Vascular endothelial overexpression of human CYP2J2 (Tie2-CYP2J2 Tr) modulates cardiac oxylipin profiles and enhances coronary reactive hyperemia in mice.
Vascular endothelial overexpression of human CYP2J2 (Tie2-CYP2J2 Tr) modulates cardiac oxylipin profiles and enhances coronary reactive hyperemia in mice.
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DOI：
10.1371/journal.pone.0174137
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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
花生四烯酸通过细胞色素 (CYP) P450 环氧化酶代谢为环氧二十碳三烯酸 (EET)，并通过 ω-羟化酶代谢为 ω 末端羟基二十碳四烯酸 (HETE)。 EET 和 HETE 通常具有相反的生物学效应； EET 具有血管舒张作用，可防止缺血/再灌注损伤，而 ω 末端 HETE 具有血管收缩作用，可导致血管功能障碍。其他氧脂素，如环氧十八碳烯酸 (EpOME)、羟基十八碳二烯酸 (HODE) 和前列腺素也具有不同的血管作用。心脏缺血后血管舒张，称为冠状动脉反应性充血（CRH），可防止缺血引起的心肌潜在损伤。在 CYP2J 环氧化酶水平改变的小鼠中，CRH 反应与缺血之间的关系尚未得到研究。因此，我们评估了小鼠 (Tie2-CYP2J2 Tr) 中人细胞色素 P450 环氧化酶 CYP2J2 的内皮过度表达对氧脂素谱和 CRH 的影响。此外，我们评估了 CYP-环氧合酶的药理学抑制和 ω-羟化酶的抑制对 CRH 的影响。我们假设，通过调节氧脂素谱，血管内皮过度表达人 CYP2J2，CRH 会在离体小鼠心脏中增强。类似地，我们预计抑制 CYP-环氧合酶会降低 CRH，而抑制 ω-羟化酶会增强 CRH。与WT小鼠相比，Tie2-CYP2J2 Tr小鼠的CRH有所增强，包括还款量、还款持续时间和还款/债务比率（P < 0.05）。同样，与 WT 小鼠相比，Tie2-CYP2J2 Tr 小鼠中 ω-羟化酶的抑制增加了还款量和还款持续时间（P < 0.05）。 CYP2J2 的内皮过度表达显着改变了氧脂素谱，包括 EET 增加（P < 0.05）、EpOME 增加（P < 0.05）和 8-iso-PGF2α 减少（P < 0.05）。 MS-PPOH 抑制 CYP 环氧化酶可减弱 CRH (P < 0.05)。缺血导致中链 HETE (5-、11-、12-、15-HETE P < 0.05) 和 HODE (P < 0.05) 减少。这些数据表明，血管内皮 CYP2J2 的过度表达通过改变氧脂素谱来增强 CRH。抑制 CYP 环氧化酶会降低 CRH，而抑制 ω-羟化酶则会增强 CRH。
Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by cytochrome (CYP) P450 epoxygenases, and to ω-terminal hydroxyeicosatetraenoic acids (HETEs) by ω-hydroxylases. EETs and HETEs often have opposite biologic effects; EETs are vasodilatory and protect against ischemia/reperfusion injury, while ω-terminal HETEs are vasoconstrictive and cause vascular dysfunction. Other oxylipins, such as epoxyoctadecaenoic acids (EpOMEs), hydroxyoctadecadienoic acids (HODEs), and prostanoids also have varied vascular effects. Post-ischemic vasodilation in the heart, known as coronary reactive hyperemia (CRH), protects against potential damage to the heart muscle caused by ischemia. The relationship among CRH response to ischemia, in mice with altered levels of CYP2J epoxygenases has not yet been investigated. Therefore, we evaluated the effect of endothelial overexpression of the human cytochrome P450 epoxygenase CYP2J2 in mice (Tie2-CYP2J2 Tr) on oxylipin profiles and CRH. Additionally, we evaluated the effect of pharmacologic inhibition of CYP-epoxygenases and inhibition of ω-hydroxylases on CRH. We hypothesized that CRH would be enhanced in isolated mouse hearts with vascular endothelial overexpression of human CYP2J2 through modulation of oxylipin profiles. Similarly, we expected that inhibition of CYP-epoxygenases would reduce CRH, whereas inhibition of ω-hydroxylases would enhance CRH. Compared to WT mice, Tie2-CYP2J2 Tr mice had enhanced CRH, including repayment volume, repayment duration, and repayment/debt ratio (P < 0.05). Similarly, inhibition of ω-hydroxylases increased repayment volume and repayment duration, in Tie2-CYP2J2 Tr compared to WT mice (P < 0.05). Endothelial overexpression of CYP2J2 significantly changed oxylipin profiles, including increased EETs (P < 0.05), increased EpOMEs (P < 0.05), and decreased 8-iso-PGF2α (P < 0.05). Inhibition of CYP epoxygenases with MS-PPOH attenuated CRH (P < 0.05). Ischemia caused a decrease in mid-chain HETEs (5-, 11-, 12-, 15-HETEs P < 0.05) and HODEs (P < 0.05). These data demonstrate that vascular endothelial overexpression of CYP2J2, through changing the oxylipin profiles, enhances CRH. Inhibition of CYP epoxygenases decreases CRH, whereas inhibition of ω-hydroxylases enhances CRH.