Activation of c-Jun N-terminal kinase promotes survival of cardiac myocytes after oxidative stress
Activation of c-Jun N-terminal kinase promotes survival of cardiac myocytes after oxidative stress
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DOI：
10.1042/0264-6021:3620561
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发表时间：
2002-03-15
影响因子：
4.1
通讯作者：
Webster, KA
中科院分区：
文献类型：
--
作者：
Dougherty, CJ;Kubasiak, LA;Webster, KA
当缺血组织再灌流时，就会发生再灌注损伤。它涉及活性氧的产生和释放，激活许多信号通路，启动细胞死亡，使分离的心肌细胞暴露在慢性低氧中，然后复氧，导致c-Jun氨基末端激酶(JNK)的早期激活，并通过约x的凋亡而死亡。300，肌细胞。尽管在许多缺血/再灌注模型中已经描述了JNK的激活。JNK的激活对细胞命运的贡献尚未确定。在此，我们报道了JNK的复氧激活与心肌细胞的存活有关。用JNK途径干扰质粒载体转染心肌细胞或用腺病毒载体感染都支持JNK具有保护作用的假说。与需氧培养或缺氧/复氧培养的对照相比，JNK抑制突变体的转染或感染可使细胞凋亡率增加近2倍。用Lehd裂解法检测，caspase 9活性在复氧过程中增加了3倍，并且在感染显性阴性JNK腺病毒的培养中，这种活性一直显著增强。缺氧-复氧介导了p38丝裂原激活蛋白激酶的双相激活(2.6和2.9倍)，以及转归坏死因子α(TNF-α)分泌的小幅增加，但p38 MAPK特异性抑制剂SB203580或饱和水平的TNFpha-1阻断抗体只能提供部分保护作用。结果表明，JNK的激活是保护性的，该通路在很大程度上不依赖于p38MAPK或分泌的TNFpha。
Reperfusion injury occurs when ischaemic tissue is reperfused. It involves the generation and release of reactive oxygen that activates numerous signalling pathways and initiates cell death, Exposure of isolated cardiac myocytes to chronic hypoxia followed by reoxygenation results in the early activation of c-Jun N-terminal kinase (JNK) and death by apoptosis of approx. 300, of the myocytes. Although JNK activation has been described in a number of models of ischaemia/reperfusion. the contribution of JNK activation to cell fate has not been established. Here we report that the activation of JNK by reoxygenation correlates with myocyte survival. Transfection of myocytes with JNK pathway interfering plasmid vectors or infection with adenoviral vectors support the hypothesis that JNK is protective. Transfection or infection with JNK inhibitory mutants increased the rates of apoptosis by almost 2-fold compared with control cultures grown aerobically or subjected to hypoxia and reoxygenation. Caspase 9 activity, measured by LEHD cleavage, increased > 3-fold during reoxygenation and this activity was enhanced significantly at all times in cultures infected with dominant negative JNK adenovirus. Hypoxia-reoxygenation mediated a biphasic (2.6- and 2.9-fold) activation of p38 mitogen-activated protein kinase, as well as a small increase of turnout necrosis factor alpha (TNF-alpha) secretion, but treatments with the p38 MAPK-specific inhibitor SB203580 or saturating levels of a TNFalpha-1 blocking antibody provided only partial protection against apoptosis. The results suggest that JNK activation is protective and that the pathway is largely independent of p38 MAPK or secreted TNFalpha.