Effect of Soluble Epoxide Hydrolase on the Modulation of Coronary Reactive Hyperemia: Role of Oxylipins and PPARγ.
Effect of Soluble Epoxide Hydrolase on the Modulation of Coronary Reactive Hyperemia: Role of Oxylipins and PPARγ.
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DOI：
10.1371/journal.pone.0162147
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发表时间：
2016
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;Nayeem MA
冠状动脉反应性充血(CRH)是对缺血性损伤的一种生理反应，以防止与血液供应中断相关的潜在损害。可溶性环氧化物水解酶(SEH)的药理抑制作用与CRH对短暂缺血的反应之间的关系尚不清楚。SEH参与了环氧二十碳三烯酸(EETs)的主要分解代谢途径，这些EETs被转化为二羟基二十碳三烯酸(DHETs)。EETs对缺血/再灌注损伤具有保护作用，具有多种有益的生理效应。我们假设，t-AUCB抑制sEH通过改变氧脂分布，包括增加EETs/DHETs比率，增强了离体鼠心脏的CRH。与对照组相比，t-AUCB处理组小鼠的CRH增加，包括还款量(RV)、还款持续时间和还款/债务比率(p<；0.05)。经t-AUCB治疗后，氧脂谱发生明显改变，包括EET/DHET比值升高，EPOME/DiHOME比值升高，HODES水平升高，中链HETE水平降低，前列腺素类物质减少(p<；0.05)。用MS-PPOH(CYP环氧合酶抑制剂)治疗可降低CRH，包括RV(p<；0.05)。用PPARγ拮抗剂(T0070907)和PPARγ激动剂(罗格列酮)证实了PPARγ参与CRH的调节。与未治疗组相比，T0070907降低了小鼠心脏CRH(p<；0.05)，而罗格列酮则增加了CRH(p<；0.05)。这些结果表明，sEH抑制增强了CRH，而CYP环氧合酶抑制减弱了CRH，PPARγ介导了CYP环氧合酶-EET途径下游的CRH，与sEH抑制相关的氧脂谱的变化共同促进了CRH的增强。
Coronary reactive hyperemia (CRH) is a physiological response to ischemic insult that prevents the potential harm associated with an interruption of blood supply. The relationship between the pharmacologic inhibition of soluble epoxide hydrolase (sEH) and CRH response to a brief ischemia is not known. sEH is involved in the main catabolic pathway of epoxyeicosatrienoic acids (EETs), which are converted into dihydroxyeicosatrienoic acids (DHETs). EETs protect against ischemia/reperfusion injury and have numerous beneficial physiological effects. We hypothesized that inhibition of sEH by t-AUCB enhances CRH in isolated mouse hearts through changing the oxylipin profiles, including an increase in EETs/DHETs ratio. Compared to controls, t-AUCB–treated mice had increased CRH, including repayment volume (RV), repayment duration, and repayment/debt ratio (p < 0.05). Treatment with t-AUCB significantly changed oxylipin profiles, including an increase in EET/DHET ratio, increase in EpOME/DiHOME ratio, increase in the levels of HODEs, decrease in the levels of mid-chain HETEs, and decrease in prostanoids (p < 0.05). Treatment with MS-PPOH (CYP epoxygenase inhibitor) reduced CRH, including RV (p < 0.05). Involvement of PPARγ in the modulation of CRH was demonstrated using a PPARγ-antagonist (T0070907) and a PPARγ-agonist (rosiglitazone). T0070907 reduced CRH (p < 0.05), whereas rosiglitazone enhanced CRH (p < 0.05) in isolated mouse hearts compared to the non-treated. These data demonstrate that sEH inhibition enhances, whereas CYP epoxygenases-inhibition attenuates CRH, PPARγ mediate CRH downstream of the CYP epoxygenases-EET pathway, and the changes in oxylipin profiles associated with sEH-inhibition collectively contributed to the enhanced CRH.
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