Tanja K Rudolph1, Thorben Ravekes1, Anna Klinke2, Kai Friedrichs1, Martin Mollenhauer1, Michaela Pekarova3, Gabriela Ambrozova3, Hana Martiskova3, Jatinder-Jit Kaur4, Bianca Matthes4, Alex Schwoerer5, Steven R Woodcock6, Lukas Kubala7, Bruce A Freeman6, Stephan Baldus1, Volker Rudolph8. 1. Department of Cardiology, University Heart Center Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany. 2. 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. 3. Institute of Biophysics, Academy of Sciences of the Czech Republic, v. v. I, Brno, Czech Republic. 4. Department of Cardiology, University Heart Center Hamburg, University Hospital Eppendorf, Hamburg, Germany. 5. Department of Cellular and Integrative Physiology, University Medical Center Hamburg Eppendorf, Hamburg, Germany DZHK (German Centre for Cardiovascular Research)-Hamburg/Kiel/Luebeck, Hamburg, Germany. 6. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. 7. 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. 8. Department of Cardiology, University Heart Center Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany volker.rudolph@uk.koeln.de.
Abstract
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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 acidnitroalkenes, 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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