Nitro-fatty acids suppress ischemic ventricular arrhythmias by preserving calcium homeostasis

Martin Mollenhauer; Dennis Mehrkens; Anna Klinke; Max Lange; Lisa Remane; Kai Friedrichs; Simon Braumann; Simon Geißen; Sakine Simsekyilmaz; Felix S Nettersheim; Samuel Lee; Gabriel Peinkofer; Anne C Geisler; Bianca Geis; Alexander P Schwoerer; Lucie Carrier; Bruce A Freeman; Matthias Dewenter; Xiaojing Luo; Ali El-Armouche; Michael Wagner; Matti Adam; Stephan Baldus; Volker Rudolph

doi:10.1038/s41598-020-71870-6

Nitro-fatty acids suppress ischemic ventricular arrhythmias by preserving calcium homeostasis

Sci Rep. 2020 Sep 18;10(1):15319. doi: 10.1038/s41598-020-71870-6.

Authors

Martin Mollenhauer^#^{1

2}, Dennis Mehrkens^#^{3

4}, Anna Klinke⁵, Max Lange^{3

4}, Lisa Remane^{3

4}, Kai Friedrichs⁵, Simon Braumann^{3

4}, Simon Geißen^{3

4}, Sakine Simsekyilmaz^{3

4}, Felix S Nettersheim^{3

4}, Samuel Lee^{3

4}, Gabriel Peinkofer^{3

4}, Anne C Geisler⁶, Bianca Geis⁶, Alexander P Schwoerer⁷, Lucie Carrier⁸, Bruce A Freeman⁹, Matthias Dewenter^{10

11}, Xiaojing Luo¹², Ali El-Armouche¹², Michael Wagner^{12

13}, Matti Adam^{3

4}, Stephan Baldus^{3

4}, Volker Rudolph⁵

Affiliations

¹ Clinic III for Internal Medicine, Department of Cardiology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany. martin.mollenhauer@uk-koeln.de.
² Center for Molecular Medicine Cologne, CMMC, University of Cologne, Cologne, Germany. martin.mollenhauer@uk-koeln.de.
³ Clinic III for Internal Medicine, Department of Cardiology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
⁴ Center for Molecular Medicine Cologne, CMMC, University of Cologne, Cologne, Germany.
⁵ Clinic for General and Interventional Cardiology/ Angiology, Herz- Und Diabeteszentrum NRW, Ruhr-Universitaet Bochum, Bad Oeynhausen, Germany.
⁶ General and Interventional Cardiology University Heart Center Hamburg, University Hospital Hamburg-Eppendorf (UKE), Hamburg, Germany.
⁷ Department of Cellular and Integrative Physiology, University Medical Center Hamburg Eppendorf, DZHK (German Centre of Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
⁸ Experimental Pharmacology and Toxicology, University Hospital Hamburg-Eppendorf (UKE), Hamburg, Germany.
⁹ Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ Institute of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany.
¹¹ German Centre for Cardiovascular Research (DZHK), Partner Site, Heidelberg/Mannheim, Germany.
¹² Department of Pharmacology and Toxicology, Technische Universitaet Dresden, Dresden, Germany.
¹³ Clinic for Internal Medicine and Cardiology, Heart Center Dresden, Dresden, Germany.

^# Contributed equally.

Abstract

Nitro-fatty acids are electrophilic anti-inflammatory mediators which are generated during myocardial ischemic injury. Whether these species exert anti-arrhythmic effects in the acute phase of myocardial ischemia has not been investigated so far. Herein, we demonstrate that pretreatment of mice with 9- and 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO₂-OA) significantly reduced the susceptibility to develop acute ventricular tachycardia (VT). Accordingly, epicardial mapping revealed a markedly enhanced homogeneity in ventricular conduction. NO₂-OA treatment of isolated cardiomyocytes lowered the number of spontaneous contractions upon adrenergic isoproterenol stimulation and nearly abolished ryanodine receptor type 2 (RyR2)-dependent sarcoplasmic Ca²⁺ leak. NO₂-OA also significantly reduced RyR2-phosphorylation by inhibition of increased CaMKII activity. Thus, NO₂-OA might be a novel pharmacological option for the prevention of VT development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Arrhythmia Agents / pharmacology*
Arrhythmias, Cardiac / drug therapy*
Arrhythmias, Cardiac / metabolism*
Calcium / metabolism*
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
Catecholamines / pharmacology
Dietary Supplements
Homeostasis / drug effects
Isoproterenol / pharmacology
Male
Mice, Inbred Strains
Myocardial Ischemia / complications
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism
Nitro Compounds / pharmacology*
Oleic Acids / pharmacology*
Phosphorylation / drug effects
Ryanodine Receptor Calcium Release Channel / metabolism
Tachycardia, Ventricular / etiology
Tachycardia, Ventricular / prevention & control

Substances

Anti-Arrhythmia Agents
Catecholamines
Nitro Compounds
Oleic Acids
Ryanodine Receptor Calcium Release Channel
ryanodine receptor 2. mouse
CXA-10
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Isoproterenol
Calcium