TAK1 activates AMPK-dependent cell death pathway in hydrogen peroxide-treated cardiomyocytes, inhibited by heat shock protein-70
TAK1 activates AMPK-dependent cell death pathway in hydrogen peroxide-treated cardiomyocytes, inhibited by heat shock protein-70
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DOI：
10.1007/s11010-013-1568-z
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发表时间：
2013-05-01
影响因子：
4.3
通讯作者：
Lai, Jiang
中科院分区：
文献类型：
--
作者：
Chen, Zhiyu;Shen, Xiaolu;Lai, Jiang
本研究旨在探讨AMP激活的蛋白激酶(AMPK)在过氧化氢(H_2O_2)诱导的心肌细胞死亡中的作用，并着重探讨H_2O_2激活AMPK的信号机制。我们观察到H_2O_2处理的心肌细胞(包括原代细胞和H9c2细胞)有显著的AMPK激活。用AMPK抑制剂或RNAi抑制AMPK可减少过氧化氢诱导的心肌细胞死亡。我们认为转化生长因子-β激活蛋白1(TAK1)可能是H_2O_2激活AMPK的上游激酶。H_2O_2诱导TAK1激活，从而募集和激活AMPK。TAK1抑制剂显著抑制过氧化氢诱导的AMPK激活和心肌细胞死亡，而TAK1过表达促进AMPK激活和心肌细胞聚集性死亡。重要的是，热休克蛋白-70(HSP-70)减少了H_2O_2诱导的活性氧(ROS)积累、TAK1/AMPK活化和心肌细胞死亡。综上所述，我们认为TAK1激活了H_2O_2处理的心肌细胞AMPK依赖的细胞死亡通路，而HSP-70通过减少ROS含量来抑制该信号通路。
The aim of this current study is to investigate the potential role of AMP-activated protein kinase (AMPK) in hydrogen peroxide (H2O2)-induced cardiomyocyte death, and focused on the signaling mechanisms of AMPK activation by H2O2. We observed a significant AMPK activation in H2O2-treated cardiomyocytes (both primary cells and H9c2 line). Inhibition of AMPK by its inhibitor or RNAi-reduced H2O2-induced cardiomyocyte death. We here proposed that transforming growth factor-beta-activating kinase 1 (TAK1) might be the upstream kinase for AMPK activation by H2O2. H2O2-induced TAK1 activation, which recruited and activated AMPK. TAK1 inhibitor significantly suppressed H2O2-induced AMPK activation and following cardiomyocyte death, while over-expression of TAK1-facilitated AMPK activation and aggregated cardiomyocyte death. Importantly, heat shock protein-70 (HSP-70)-reduced H2O2-induced reactive oxygen species (ROS) accumulation, the TAK1/AMPK activation and cardiomyocyte death. In conclusion, we here suggest that TAK1 activates AMPK-dependent cell death pathway in H2O2-treated cardiomyocytes, and HSP-70 inhibits the signaling pathway by reducing ROS content.