Inhibition of soluble epoxide hydrolase by trans-4- [4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid is protective against ischemia-reperfusion injury.
Inhibition of soluble epoxide hydrolase by trans-4- [4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid is protective against ischemia-reperfusion injury.
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DOI：
10.1097/fjc.0b013e3181c37d69
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发表时间：
2010-01
影响因子：
3
通讯作者：
Seubert JM
中科院分区：
文献类型：
--
作者：
Chaudhary KR;Abukhashim M;Hwang SH;Hammock BD;Seubert JM
花生四烯酸是一种多不饱和脂肪酸，可通过细胞色素 P450 环氧化酶代谢为具有心脏保护作用的环氧二十碳三烯酸 (EET)，随后通过可溶性环氧化物水解酶 (sEH) 水解为生物活性较低的二羟基二十碳三烯酸。为了研究 sEH (sEHi) 药物抑制剂的作用，C57BL6 小鼠心脏在 Langendorff 模式下灌注 40 分钟基线，并经历 30 分钟整体无流量缺血，然后再灌注 40 分钟。用 sEHi、反式-4-[4-(3-金刚烷-1-y1-脲基)-环己氧基]-苯甲酸（t-AUCB；0.05 µM、0.1 µM、0.5 µM 和 1 µM）灌注心脏。为了研究机制，在存在或不存在推定的 EET 受体拮抗剂 14,15-环氧二十碳五烯酸 (14,15-EEZE，10 µM) 或磷脂酰肌醇 3-激酶 (PI3K) 抑制剂渥曼青霉素 (200 nM) 或 LY294002 (5) 的情况下，用 0.1 µM t-AUCB 灌注心脏。 微米）。 2小时再灌注结束时通过TTC染色测定梗塞大小。与对照心脏相比，t-AUCB 对 sEH 的抑制显着改善了缺血后左心室发展压 (LVDP) 的恢复，并减少了缺血再灌注后的梗塞面积。缺血前灌注 14,15-EEZE、渥曼青霉素或 LY294002 消除了心脏保护表型；然而，t-AUCB 和 11,12-EET 的共同灌注并没有对改善 LVDP 恢复产生相加效应。总之，我们的数据表明 t-AUCB 对 sEH 的药理学抑制具有心脏保护作用。
Arachidonic acid, a polyunsaturated fatty acid, can be metabolized to cardioprotective epoxyeicosatrienoic acids (EETs) by cytochrome P450 epoxygenases, which are subsequently hydrolyzed to less bioactive dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). To study the effects of pharmacological inhibitor of sEH (sEHi), C57BL6 mice hearts were perfused in Langendorff mode for 40min of baseline and subjected to 30min of global no-flow ischemia followed by 40 min of reperfusion. Hearts were perfused with the sEHi, trans-4-[4-(3-adamantan-1-y1-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB; 0.05 µM, 0.1 µM, 0.5 µM and 1 µM). To study the mechanism(s), hearts were perfused with 0.1 µM t-AUCB in the presence or absence of putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 µM) or phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin (200 nM) or LY294002 (5 µM). Infarct size was determined at the end of 2 h reperfusion by TTC staining. Inhibition of sEH by t-AUCB significantly improved postischemic left ventricular developed pressure (LVDP) recovery and reduced the infarct size following ischemia-reperfusion, as compared to control hearts. Perfusion with 14,15-EEZE, wortmannin or LY294002 prior to ischemia abolished the cardioprotective phenotype; however, co-perfusion of both t-AUCB and 11,12-EET did not result in an additive effect on improved LVDP recovery. Together, our data suggest that pharmacological inhibition of sEH by t-AUCB is cardioprotective.