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首页> 外文期刊>Cytokine >Upregulation of cytochrome P450 2J3/11,12-epoxyeicosatrienoic acid inhibits apoptosis in neonatal rat cardiomyocytes by a caspase-dependent pathway
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Upregulation of cytochrome P450 2J3/11,12-epoxyeicosatrienoic acid inhibits apoptosis in neonatal rat cardiomyocytes by a caspase-dependent pathway

机译：细胞色素P450 2J3 / 11,12-环氧二十碳三烯酸的上调通过caspase依赖性途径抑制新生大鼠心肌细胞的凋亡

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摘要

Short, nonlethal ischemic episodes administered to hearts directly after ischemic events (ischemic postconditioning, IPost) have an advantage over ischemic preconditioning (IPC). The endogenous cytochrome P450 2J3/11,12-epoxyeicosatrienoic acid (CYP2J3/11,12-EET) is upregulated by IPost, but not IPC, in the rat heart. The CYP epoxygenase inhibitor N-methylsulphonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH) reduces the cardioprotective effects of IPost, but not IPC. We proposed that upregulation of CYP2J3/11,12-EET during IPost induces cardioprotection by inhibiting cardiomyocyte apoptosis and that multiple apoptotic signals, including changes in mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) opening, mitochondrial cytochrome c leakage, caspase-3 levels, and levels of protective kinases such as Bcl-2 and Bax, are involved in the process. Neonatal rat cardiomyocytes underwent 3-h hypoxia followed by 2-, 5-, or 6-h reoxygenation (H/R) or three cycles of 5-min reoxygenation followed by 5-min hypoxia before 90-min reoxygenation (HPost); or were transfected with pcDNA3.1-CYP2J3 for 48. h before H/R; or were treated with MS-PPOH for 10. min before HPost. For HPost alone, pcDNA3.1-CYP2J3 transfection attenuated cardiomyocyte apoptosis to 68.4% (p< 0.05) of that with H/R. pcDNA3.1-CYP2J3 transfection significantly decreased MMP and inhibited mPTP opening induced by H/R, reduced mitochondrial cytochrome c leakage, cleaved caspase-3 protein expression, and increased the ratio of Bcl-2 to Bax expression. MS-PPOH abolished this effect. Therefore, upregulation of CYP2J3/11,12-EET during HPost is involved in cardioprotection by inhibiting apoptosis via a caspase-dependent pathway, and the apoptosis-suppressive effect may have important clinical implications during HPost.
机译：缺血事件（缺血后处理，IPost）后直接施用于心脏的短暂，非致命性缺血发作优于缺血预处理（IPC）。内源性细胞色素P450 2J3 / 11,12-环氧二十碳三烯酸（CYP2J3 / 11,12-EET）在大鼠心脏中被IPost上调，但不被IPC上调。 CYP环氧合酶抑制剂N-甲基磺酰基-6-（2-炔丙基氧基苯基）己酰胺（MS-PPOH）会降低IPost的心脏保护作用，但不会降低IPC的心脏保护作用。我们提出IPost期间CYP2J3 / 11,12-EET的上调可通过抑制心肌细胞凋亡来诱导心脏保护作用，并提示多种凋亡信号，包括线粒体膜电位（MMP）和线粒体通透性过渡孔（mPTP）打开，线粒体细胞色素c泄漏，该过程涉及caspase-3水平以及保护性激酶（例如Bcl-2和Bax）的水平。新生大鼠心肌细胞进行3小时缺氧，然后进行2、5或6小时复氧（H / R）或三个周期的5分钟复氧，然后在90分钟复氧之前进行5分钟缺氧（HPost）;在H / R之前，用pcDNA3.1-CYP2J3转染48小时。或在HPost之前用MS-PPOH处理10分钟。对于单独的HPost，pcDNA3.1-CYP2J3转染将心肌细胞的凋亡减至H / R的68.4％（p <0.05）。 pcDNA3.1-CYP2J3转染可显着降低H / R诱导的MMP并抑制mPTP开放，减少线粒体细胞色素c泄漏，切割caspase-3蛋白表达并增加Bcl-2与Bax表达的比率。 MS-PPOH取消了这种效果。因此，HPost期间CYP2J3 / 11,12-EET的上调通过半胱天冬酶依赖性途径抑制细胞凋亡，从而参与了心脏保护作用，而细胞凋亡抑制作用可能在HPost过程中具有重要的临床意义。

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