title: Nitrated fatty acids suppress angiotensin II-mediated fibrotic remodelling and atrial fibrillation.
abstract: OBJECTIVE
  Atrial fibrosis, one of the most striking features in the pathology of atrial fibrillation (AF), is promoted by local and systemic inflammation. Electrophilic fatty acid nitroalkenes, endogenously generated by both metabolic and inflammatory reactions, are anti-inflammatory mediators that in synthetic form may be useful as drug candidates. Herein we investigate whether an exemplary nitro-fatty acid can limit atrial fibrosis and AF.
  
  
  RESULTS
  Wild-type C57BL6/J mice were treated for 2 weeks with angiotensin II (AngII) and vehicle or nitro-oleic acid (10-nitro-octadec-9-enoic acid, OA-NO2, 6 mg/kg body weight) via subcutaneous osmotic minipumps. OA-NO2 significantly inhibited atrial fibrosis and depressed vulnerability for AF during right atrial electrophysiological stimulation to levels observed for AngII-naive animals. Left atrial epicardial mapping studies demonstrated preservation of conduction homogeneity by OA-NO2. The protection from fibrotic remodelling was mediated by suppression of Smad2-dependent myofibroblast transdifferentiation and inhibition of Nox2-dependent atrial superoxide formation.
  
  
  CONCLUSIONS
  OA-NO2 potently inhibits atrial fibrosis and subsequent AF. Nitro-fatty acids and possibly other lipid electrophiles thus emerge as potential therapeutic agents for AF, either by increasing endogenous levels through dietary modulation or by administration as synthetic drugs.
authors.affiliation: Department of Cardiology, University Heart Center Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Tanja K
authors.initials: TK
authors.lastname: Rudolph
authors.affiliation: Department of Cardiology, University Heart Center Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Thorben
authors.initials: T
authors.lastname: Ravekes
authors.affiliation: Department of Cardiology, University Heart Center Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany International Clinical Research Center-Center of Biomolecular and Cellular Engineering, St Anne's University Hospital Brno, Brno, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Klinke
authors.affiliation: Department of Cardiology, University Heart Center Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Friedrichs
authors.affiliation: Department of Cardiology, University Heart Center Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Mollenhauer
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v. v. I, Brno, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Pekarova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v. v. I, Brno, Czech Republic.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ambrozova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v. v. I, Brno, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Martiskova
authors.affiliation: Department of Cardiology, University Heart Center Hamburg, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Jatinder-Jit
authors.initials: JJ
authors.lastname: Kaur
authors.affiliation: Department of Cardiology, University Heart Center Hamburg, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Matthes
authors.affiliation: Department of Cellular and Integrative Physiology, University Medical Center Hamburg Eppendorf, Hamburg, Germany DZHK (German Centre for Cardiovascular Research)-Hamburg/Kiel/Luebeck, Hamburg, Germany.
authors.forename: Alex
authors.initials: A
authors.lastname: Schwoerer
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Woodcock
authors.affiliation: International Clinical Research Center-Center of Biomolecular and Cellular Engineering, St Anne's University Hospital Brno, Brno, Czech Republic Institute of Biophysics, Academy of Sciences of the Czech Republic, v. v. I, Brno, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kubala
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.affiliation: Department of Cardiology, University Heart Center Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.affiliation: Department of Cardiology, University Heart Center Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany volker.rudolph@uk.koeln.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Rudolph
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001281:Atrial Fibrillation / Q000517:prevention & control*; D064752:Atrial Remodeling / Q000187:drug effects*; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D018031:Connexin 43 / Q000032:analysis; D005355:Fibrosis; D006325:Heart Atria / Q000473:pathology; D008041:Linoleic Acids / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009574:Nitro Compounds / Q000494:pharmacology*; D051899:Smad2 Protein / Q000037:antagonists & inhibitors
chemical_list: C501855:10-nitro-9,12-octadecadienoic acid; D018031:Connexin 43; D008041:Linoleic Acids; D009574:Nitro Compounds; D051899:Smad2 Protein; D000804:Angiotensin II
keywords: Atrial fibrillation; Fibrosis; Nitro-fatty acids; Reactive oxygen species