Cardioprotective effect of a dual acting epoxyeicosatrienoic acid analogue towards ischaemia reperfusion injury
Cardioprotective effect of a dual acting epoxyeicosatrienoic acid analogue towards ischaemia reperfusion injury
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DOI：
10.1111/j.1476-5381.2010.01093.x
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发表时间：
2011-02-01
影响因子：
7.3
通讯作者：
Seubert, J. M.
中科院分区：
文献类型：
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作者：
Batchu, S. N.;Lee, S. B.;Seubert, J. M.
背景与目的环氧二十碳三烯酸(EETs)是花生四烯酸的细胞色素P450环氧酶的代谢产物，在可溶性环氧化物水解酶(SEH)的作用下被代谢成二羟基环氧二十碳三烯酸(DHET)。为探讨UA-8(13-(3-丙基脲)三碳-8-烯酸)对心肌缺血再灌注损伤的保护作用，合成了一种兼具EET模拟活性和sEH抑制活性的化合物。机制研究包括用14，15-EEZE(一种可能的EET受体拮抗剂)、Wortmannin或PI-103(I类PI3K抑制剂)共灌流心脏。结果与对照组和11，12-EET相比，灌流UA-8可显著改善缺血后左室发展压(LVDP)，减少缺血再灌流后心肌梗死。UA-7(13-(2-(butylamino)-2-oxoacetamido)tridec-8(Z)-enoic酸)，一种缺乏sEH抑制作用的化合物，也能改善缺血后的左心室收缩压，而与14，15-EEZE、Wortmannin或PI-103共灌流可减弱改善的恢复率。UA-8可保护H9c2细胞线粒体膜电位的降低和细胞死亡，其作用可被PI-103联合治疗所阻断。结论UA-8对H9c2细胞缺血再灌注损伤具有明显的心肌保护作用。这些效应归因于EETs的模拟特性，它通过I类PI3K信号限制线粒体功能障碍。
BACKGROUND AND PURPOSEEpoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase metabolites of arachidonic acid that are metabolized into dihydroxyepoxyeicosatrienoic acids (DHET) by soluble epoxide hydrolase (sEH). The current investigations were performed to examine the cardioprotective effects of UA-8 (13-(3-propylureido)tridec-8-enoic acid), a synthetic compound that possesses both EET-mimetic and sEH inhibitory properties, against ischaemia-reperfusion injury.EXPERIMENTAL APPROACHHearts from C57BL/6 mice were perfused in Langendorff mode and subjected to ischaemia reperfusion. Mechanistic studies involved co-perfusing hearts with either 14,15-EEZE (a putative EET receptor antagonist), wortmannin or PI-103 (class-I PI3K inhibitor). H9c2 cells were utilized to investigate the protective effects against mitochondrial injury following anoxia reoxygenation.KEY RESULTSPerfusion of UA-8 significantly improved postischaemic left ventricular developed pressure (LVDP) and reduced infarction following ischaemia reperfusion compared with control and 11,12-EET. UA-7 (13-(2-(butylamino)-2-oxoacetamido)tridec-8(Z)-enoic acid), a compound lacking sEH inhibitory properties, also improved postischaemic LVDP, while co-perfusion with 14,15-EEZE, wortmannin or PI-103 attenuated the improved recovery. UA-8 prevented anoxia-reoxygenation induced loss of mitochondrial membrane potential and cell death in H9c2 cells, which was blocked by co-treatment of PI-103.CONCLUSIONS AND IMPLICATIONSUA-8 provides significant cardioprotection against ischaemia reperfusion injury. The effects are attributed to EETs mimetic properties, which limits mitochondrial dysfunction via class-I PI3K signalling.