AIM: 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. METHODS AND 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. CONCLUSION: 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.

Department of Cardiology University Heart Center Cologne University of Cologne Kerpener Str 62 50937 Cologne Germany

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

Department of Cardiology University Heart Center Hamburg University Hospital Eppendorf Hamburg Germany

Department of Cellular and Integrative Physiology University Medical Center Hamburg Eppendorf Hamburg Germany DZHK Hamburg Kiel Luebeck Hamburg Germany

Department of Pharmacology and Chemical Biology University of Pittsburgh Pittsburgh PA USA

Institute of Biophysics Academy of Sciences of the Czech Republic v v 1 Brno Czech Republic

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 1 Brno Czech Republic

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