title: C/EBP homologous binding protein (CHOP) underlies neural injury in sleep apnea model.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Within/between mice subjects.
  
  
  METHODS
  Laboratory setting. PARTICIPANTSSUBJECTS: CHOP null and wild-type adult male mice.
  
  
  METHODS
  LTIH or sham LTIH.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sleep Center, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Chou
authors.forename: Guanxia
authors.initials: G
authors.lastname: Zhan
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Polina
authors.initials: P
authors.lastname: Fenik
authors.forename: Lori
authors.initials: L
authors.lastname: Panossian
authors.forename: Yanpeng
authors.initials: Y
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Sigrid
authors.initials: S
authors.lastname: Veasey
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012891:Sleep Apnea Syndromes / Q000378:metabolism* / Q000503:physiopathology*; D051742:Transcription Factor CHOP / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051742:Transcription Factor CHOP; D019255:NADPH Oxidases
keywords: GADD153 and gp91phox; Hypoxia; PERK; reoxygenation; unfolded protein response
references.citation: Am J Respir Crit Care Med. 1999 Jan;159(1):213-9
references.pmid: 9872841
references.citation: Am J Respir Cell Mol Biol. 2009 May;40(5):601-9
references.pmid: 18952568
references.citation: Mol Cell. 2004 Sep 10;15(5):767-76
references.pmid: 15350220
references.citation: J Biol Chem. 2010 Jul 9;285(28):21329-40
references.pmid: 20448044
references.citation: J Physiol. 2007 Nov 15;585(Pt 1):135-46
references.pmid: 17916615
references.citation: Trends Mol Med. 2012 Jan;18(1):59-68
references.pmid: 21889406
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19794-9
references.pmid: 17167049
references.citation: J Comp Neurol. 1991 Feb 22;304(4):596-607
references.pmid: 1849521
references.citation: Am J Respir Crit Care Med. 2012 Feb 1;185(3):322-9
references.pmid: 22016445
references.citation: Aging Cell. 2011 Aug;10(4):640-9
references.pmid: 21388495
references.citation: J Appl Physiol (1985). 2005 Nov;99(5):1998-2007
references.pmid: 16227461
references.citation: Neuromolecular Med. 2012 Sep;14(3):168-79
references.pmid: 22169915
references.citation: J Neurol Neurosurg Psychiatry. 2007 Mar;78(3):295-7
references.pmid: 17012335
references.citation: Biochem Biophys Res Commun. 2012 Jan 6;417(1):147-52
references.pmid: 22138650
references.citation: Regul Pept. 1997 Jul 23;71(1):29-36
references.pmid: 9299639
references.citation: J Comp Neurol. 1984 Nov 1;229(3):329-46
references.pmid: 6389613
references.citation: J Cell Physiol. 2011 Nov;226(11):2925-33
references.pmid: 21302291
references.citation: Gene Expr. 1999;7(4-6):293-300
references.pmid: 10440230
references.citation: Diabetes Res Clin Pract. 2012 Aug;97(2):267-75
references.pmid: 22445233
references.citation: J Cell Physiol. 2008 Dec;217(3):674-85
references.pmid: 18651560
references.citation: Am J Respir Crit Care Med. 2008 May 15;177(10):1135-41
references.pmid: 18276944
references.citation: J Clin Invest. 2009 Oct;119(10):2925-41
references.pmid: 19741297
references.citation: Antioxid Redox Signal. 2011 Feb 15;14(4):533-42
references.pmid: 20618070
references.citation: Nat Cell Biol. 2011 Mar;13(3):184-90
references.pmid: 21364565
references.citation: Eur J Intern Med. 2012 Apr;23(3):219-26
references.pmid: 22385877
references.citation: Am J Respir Crit Care Med. 2004 Sep 15;170(6):665-72
references.pmid: 15229096
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5727-32
references.pmid: 15824309
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1978 Jun;44(6):931-8
references.pmid: 670014
references.citation: PLoS One. 2011;6(5):e19847
references.pmid: 21625437
references.citation: Sleep. 2004 Mar 15;27(2):194-201
references.pmid: 15124711
references.citation: Mol Cell. 2003 Mar;11(3):619-33
references.pmid: 12667446
references.citation: J Neurol Neurosurg Psychiatry. 2001 May;70(5):685-7
references.pmid: 11309469
references.citation: Eur Arch Otorhinolaryngol. 2008 May;265(5):581-6
references.pmid: 17952449
references.citation: Neurobiol Dis. 2009 Dec;36(3):470-6
references.pmid: 19733664
references.citation: J Neurosci. 2011 Mar 16;31(11):4025-36
references.pmid: 21411645
references.citation: J Clin Invest. 2008 Oct;118(10):3378-89
references.pmid: 18776938
references.citation: PLoS One. 2011;6(10):e26420
references.pmid: 22046282
references.citation: Am J Respir Crit Care Med. 2005 Oct 1;172(7):921-9
references.pmid: 15994465
references.citation: Sleep Med. 2010 Feb;11(2):205-12
references.pmid: 20083433
references.citation: Am J Respir Crit Care Med. 2001 Jul 15;164(2):187-9
references.pmid: 11463584
references.citation: Mol Cell Biol. 2001 Feb;21(4):1249-59
references.pmid: 11158311
references.citation: Am J Physiol Heart Circ Physiol. 2008 May;294(5):H2197-203
references.pmid: 18326795
references.citation: J Neurosci. 2008 Feb 27;28(9):2168-78
references.pmid: 18305250
references.citation: Am J Respir Crit Care Med. 2004 Sep 1;170(5):541-6
references.pmid: 15151922
references.citation: Am J Physiol Cell Physiol. 2010 Jun;298(6):C1594-602
references.pmid: 20357179
references.citation: Antioxid Redox Signal. 2009 Sep;11(9):2317-31
references.pmid: 19243234
references.citation: Am J Respir Crit Care Med. 1998 Feb;157(2):586-93
references.pmid: 9476877
references.citation: J Neurosci. 2007 Sep 12;27(37):10060-71
references.pmid: 17855620
references.citation: J Physiol. 2006 Dec 1;577(Pt 2):705-16
references.pmid: 16973705
references.citation: Am J Geriatr Psychiatry. 2006 Feb;14(2):95-103
references.pmid: 16473973
references.citation: Laryngoscope. 1991 Dec;101(12 Pt 1):1318-22
references.pmid: 1766303