CRH 的降低。 sEH 的内皮过度表达显着改变了氧脂质谱，包括 DHET、中链 HETE 和前列腺素的减少 (P < 0.05)。使用 PPARγ 激动剂罗格列酮治疗，Tie2-sEH Tr 和野生型 (WT) 小鼠的 CRH 均得到增强 (P < 0.05)。这些数据表明，内皮细胞过度表达 sEH（通过改变氧脂质谱）会减弱 CRH，而抑制 ω-羟化酶和激活 PPARγ 则会增强 CRH。
Cytochromes P450 metabolize arachidonic acid (AA) into two vasoactive oxylipins with opposing biologic effects: epoxyeicosatrienoic acids (EETs) and omega-(ω)-terminal hydroxyeicosatetraenoic acids (HETEs). EETs have numerous beneficial physiological effects, including vasodilation and protection against ischemia/reperfusion injury, whereas ω-terminal HETEs induce vasoconstriction and vascular dysfunction. We evaluated the effect of these oxylipins on post-ischemic vasodilation known as coronary reactive hyperemia (CRH). CRH prevents the potential harm associated with transient ischemia. The beneficial effects of EETs are reduced after their hydrolysis to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). ω-terminal HETEs are formed by ω-hydroxylase family members. The relationship among endothelial over-expression of sEH (Tie2-sEH Tr), the changes in oxylipins it may produce, the pharmacologic inhibition of ω-hydroxylases, activation of PPARγ, and CRH response to a brief ischemia is not known. We hypothesized that CRH is attenuated in isolated mouse hearts with endothelial sEH over-expression through modulation of oxylipin profiles, whereas both inhibition of ω-hydroxylases and activation of PPARγ enhance CRH. Compared to WT mice, Tie2-sEH Tr mice had decreased CRH, including repayment volume, repayment duration, and repayment/debt ratio (P < 0.05), whereas inhibition of ω-hydroxylases increased these same CRH parameters in Tie2-sEH Tr mice. Inhibition of sEH with t-AUCB reversed the decreased CRH in Tie2-sEH Tr mice. Endothelial over-expression of sEH significantly changed oxylipin profiles, including decreases in DHETs, mid-chain HETEs, and prostaglandins (P < 0.05). Treatment with rosiglitazone, PPARγ-agonist, enhanced CRH (P < 0.05) in both Tie2-sEH Tr and wild type (WT) mice. These data demonstrate that endothelial over-expression of sEH (through changing the oxylipin profiles) attenuates CRH, whereas inhibition of ω-hydroxylases and activation of PPARγ enhance it.
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影响因子：
4.8
作者：
Cowart, LA;Wei, SZ;Capdevila, JH
通讯作者：
Capdevila, JH
影响因子：
20.1
作者：
Fang, X;Kaduce, TL;Spector, AA
通讯作者：
Spector, AA
影响因子：
20.1
作者：
Campbell, WB;Gebremedhin, D;Harder, DR
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影响因子：
2.4
作者：
Berwick, Zachary C.;Payne, Gregory A.;Tune, Johnathan D.
通讯作者：
Tune, Johnathan D.
影响因子：
2.9
作者：
Hoopes SL;Garcia V;Edin ML;Schwartzman ML;Zeldin DC
通讯作者：
Zeldin DC