title: Intermittent hypoxia causes NOX2-dependent remodeling of atrial connexins.
abstract: Obstructive sleep apnea has been linked to the development of heart disease and arrhythmias, including atrial fibrillation. Since altered conduction through gap junction channels can contribute to the pathogenesis of such arrhythmias, we examined the abundance and distributions of the major cardiac gap junction proteins, connexin40 (Cx40) and connexin43 (Cx43) in mice treated with sleep fragmentation or intermittent hypoxia (IH) as animal models of the components of obstructive sleep apnea.
  
  
  
  Wild type C57BL/6 mice or mice lacking NADPH 2 (NOX2) oxidase activity (gp91phox(-/Y)) were exposed to room air or to SF or IH for 6 weeks. Then, the mice were sacrificed, and atria and ventricles were immediately dissected. The abundances of Cx40 or Cx43 in atria and ventricles were unaffected by SF. In contrast, immunoblots showed that the abundance of atrial Cx40 and Cx43 and ventricular Cx43 were reduced in mice exposed to IH. qRT-PCR demonstrated significant reductions of atrial Cx40 and Cx43 mRNAs. Immunofluorescence microscopy revealed that the abundance and size of gap junctions containing Cx40 or Cx43 were reduced in atria by IH treatment of mice. However, no changes of connexin abundance or gap junction size/abundance were observed in IH-treated NOX2-null mice.
  
  
  
  These results demonstrate that intermittent hypoxia (but not sleep fragmentation) causes reductions and remodeling of atrial Cx40 and Cx43. These alterations may contribute to the substrate for atrial fibrillation that develops in response to obstructive sleep apnea. Moreover, these connexin changes are likely generated in response to reactive oxygen species generated by NOX2.
authors.affiliation: Department of Pediatrics, University of Chicago, 900 E. 57th St. KCBD 5152, Chicago, IL, 60637, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Gemel
authors.affiliation: Present address: Williams College, Williamstown, MA, USA.
authors.forename: Zihan
authors.initials: Z
authors.lastname: Su
authors.affiliation: Present address: Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mt. Scopus, Jerusalem, Israel.
authors.forename: Alex
authors.initials: A
authors.lastname: Gileles-Hillel
authors.affiliation: Department of Pediatrics, University of Chicago, 900 E. 57th St. KCBD 5152, Chicago, IL, 60637, USA.
authors.forename: Abdelnaby
authors.initials: A
authors.lastname: Khalyfa
authors.affiliation: Department of Pediatrics, University of Chicago, 900 E. 57th St. KCBD 5152, Chicago, IL, 60637, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gozal
authors.affiliation: Department of Pediatrics, University of Chicago, 900 E. 57th St. KCBD 5152, Chicago, IL, 60637, USA. ecbeyer@uchicago.edu.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Beyer
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism*; D017630:Connexins / Q000378:metabolism*; D006325:Heart Atria / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D015820:Cadherins; D018031:Connexin 43; D017630:Connexins; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000097003:Gap Junction alpha-5 Protein; C488842:Cybb protein, mouse
keywords: Atrial fibrillation; Connexin; Gap junctions; Intermittent hypoxia; Obstructive sleep apnea