Heme oxygenase-1 protects spinal cord neurons from hydrogen peroxide-induced apoptosis via suppression of Cdc42/MLK3/MKK7/JNK3 signaling
Heme oxygenase-1 protects spinal cord neurons from hydrogen peroxide-induced apoptosis via suppression of Cdc42/MLK3/MKK7/JNK3 signaling
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血红素加氧酶-1 通过抑制 Cdc42/MLK3/MKK7/JNK3 信号传导保护脊髓神经元免受过氧化氢诱导的细胞凋亡
DOI：
10.1007/s10495-016-1329-z
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发表时间：
2017-03
期刊：
影响因子：
7.2
通讯作者：
Lin Wenping
中科院分区：
文献类型：
--
作者：
Wang Siyuan;Zhang Tao;Yang Zhen;Lin Jianhua;Cai Bin;Ke Qingfeng;Lan Wenbin;Shi Jinxing;Wu Shiqiang;Lin Wenping
氧化应激诱导脊髓神经元死亡的机制尚不完全清楚。研究氧化应激介导的神经元死亡的分子信号通路对开发氧化应激相关脊髓疾病的新疗法具有重要意义。在当前的研究中，我们研究了血红素加氧酶-1 （HO-1）在用H2O2处理原代脊髓神经元后对MLK3/MKK7/JNK3信号通路的调节中的作用，这是一个促凋亡通路。我们发现MLK3/MKK7/JNK3信号被h2o2以时间依赖性的方式激活，表现为MLK3、MKK7和JNK3激活磷酸化的增加。h2o2也能诱导HO-1的表达。在h2o2处理前用表达HO-1的腺相关病毒转导神经元引入外源性HO-1在神经元中的表达。外源性HO-1降低了MLK3、MKK7和JNK3的磷酸化。与其抑制MLK3/MKK7/JNK3信号传导的作用一致，外源性HO-1减少h2o2诱导的神经元凋亡和坏死。此外，我们发现外源性HO-1抑制Cdc42的表达，而Cdc42对MLK3的激活至关重要。此外，ho -1诱导的MLK3/MKK7/JNK3信号的下调可能与microRNA-137 （mir-137）的上调有关。mir-137抑制剂可减轻HO-1对JNK3激活的抑制作用。即使外源性HO-1表达，这种抑制剂也会增加神经元死亡。因此，我们的研究提示了HO-1在氧化应激中发挥神经保护作用的新机制。
The mechanisms by which oxidative stress induces spinal cord neuron death has not been completely understood. Investigation on the molecular signal pathways involved in oxidative stress-mediated neuronal death is important for development of new therapeutics for oxidative stress-associated spinal cord disorders. In current study we examined the role of heme oxygenase-1 (HO-1) in the modulation of MLK3/MKK7/JNK3 signaling, which is a pro-apoptotic pathway, after treating primary spinal cord neurons with H2O2. We found that MLK3/MKK7/JNK3 signaling was substantially activated by H2O2in a time-dependent manner, demonstrated by increase of activating phosphorylation of MLK3, MKK7 and JNK3. H2O2also induced expression of HO-1. Transduction of neurons with HO-1-expressing adeno-associated virus before H2O2treatment introduced expression of exogenous HO-1 in neurons. Exogenous HO-1 reduced phosphorylation of MLK3, MKK7 and JNK3. Consistent with its inhibitory effect on MLK3/MKK7/JNK3 signaling, exogenous HO-1 decreased H2O2-induced neuronal apoptosis and necrosis. Furthermore, we found that exogenous HO-1 inhibited expression of Cdc42, which is crucial for MLK3 activation. In addition, HO-1-induced down-regulation of MLK3/MKK7/JNK3 signaling might be related to up-regulation of microRNA-137 (mir-137). A mir-137 inhibitor alleviated the inhibitory effect of HO-1 on JNK3 activation. This inhibitor also increased neuronal death even when exogenous HO-1 was expressed. Therefore, our study suggests a novel mechanism by which HO-1 exerted its neuroprotective efficacy on oxidative stress.
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