Heme oxygenase-1 protects spinal cord neurons from hydrogen peroxide-induced apoptosis via suppression of Cdc42/MLK3/MKK7/JNK3 signaling

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• 作者：Siyuan Wang ; Tao Zhang ; Zhen Yang ; Jianhua Lin ; Bin Cai ; Qingfeng Ke…
• 关键词：Spinal cord injury ; Apoptosis ; Cell signaling ; Mir ; 137
• 刊名：Apoptosis
• 出版年：2017
• 出版时间：March 2017
• 年：2017
• 卷：22
• 期：3
• 页码：449-462
• 全文大小：
• 刊物类别：Medicine
• 刊物主题：Cancer Research; Cell Biology; Oncology; Biochemistry, general; Virology;
• 出版者：Springer US
• ISSN：1573-675X
• 卷排序：22

文摘

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 H₂O₂ in a time-dependent manner, demonstrated by increase of activating phosphorylation of MLK3, MKK7 and JNK3. H₂O₂ also induced expression of HO-1. Transduction of neurons with HO-1-expressing adeno-associated virus before H₂O₂ treatment 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.