Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function
Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function
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DOI：
10.1161/01.res.0000237390.92932.37
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发表时间：
2006-08-18
影响因子：
20.1
通讯作者：
Zeldin, Darryl C.
中科院分区：
文献类型：
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作者：
Seubert, John M.;Sinal, Christopher J.;Zeldin, Darryl C.
细胞色素P450环氧合酶将花生四烯酸代谢为环氧二十碳三烯酸（Epoxyeicosatrienoic Acids，EHF），EHF通过可溶性环氧化物水解酶（Ephx 2，sEH）转化为二羟基二十碳三烯酸（dihydroxyeicosatrienoic Acids，DHHF）。为了检查sEH在心脏中的功能作用，研究了具有Ephx 2基因的靶向破坏的小鼠。来自sEH敲除小鼠的心脏具有不可检测的sEH mRNA和蛋白水平，并且不能将EkD转化为DHkD。sEH敲除小鼠具有正常心脏解剖结构和基础收缩功能，但与野生型（WT）相比，在血浆和心肌细胞培养基中具有更高的脂肪酸环氧化物：二醇比率。与WT心脏相比，sEH无效心脏在缺血20分钟后具有改善的左室发展压（LVDP）恢复和较少的梗死。在缺血前灌注假定的EET受体拮抗剂14，15-epoxyeicosa-5（Z）-enoic acid（10 - 100 nmol/L）可消除这种心脏保护表型。抑制剂研究表明，灌注磷脂酰肌醇-3激酶（PI 3 K）抑制剂渥曼青霉素（200 nmol/L）或LY 294002（5 μ mol/ L），ATP敏感性K+通道（KATP）抑制剂格列本脲（1 μ mol/ L），线粒体KATP（mitoKATP）抑制剂5-羟基癸酸（100 - 200 μ mol/L）或Ca 2+敏感性K+通道（KCa）抑制剂paxilline（10 μ mol/ L）可消除sEH无效心脏的心脏保护作用。与PI 3 K级联激活增加一致，sEH缺失小鼠在缺血后表现出糖原合成酶激酶-3 β（GSK-3 β）磷酸化蛋白的心脏表达增加。总之，这些数据表明，sEH的靶向破坏增加了通过激活PI 3 K信号通路和K+通道起作用的心脏保护性Ehrs的可用性。
Cytochrome P450 epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which are converted to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (Ephx2, sEH). To examine the functional role of sEH in the heart, mice with targeted disruption of the Ephx2 gene were studied. Hearts from sEH null mice have undetectable levels of sEH mRNA and protein and cannot convert EETs to DHETs. sEH null mice have normal heart anatomy and basal contractile function, but have higher fatty acid epoxide: diol ratios in plasma and cardiomyocyte cell culture media compared with wild type (WT). sEH null hearts have improved recovery of left ventricular developed pressure (LVDP) and less infarction compared with WT hearts after 20 minutes ischemia. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid ( 10 to 100 nmol/L) before ischemia abolishes this cardioprotective phenotype. Inhibitor studies demonstrate that perfusion with phosphatidylinositol-3 kinase (PI3K) inhibitors wortmannin (200 nmol/L) or LY294002 (5 mu mol/ L), the ATP-sensitive K+ channel (KATP) inhibitor glibenclamide (1 mu mol/ L), the mitochondrial KATP (mitoKATP) inhibitor 5-hydroxydecanoate (100 to 200 mu mol/L), or the Ca2+-sensitive K+ channel (KCa) inhibitor paxilline (10 mu mol/ L) abolishes the cardioprotection in sEH null hearts. Consistent with increased activation of the PI3K cascade, sEH null mice exhibit increased cardiac expression of glycogen synthase kinase-3 beta(GSK-3 beta) phospho-protein after ischemia. Together, these data suggest that targeted disruption of sEH increases the availability of cardioprotective EETs that work by activating PI3K signaling pathways and K+ channels.