Heme oxygenase-1 regulates the JNK signaling pathway through the MLK3–MKK7–JNK3 signaling module in brain ischemia injury
Heme oxygenase-1 regulates the JNK signaling pathway through the MLK3–MKK7–JNK3 signaling module in brain ischemia injury
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DOI：
10.1016/j.brainres.2011.10.021
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发表时间：
2012-01
期刊：
影响因子：
2.9
通讯作者：
Yuan-Jian Song;Z. Zong;Hongzhi Liu;R. Mukasa;D. Pei;J. Mou;Xiang-ru Wen;Zhi’an Liu;Xianyong Wei
中科院分区：
文献类型：
--
作者：
Yuan-Jian Song;Z. Zong;Hongzhi Liu;R. Mukasa;D. Pei;J. Mou;Xiang-ru Wen;Zhi’an Liu;Xianyong Wei
虽然已有研究表明血红素氧合酶-1（HO-1）在脑缺血再灌注损伤中起重要作用，但其作用机制尚不清楚。在这项工作中，我们研究HO-1是否参与了c-Jun N-末端激酶（JNK）信号通路的调节和脑缺血再灌注引起的神经细胞损伤。缺血前20 min侧脑室注射HO-1激活剂钴原卟啉（CoPP）诱导HO-1过表达。结果显示，四血管阻断15 min后，HO-1-混合谱系激酶3（MLK 3）、MLK 3-丝裂原活化激酶7（MKK 7）和MKK 7-JNK 3的结合在再灌注6 h时达到高峰，CoPP可下调上述作用。此外，CoPP还能抑制JNK 3、c-Jun和caspase-3的活化。再灌注5d后，CoPP预处理可显著增加神经元的存活。与此相反，CoPP的上述作用都被HO-1的选择性抑制剂锌原卟啉（ZnPP）逆转。本研究结果提示HO-1通过下调JNK信号通路中MLK 3-MKK 7-JNK 3信号通路对脑缺血损伤神经元具有保护作用。
Although previous researches indicated that heme oxygenase-1 (HO-1) plays a conspicuous role in neuronal injury induced by reperfusion following the brain ischemia, reasonable mechanisms for the role of HO-1 are not clear. In this work, we investigated whether HO-1 was involved in the regulation of the c-Jun N-terminal kinase (JNK) signaling pathway and neuronal cell injury induced by the brain ischemia followed by reperfusion. Cobaltic protoporphyrin (CoPP), an activator of HO-1, was administrated to induce the overexpression of HO-1 by intracerebroventricular infusion 20min before ischemia. The results showed that the combination of HO-1-mixed lineage kinase 3 (MLK3), MLK3-mitogen-activated kinase kinase 7 (MKK7) and MKK7–JNK3 increased to a peak at 6h of reperfusion following 15min of ischemia induced by four-vessel occlusion in rats, and these effects were downregulated by CoPP. In addition, CoPP could inhibit the activation of JNK3, c-Jun and caspase-3. Furthermore, pretreatment with CoPP significantly increased the survival of neurons after 5days of reperfusion. In contrast, all of the above effects of CoPP were reversed by zinc protoporphyrin (ZnPP), a selective inhibitor of HO-1. Our results suggested that HO-1 could protect neurons against brain ischemic injury by downregulating the JNK signaling pathway through the MLK3–MKK7–JNK3 signaling module.