Suppression of CHOP Reduces Neuronal Apoptosis and Rescues Cognitive Impairment Induced by Intermittent Hypoxia by Inhibiting Bax and Bak Activation.

Linhao Xu,Yanli Bi,Xiaoxue Du,Yizhou Xu,Yixuan Mou,Yihao Wu,Jian Chen,Fernando Peña-Ortega

doi:10.1155/2021/4090441

Abstract

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.

Highlights

Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive collapse of the pharyngeal airway during sleep, resulting in sleep fragmentation and intermittent hypoxia (IH) [1]
As one harmful consequence induced by chronic IH, apoptotic neuronal cell death is strongly believed to contribute to cognitive impairment in OSA disease which was shown in animal models and clinical studies [3, 4]
Three main pathways are involved in endoplasmic reticulum (ER) stressinduced CHOP expression, which was increased after 2 weeks of IH treatment; in this study, we first investigated which specific pathway plays an important role in regulating the expression of CHOP

Summary

Introduction

Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive collapse of the pharyngeal airway during sleep, resulting in sleep fragmentation and intermittent hypoxia (IH) [1]. The ER is an important organelle with multiple functions in which all secretory and integral membrane proteins are folded. When a stressor, such as hypoxia, glucose deprivation, or protein overload from a virus, blocks ER function, the accumulation of unfolded or misfolded proteins in the ER affects cellular functions, and the adaptive unfolded protein response (UPR) is triggered [7]. Three signaling pathways, including the protein kinase-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) pathways, are all necessary for the activation of growth arrest and DNA damage-inducible gene 153- (CHOP/GAD153-) mediated apoptosis [8]

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