title: Oxidative stress and inflammation modulate Rev-erbα signaling in the neonatal lung and affect circadian rhythmicity.
abstract: OBJECTIVE
  The response to oxidative stress and inflammation varies with diurnal rhythms. Nevertheless, it is not known whether circadian genes are regulated by these stimuli. We evaluated whether Rev-erbα, a key circadian gene, was regulated by oxidative stress and/or inflammation in vitro and in a mouse model.
  
  
  RESULTS
  A unique sequence consisting of overlapping AP-1 and nuclear factor kappa B (NFκB) consensus sequences was identified on the mouse Rev-erbα promoter. This sequence mediates Rev-erbα promoter activity and transcription in response to oxidative stress and inflammation. This region serves as an NrF2 platform both to receive oxidative stress signals and to activate Rev-erbα, as well as an NFκB-binding site to repress Rev-erbα with inflammatory stimuli. The amplitude of the rhythmicity of Rev-erbα was altered by pre-exposure to hyperoxia or disruption of NFκB in a cell culture model of circadian simulation. Oxidative stress overcame the inhibitory effect of NFκB binding on Rev-erbα transcription. This was confirmed in neonatal mice exposed to hyperoxia, where hyperoxia-induced lung Rev-erbα transcription was further increased with NFκB disruption. Interestingly, this effect was not observed in similarly exposed adult mice.
  
  
  METHODS
  These data provide novel mechanistic insights into how key circadian genes are regulated by oxidative stress and inflammation in the neonatal lung.
  
  
  CONCLUSIONS
  Rev-erbα transcription and circadian oscillation are susceptible to oxidative stress and inflammation in the neonate. Due to Rev-erbα's role in cellular metabolism, this could contribute to lung cellular function and injury from inflammation and oxidative stress.
authors.affiliation: 1 Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Clyde J
authors.initials: CJ
authors.lastname: Wright
authors.forename: Maurice D
authors.initials: MD
authors.lastname: Hinson
authors.forename: Amal P
authors.initials: AP
authors.lastname: Fernando
authors.forename: Shaon
authors.initials: S
authors.lastname: Sengupta
authors.forename: Chhanda
authors.initials: C
authors.lastname: Biswas
authors.forename: Ping
authors.initials: P
authors.lastname: La
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Dennery
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000187:drug effects*; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016328:NF-kappa B; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D012333:RNA, Messenger; D006861:Hydrogen Peroxide