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

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.

ROS‐mediated PERK‐CHOP pathway plays an important role in cadmium‐induced HepG2 cells apoptosis

“…CHOP, as a marker of severe ER stress, also as a transcription factor, controls apoptotic‐related gene expression. It is well known that high levels of CHOP trigger the ER stress‐related cascade in cell apoptosis 38,39 . Our data revealed that Cd treatment increased cleaved caspase 12 level in HepG2.…”

“…It is well known that high levels of CHOP trigger the ER stress-related cascade in cell apoptosis. 38,39 Our data revealed that Cd treatment increased cleaved caspase 12 level in HepG2. Specifically, GSK2606411, a PERK inhibitor, efficiently inhibited CHOP up-regulation and abrogated Cd-induced ER stressmediated apoptotic cascade, thus restored cell viability (Figure 4).…”

Phenylbutyric acid inhibits hypoxia‐induced trophoblast apoptosis and autophagy in preeclampsia via the PERK/ATF‐4/CHOP pathway

“…Among them, CHOP is considered a key molecule in the ERS‐related unfolded protein‐mediated apoptotic pathway (Delbrel et al, 2018; Hu et al, 2019). High CHOP expression promotes apoptosis in various cell types, including cardiac fibroblasts (Olivares‐Silva et al, 2021), vascular smooth muscle cells (Tan et al, 2021), and neuronal cells (Xu et al, 2021). We detected the level of trophoblast apoptosis using Hoechst 33342 staining and flow cytometry.…”

Endoplasmic Reticulum Stress-Associated Neuronal Death and Innate Immune Response in Neurological Diseases

“…Persistent ER stress-induced PERK activation and concomitant downstream eIF2α/ATF4/CHOP activation play vital roles in promoting neuronal apoptotic death ( 43 – 45 ). CHOP, a transcription factor downstream of the PERK/ATF4 pathway, is thought to be essential to ER stress-induced apoptosis, as its depletion or inhibition attenuates tissue insults in response to ER stress ( 46 – 49 ). Downregulation of CHOP using siRNA significantly reduced neuronal apoptosis in a mouse model of intracerebral hemorrhage (ICH) ( 50 ).…”