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Suppression of CHOP Reduces Neuronal Apoptosis and Rescues Cognitive Impairment Induced by Intermittent Hypoxia by Inhibiting Bax and Bak Activation
Neural Plasticity ( IF 3.1 ) Pub Date : 2021-08-23 , DOI: 10.1155/2021/4090441
Linhao Xu 1, 2, 3 , Yanli Bi 4 , Yizhou Xu 1 , Yihao Wu 1 , Xiaoxue Du 3 , Yixuan Mou 2 , Jian Chen 2
Affiliation  

Our previous study showed that growth arrest- and DNA damage-inducible gene 153 (GAD153/CHOP) plays an important role in intermittent hypoxia- (IH-) induced apoptosis and impaired synaptic plasticity. This study is aimed at determining which signaling pathway is activated to induce CHOP and the role of this protein in mitochondria-dependent apoptosis induced by IH. In the in vivo study, mice were placed in IH chambers for 8 h daily over a period of 2 weeks; the IH chambers had oxygen (O2) concentrations that oscillated between 10% and 21%, cycling every 90 s. In the in vitro study, PC12 cells were exposed to 21% O2 (normoxia) or 8 IH cycles (25 min at 21% O2 and 35 min at 0.1% O2 for each cycle). After 2 weeks of IH treatment, we observed that the expression levels of phosphorylated protein kinase-like endoplasmic reticulum kinase (p-PERK), activating transcription factor 4 (ATF-4) and phosphorylated eukaryotic initiation factor 2 alpha (p-elf2α), were increased, but the levels of activating transcription factor 6 (ATF-6) and inositol-requiring enzyme 1 (IRE-1) were not increased. GSK2606414, a specific chemical inhibitor of the PERK pathway, reduced the expression of p-PERK, ATF-4, p-elf2α, and CHOP and rescued ER structure. In addition, Bax and Bak accumulated in the mitochondria after IH treatment, which induced cytochrome c release and initiated apoptosis. These effects were prevented by GSK2606414 and CHOP shRNA. Finally, the impaired long-term potentiation and long-term spatial memory in the IH group were rescued by GSK2606414. Together, the data from the in vitro and in vivo experiments indicate that IH-induced apoptosis and impaired synaptic plasticity were mediated by the PERK-ATF-4-CHOP pathway. Suppressing PERK-ATF-4-CHOP signaling pathway attenuated mitochondria-dependent apoptosis by reducing the expression of Bax and Bak in mitochondria, which may serve as novel adjunct therapeutic strategy for ameliorating obstructive sleep apnea- (OSA-) induced neurocognitive impairment.

中文翻译:

抑制 CHOP 通过抑制 Bax 和 Bak 激活来减少神经元凋亡并挽救由间歇性缺氧引起的认知障碍

我们之前的研究表明,生长停滞和 DNA 损伤诱导基因 153 (GAD153/CHOP) 在间歇性缺氧 (IH-) 诱导的细胞凋亡和突触可塑性受损中起重要作用。本研究旨在确定激活哪个信号通路以诱导 CHOP 以及该蛋白在 IH 诱导的线粒体依赖性细胞凋亡中的作用。在体内研究中,将小鼠置于 IH 室中,每天 8 小时,为期 2 周;IH 室的氧气 (O 2 ) 浓度在 10% 和 21% 之间波动,每 90 秒循环一次。在体外研究中,PC12 细胞暴露于 21% O 2(常氧)或 8 个 IH 循环(21% O 2下 25 分钟和 0.1% O 2下 35 分钟)每个周期)。在 IH 治疗 2 周后,我们观察到磷酸化蛋白激酶样内质网激酶 (p-PERK)、激活转录因子 4 (ATF-4) 和磷酸化真核起始因子 2 α (p-elf2α )的表达水平, 增加,但激活转录因子 6 (ATF-6) 和肌醇需要酶 1 (IRE-1) 的水平没有增加。GSK2606414,一种 PERK 通路的特异性化学抑制剂,可降低 p-PERK、ATF-4、p-elf2 α的表达,以及 CHOP 和拯救的 ER 结构。此外,IH 处理后,Bax 和 Bak 在线粒体中积累,从而诱导细胞色素 c 释放并引发细胞凋亡。GSK2606414 和 CHOP shRNA 阻止了这些影响。最后,GSK2606414 挽救了 IH 组受损的长期增强和长期空间记忆。总之,来自体外和体内实验的数据表明,IH 诱导的细胞凋亡和突触可塑性受损是由 PERK-ATF-4-CHOP 途径介导的。抑制 PERK-ATF-4-CHOP 信号通路通过降低线粒体中 Bax 和 Bak 的表达来减弱线粒体依赖性细胞凋亡,这可能作为改善阻塞性睡眠呼吸暂停 (OSA-) 诱导的神经认知障碍的新型辅助治疗策略。
更新日期:2021-08-23
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