title: Role of nitric oxide and oxidative stress in a sheep model of persistent atrial fibrillation.
abstract: OBJECTIVE
  Oxidative stress can modulate nitric oxide (NO) signalling pathways. Both pathways have been shown to be involved in the pathophysiology of atrial fibrillation (AF), but data are conflicting. We aimed to characterize the NO-pathway and its relation to oxidative stress in persistent AF in a sheep model.
  
  
  RESULTS
  Persistent AF was induced by rapid atrial pacing for a mean of 136.5 ± 21.7 days. Non-stimulated sheep served as controls. Nicotine adenine dinucleotide phosphate (NADPH) oxidase-stimulated superoxide production was significantly increased in the AF group (+51.3 ± 23.2%, P < 0.01). Although there were no changes in mRNA expression of the different NADPH oxidase subunits, the increased activity was associated with markedly increased protein expression of the NADPH oxidase activator, Rac1 (+26 ± 4.6%, P < 0.05). No differences were seen in superoxide dismutase activity, but glutathione peroxidase activity was lower in the AF group. There was a marked accumulation of 3-nitrotyrosine, a biomarker for peroxynitrite, in atrial tissue of AF animals, as demonstrated by immunohistochemical staining and dot blot analysis (+15.6 ± 1.8%, P < 0.05). Expression of atrial NOS3 mRNA was 24.9 ± 4.4% lower in the AF group vs. control (P < 0.05), while NOS1 and 2 were unchanged. Immunoblot analysis revealed no changes in protein expression. Nitrite/nitrate levels were significantly lower during AF (-24.8 ± 5.8%, P < 0.05).
  
  
  CONCLUSIONS
  In a sheep model of persistent AF, NOS3 transcript levels are attenuated and circulating NOx levels decreased. Persistent AF is associated with increased oxidative stress, probably resulting from increased NADPH oxidase activity, without major changes in anti-oxidant capacity of the atrial tissue.
authors: Division of Experimental Cardiology, Department of Cardiovascular Medicine, University of Leuven, Leuven, Belgium.
authors: Ilse
authors: I
authors: Lenaerts
authors: Ronald B
authors: RB
authors: Driesen
authors: Nerea
authors: N
authors: Hermida
authors: Nerea Hermida
authors: NH
authors: Blanco
authors: Patricia
authors: P
authors: Holemans
authors: Hein
authors: H
authors: Heidbüchel
authors: Stefan
authors: S
authors: Janssens
authors: Jean-Luc
authors: JL
authors: Balligand
authors: Karin R
authors: KR
authors: Sipido
authors: Rik
authors: R
authors: Willems
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism*; D002908:Chronic Disease; D005260:Female; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012756:Sheep
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase