C/EBP Homologous Binding Protein (CHOP) Underlies Neural Injury in Sleep Apnea Model

• DOI: 10.5665/sleep.2528
• Publication Date: 2013-03-29T21:21:44Z
• Authors: Yu-Ting Chou; Guanxia Zhan; Yan Zhu; Polina Fenik; Lori Panossian; YanPeng Li; Jing Zhang; Sigrid Veasey
• Keywords: Male; Motor Neurons; Analysis of Variance; 0303 health sciences; Blotting, Western; Brain; NADPH Oxidases; Apoptosis; Hypoxia-Inducible Factor 1, alpha Subunit; Real-Time Polymerase Chain Reaction; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Mice; Oxidative Stress; 03 medical and health sciences; Sleep Apnea Syndromes; Animals; Transcription Factor CHOP

Obstructive sleep apnea (OSA) is associated with cognitive impairment and neuronal injury. Long-term exposure to intermittent hypoxia (LTIH) in rodents, modeling the oxygenation patterns in sleep apnea, results in NADPH oxidase 2 (Nox2) oxidative injury to many neuronal populations. Brainstem motoneurons susceptible to LTIH injury show uncompensated endoplasmic reticulum stress responses with increased (CCAAT/enhancer binding protein homologous protein (CHOP). We hypothesized that CHOP underlies LTIH oxidative injury. In this series of studies, we first determined whether CHOP is upregulated in other brain regions susceptible to LTIH oxidative Nox2 injury and then determined whether CHOP plays an adaptive or injurious role in the LTIH response. To integrate these findings with previous studies examining LTIH neural injury, we examined the role of CHOP in Nox2, hypoxia-inducible factor-1α (HIF-1α) responses, oxidative injury and apoptosis, and neuron loss.Within/between mice subjects.Laboratory setting. PARTICIPANTSSUBJECTS: CHOP null and wild-type adult male mice.LTIH or sham LTIH.Relative to wild-type mice, CHOP-/- mice conferred resistance to oxidative stress (superoxide production/ carbonyl proteins) in brain regions examined: cortex, hippocampus, and motor nuclei. CHOP deletion prevented LTIH upregulation of Nox2 and HIF-1α in the hippocampus, cortex, and brainstem motoneurons and protected mice from neuronal apoptosis and motoneuron loss.Endogenous CHOP is necessary for LTIH-induced HIF-1α, Nox2 upregulation, and oxidative stress; CHOP influences LTIH-induced apoptosis in neurons and loss of neurons. Findings support the concept that minimizing CHOP may provide neuroprotection in OSA.