Epoxyeicosatrienoic acids limit damage to mitochondrial function following stress in cardiac cells
Epoxyeicosatrienoic acids limit damage to mitochondrial function following stress in cardiac cells
复制标题
DOI：
10.1016/j.yjmcc.2009.02.028
复制
发表时间：
2009-06-01
影响因子：
5
通讯作者：
Seubert, J. M.
中科院分区：
文献类型：
--
作者：
Katragadda, D.;Batchu, S. N.;Seubert, J. M.
环氧二十碳三烯酸 (EET) 是由花生四烯酸通过 CYP2J2 环氧化酶合成的多不饱和脂肪酸，并被可溶性环氧化物水解酶（sEH 或 Ephx2）灭活为二羟基二十碳三烯酸。缺血性损伤后的线粒体功能是再灌注诱导的心肌细胞死亡的关键决定因素。本研究的目的是研究 EET 对线粒体功能的保护作用。与野生型 (WT) 相比，靶向破坏 Ephx2 基因、心肌细胞特异性过度表达 CYP2J2 或灌注 EET 的小鼠均改善了缺血后 LVDP 恢复。 mPTP开启剂白术苷的灌注消除了在CYP2J2 Tr、sEH null和EET灌注心脏中观察到的改善的缺血后功能恢复。电子显微照片显示，在 20 分钟整体缺血和 20 分钟再灌注后，与 CYP2J2 Tr 心脏相比，WT 心脏线粒体破碎和 T 管肿胀增加。在分离的大鼠心肌细胞和 H9c2 细胞中评估了 EET 对线粒体的直接影响。在用 14, 15-EET (1 mu M) 处理的细胞中，激光诱导的线粒体膜电位损失 (Delta Psi(m)) 和 mPTP 打开显着减少。 EET 保护作用被假定的 EET 拮抗剂 14,15-epoxyeicosa-5(Z)-enoic Acid (1 muM, 14,15-EEZE)、paxilline (10 muM, BKCa 抑制剂) 和 5HD (100 muM, K-ATP 抑制剂) 阻断。我们的研究表明，EET 可以通过 K+ 通道依赖性机制限制细胞应激后的线粒体功能障碍。 (C) 2009 Elsevier Inc. 保留所有权利。
Epoxyeicosatrienoic acids (EETs) are polyunsaturated fatty acids synthesized from arachidonic acid by CYP2J2 epoxygenase and inactivated by soluble epoxide hydrolase (sEH or Ephx2) to dihydroxyeicosatrienoic acids. Mitochondrial function following ischemic insult is a critical determinant of reperfusion-induced cell death in the myocardium. The objectives of the current study were to investigate the protective role of EETs in mitochondrial function. Mice with the targeted disruption of the Ephx2 gene, cardiomyocyte-specific overexpression of CYP2J2 or perfused with EETs all have improved postischemic LVDP recovery compared to wild-type (WT). Perfusion with the mPTP opener, atractyloside, abolished the improved postischemic functional recovery observed in CYP2J2 Tr, sEH null and EET perfused hearts. Electron micrographs demonstrated WT hearts to have increased mitochondrial fragmentation and T-tubule swelling compared to CYP2J2 Tr hearts following 20 min global ischemia and 20 min reperfusion. Direct effects of EETs on mitochondria were assessed in isolated rat cardiomyocytes and H9c2 cells. Laser-induced loss of mitochondrial membrane potential (Delta Psi(m)) and mPTP opening was significantly reduced in cells treated with 14, 15-EET (1 mu M). The EET protective effect was blocked by the putative EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (1 mu M, 14,15-EEZE), paxilline (10 mu M, BKCa inhibitor) and 5HD (100 mu M, K-ATP inhibitor). Our studies show that EETs can limit mitochondrial dysfunction following cellular stress via a K+ channel-dependent mechanism. (C) 2009 Elsevier Inc. All rights reserved.