Inhibition of soluble epoxide hydrolase preserves cardiomyocytes: role of STAT3 signaling
Inhibition of soluble epoxide hydrolase preserves cardiomyocytes: role of STAT3 signaling
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DOI：
10.1152/ajpheart.00533.2009
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发表时间：
2010-02-01
影响因子：
4.8
通讯作者：
Van Winkle, Donna M.
中科院分区：
文献类型：
--
作者：
Merkel, Matthias J.;Liu, Lijuan;Van Winkle, Donna M.
刘丽娟，刘丽娟，曹志刚，杨建军，杨建军，杨建军，杨建军。可溶性环氧化物水解酶对心肌细胞凋亡的影响。[J] .中华心脏杂志，2016,31(2):679- 687。首次发表于2009年12月11日；doi: 10.1152 / ajpheart.00533.2009。-可溶性环氧化物水解酶（sEH）代谢环氧二碳三烯酸（eet），主要是14,15- eet。eet通过P-450环氧合酶从花生四烯酸中提取，具有心脏保护作用。我们在体外和体内验证了sEH缺乏和药物抑制通过eet介导的STAT3信号通路诱导缺血耐受的假设。此外，通过转录反激活因子（TAT）介导的sEH突变蛋白转导，在男性C57BL lambda 6J （WT）或sEH敲除（sEHKO）心肌细胞中评估EPHX2（编码sEH的基因）单核苷酸多态性（snp）与氧和葡萄糖剥夺耐受性以及再氧化和葡萄糖补充（OGD/RGR）的相关性。与未转导的对照相比，Arg287Gln EPHX2突变体的细胞死亡和水解酶活性较低。过量的14,15- eet和SEH抑制并不能提高Arg287Gln突变体的细胞存活率。在WT细胞中，假定的EET受体拮抗剂14,15- eeze可以消除14,15-EET和sEH的抑制作用。与14,15- eet和SEH抑制剂共同治疗并没有增加保护作用。体外实验中，STAT3抑制可阻断14,15- eet的细胞保护作用，但不影响SEH的抑制作用。然而，STAT3小干扰RNA （siRNA）通过抑制14,15- eet和sEH来消除细胞保护作用，但用JAK2 siRNA预处理的细胞仍然受到保护。在体内，STAT3抑制可消除14,15- eet介导的梗死面积减少。总之，Arg287Gln突变与体外对缺血耐受性的改善有关，抑制sEH通过eet依赖机制保持OGD/RGR后心肌细胞的活力。在体内和体外，14,15- eet介导的保护部分是由STAT3介导的。
Merkel MJ, Liu L, Cao Z, Packwood W, Young J, Alkayed NJ, Van Winkle DM. Inhibition of soluble epoxide hydrolase preserves cardiomyocytes: role of STAT3 signaling. Am J Physiol Heart Circ Physiol 298: H679-H687, 2010. First published December 11, 2009; doi:10.1152/ajpheart.00533.2009.-Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), primarily 14,15-EET. EETs are derived from arachidonic acid via P-450 epoxygenases and are cardioprotective. We tested the hypothesis that sEH deficiency and pharmacological inhibition elicit tolerance to ischemia via EET-mediated STAT3 signaling in vitro and in vivo. In addition, the relevance of single nucleotide polymorphisms (SNPs) of EPHX2 (the gene encoding sEH) on tolerance to oxygen and glucose deprivation and reoxygenation and glucose repletion (OGD/RGR) was assessed in male C57BL lambda 6J (WT) or sEH knockout (sEHKO) cardiomyocytes by using transactivator of transcription (TAT)-mediated transduction with sEH mutant proteins. Cell death and hydrolase activity was lower in Arg287Gln EPHX2 mutants vs. nontransduced controls. Excess 14,15-EET and SEH inhibition did not improve cell survival in Arg287Gln mutants. In WT cells, the putative EET receptor antagonist, 14,15-EEZE, abolished the effect of 14,15-EET and sEH inhibition. Cotreatment with 14,15-EET and SEH inhibition did not provide increased protection. In vitro, STAT3 inhibition blocked 14,15-EET cytoprotection, but not the effect of SEH inhibition. However, STAT3 small interfering RNA (siRNA) abolished cytoprotection by 14,15-EET and sEH inhibition, but cells pretreated with JAK2 siRNA remained protected. In vivo, STAT3 inhibition abolished 14,15-EET-mediated infarct size reduction. In summary, the Arg287Gln mutation is associated with improved tolerance against ischemia in vitro, and inhibition of sEH preserves cardiomyocyte viability following OGD/RGR via an EET-dependent mechanism. In vivo and in vitro, 14,15-EET-mediated protection is mediated in part by STAT3.