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首页> 外文期刊>Cellular Signalling >Involvement of JNKs and p38-MAPK/MSK1 pathways in H2O2-induced upregulation of heme oxygenase-1 mRNA in H9c2 cells
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Involvement of JNKs and p38-MAPK/MSK1 pathways in H2O2-induced upregulation of heme oxygenase-1 mRNA in H9c2 cells

机译：JNK和p38-MAPK / MSK1通路参与H2O2诱导H9c2细胞血红素加氧酶-1 mRNA的上调

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One of the most important challenges that cardiomyocytes experience is an increase in the levels of reactive oxygen species (ROS), i.e., during ischemia, reperfusion as well as in the failing myocardium. HOX-1 has been found to protect cells and tissues against oxidative damage; therefore, we decided to study the signalling cascades involved in its transcriptional regulation. HOX-1 mRNA levels were found to be maximally induced after 6h of treatment with 200 mu M H2O2 and remained elevated for at least 24h. Inhibition of JNKs, p38-MAPK and MSK1 pathways, by pharmacological inhibitors, reduced HOX-1 mRNA levels in H2O2-treated H9c2 cells. In parallel, we observed that all three subfamilies of the mitogen-activated protein kinases (MAPKs) attained their maximal phosphorylation levels at 5-15min of H2O2 treatment, with mitogen- and stress-activated-protein kinase 1 (MSK1) also being maximally phosphorylated at 15 min. H2O2-induced MSK1 phosphorylation was completely abrogated in the presence of the selective p38-MAPK inhibitor SB203580. In an effort to define possible substrates of MSK1, we found that ATF2 as well as cJun phosphorylation were equally induced after 30min and 60min, respectively, a response inhibited by SP600125 (JNKs inhibitor) and H89 (MSK1 inhibitor), indicating the involvement of these kinases in the observed response. This finding was further substantiated with the detection of a potential signalling complex composed of either p-MSK1 and p-cJun or p-MSK1 and p-ATF2 (co-immunoprecipitation). ATF2 and cJun are known AP1 components. Given the presence of an AP-1 site in HOX-1 promoter region, the activity of AP1 transcription factor was examined. Electrophoretic mobility shift assays performed showed a maximal upregulation of AP1 binding activity after 60min of H2O2 treatment, which was significantly inhibited by SP600125 and H89. Our results show for the first time the potential role of JNKs, p38-MAPK and MSK1 in the mechanism of transducing the oxidative stress-signal to HOX-1, possibly promoting cell survival and preserving homeostasis. (c) 2006 Elsevier Inc. All rights reserved.
机译：心肌细胞经历的最重要的挑战之一是活性氧（ROS）水平的增加，即在缺血，再灌注以及衰竭的心肌中。已经发现HOX-1可以保护细胞和组织免受氧化损伤。因此，我们决定研究涉及其转录调控的信号级联反应。发现在用200μMH2O2处理6小时后，HOX-1 mRNA的水平被最大程度地诱导，并至少持续24h升高。通过药理抑制剂抑制JNKs，p38-MAPK和MSK1途径可降低H2O2处理的H9c2细胞中HOX-1 mRNA的水平。同时，我们观察到丝裂原活化蛋白激酶（MAPKs）的所有三个亚家族在H2O2处理5-15分钟时均达到最大磷酸化水平，丝裂原活化蛋白应激蛋白激酶1（MSK1）也被最大程度地磷酸化15分钟后在选择性p38-MAPK抑制剂SB203580存在下，H2O2诱导的MSK1磷酸化被完全消除。为了确定MSK1的可能底物，我们发现分别在30min和60min后分别诱导了ATF2和cJun磷酸化，该反应被SP600125（JNKs抑制剂）和H89（MSK1抑制剂）抑制，表明它们参与了观察到的反应中的激酶。通过检测由p-MSK1和p-cJun或p-MSK1和p-ATF2组成的潜在信号复合物进一步证实了这一发现（共免疫沉淀）。 ATF2和cJun是已知的AP1组件。给定HOX-1启动子区域中存在AP-1位点，检查AP1转录因子的活性。进行的电泳迁移率变动分析显示，H2O2处理60分钟后，AP1结合活性最大上调，这被SP600125和H89显着抑制。我们的结果首次显示了JNKs，p38-MAPK和MSK1在将氧化应激信号转导到HOX-1的机制中的潜在作用，可能促进细胞存活并保持体内稳态。 （c）2006 Elsevier Inc.保留所有权利。

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