Heme Oxygenase-1 Inhibits Neuronal Apoptosis in Spinal Cord Injury through Down-Regulation of Cdc42-MLK3-MKK7-JNK3 Axis
Heme Oxygenase-1 Inhibits Neuronal Apoptosis in Spinal Cord Injury through Down-Regulation of Cdc42-MLK3-MKK7-JNK3 Axis
复制标题
Heme Oxygenase-1 通过下调 Cdc42-MLK3-MKK7-JNK3 轴抑制脊髓损伤中的神经元凋亡。
DOI：
10.1089/neu.2016.4608
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发表时间：
2017-02-01
影响因子：
4.2
通讯作者：
Cai, Bin
中科院分区：
文献类型：
--
作者：
Lin, Wenping;Wang, Siyuan;Cai, Bin
脊髓损伤（SCI）引起神经元死亡的机制尚未完全清楚。研究 SCI 介导的神经元凋亡的分子信号通路对于开发 SCI 新疗法非常重要。在本研究中，我们探讨了血红素加氧酶-1 (HO-1) 在调节混合谱系激酶 3/丝裂原激活蛋白激酶激酶/cJUN N 末端激酶 3 (MLK3/MKK7/JNK3) 信号传导中的作用，这是 SCI 后的一条促凋亡途径。我们发现 SCI 以时间依赖性方式激活 MLK3/MKK7/JNK3 信号传导，这通过 MLK3、MKK7 和 JNK3 激活磷酸化的增加来证明。 SCI 还诱导 HO-1 表达。在 SCI 之前施用表达 HO-1 的腺相关病毒可在受损脊髓中引入外源性 HO-1 的表达。外源 HO-1 降低 MLK3、MKK7 和 JNK3 的磷酸化。与其对 MLK3/MKK7/JNK3 信号传导的抑制作用一致，外源性 HO-1 减少了 SCI 诱导的神经元凋亡并改善了神经评分。此外，我们发现外源 HO-1 抑制细胞分裂周期 42 (Cdc42) 的表达，这对于 MLK3 激活至关重要。体外实验表明，Cdc42对于神经元凋亡至关重要，而用表达HO-1的腺相关病毒转导神经元可显着减少神经元凋亡，从而提高神经元存活率。因此，我们的研究揭示了 HO-1 发挥神经保护功效的新机制。我们的发现对于开发 SCI 的新治疗方法可能很有价值。
The mechanism by which spinal cord injury (SCI) induces neuronal death has not been thoroughly understood. Investigation on the molecular signal pathways involved in SCI-mediated neuronal apoptosis is important for development of new therapeutics for SCI. In the current study, we explore the role of heme oxygenase-1 (HO-1) in the modulation of mixed lineage kinase 3/mitogen-activated protein kinase kinase/cJUN N-terminal kinase 3 (MLK3/MKK7/JNK3) signaling, which is a pro-apoptotic pathway, after SCI. We found that MLK3/MKK7/JNK3 signaling was activated by SCI in a time-dependent manner, demonstrated by increase in activating phosphorylation of MLK3, MKK7, and JNK3. SCI also induced HO-1 expression. Administration of HO-1-expressing adeno-associated virus before SCI introduced expression of exogenous HO-1 in injured spinal cords. Exogenous HO-1 reduced phosphorylation of MLK3, MKK7, and JNK3. Consistent with its inhibitory effect on MLK3/MKK7/JNK3 signaling, exogenous HO-1 decreased SCI-induced neuronal apoptosis and improved neurological score. Further, we found that exogenous HO-1 inhibited expression of cell division cycle 42 (Cdc42), which is crucial for MLK3 activation. In vitro experiments indicated that Cdc42 was essential for neuronal apoptosis, while transduction of neurons with HO-1-expressing adeno-associated virus significantly reduced neuronal apoptosis to enhance neuronal survival. Therefore, our study disclosed a novel mechanism by which HO-1 exerted its neuroprotective efficacy. Our discovery might be valuable for developing a new therapeutic approach for SCI.