Nonenzymatic lipid mediators, neuroprostanes, exert the antiarrhythmic properties of docosahexaenoic acid.
Neuroprostanes are lipid mediators produced by nonenzymatic free radical peroxidation of docosahexaenoic acid (DHA). DHA is associated with a lower atherosclerosis risk, suggesting a beneficial role in cardiovascular diseases. The aim of this study was to investigate the influence of DHA peroxidation on its potentially antiarrhythmic properties (AAP) in isolated ventricular cardiomyocytes and in vivo in post-myocardial infarcted mice. Calcium imaging and biochemical experiments indicate that cardiac arrhythmias induced by isoproterenol are associated with Ca(2+) leak from the sarcoplasmic reticulum after oxidation and phosphorylation of the type 2 ryanodine receptor (RyR2) leading to dissociation of the FKBP12.6/RyR2 complex. Both oxidized DHA and 4(RS)-4-F4t-NeuroP prevented cellular arrhythmias and posttranslational modifications of the RyR2 leading to a stabilized FKBP12.6/RyR2 complex. DHA per se did not have AAP. The AAP of 4(RS)-4-F4t-NeuroP was also observed in vivo. In this study, we challenged the paradigm that spontaneously formed oxygenated metabolites of lipids are undesirable as they are unconditionally toxic. This study reveals that the lipid mediator 4(RS)-4-F4t-neuroprostane derived from nonenzymatic peroxidation of docosahexaenoic acid can counteract such deleterious effects through cardiac antiarrhythmic properties. Our findings demonstrate 4(RS)-4-F4t-NeuroP as a mediator of the cardioprotective AAP of DHA. This discovery opens new perspectives for products of nonenzymatic oxidized ω3 polyunsaturated fatty acids as potent mediators in diseases that involve ryanodine complex destabilization such as ischemic events.
INSERM U1046-UMR 9214, Centre National de la Recherche Scientifique, Physiologie et Médecine Expérimentale du Coeur et des Muscles, Université de Montpellier, 34295 Montpellier Cedex 5, France.
Jérôme
J
Roy
Institut des Biomolécules Max Mousseron, UMR 5247, Centre National de la Recherche Scientifique, Université de Montpellier, ENSCM, Montpellier, France.
Camille
C
Oger
Institut des Biomolécules Max Mousseron, UMR 5247, Centre National de la Recherche Scientifique, Université de Montpellier, ENSCM, Montpellier, France.
Jérôme
J
Thireau
INSERM U1046-UMR 9214, Centre National de la Recherche Scientifique, Physiologie et Médecine Expérimentale du Coeur et des Muscles, Université de Montpellier, 34295 Montpellier Cedex 5, France.
Julien
J
Roussel
INSERM U1046-UMR 9214, Centre National de la Recherche Scientifique, Physiologie et Médecine Expérimentale du Coeur et des Muscles, Université de Montpellier, 34295 Montpellier Cedex 5, France.
Olivia
O
Mercier-Touzet
INSERM U1046-UMR 9214, Centre National de la Recherche Scientifique, Physiologie et Médecine Expérimentale du Coeur et des Muscles, Université de Montpellier, 34295 Montpellier Cedex 5, France; Institut des Biomolécules Max Mousseron, UMR 5247, Centre National de la Recherche Scientifique, Université de Montpellier, ENSCM, Montpellier, France.
Delinger
D
Faure
Institut des Biomolécules Max Mousseron, UMR 5247, Centre National de la Recherche Scientifique, Université de Montpellier, ENSCM, Montpellier, France.
Edith
E
Pinot
INSERM U1046-UMR 9214, Centre National de la Recherche Scientifique, Physiologie et Médecine Expérimentale du Coeur et des Muscles, Université de Montpellier, 34295 Montpellier Cedex 5, France.
Charlotte
C
Farah
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA.
Douglass F
DF
Taber
INSERM U1046-UMR 9214, Centre National de la Recherche Scientifique, Physiologie et Médecine Expérimentale du Coeur et des Muscles, Université de Montpellier, 34295 Montpellier Cedex 5, France.
Jean-Paul
JP
Cristol
School of Biological Sciences, The University of Hong Kong, Hong Kong, SAR.
Jetty C Y
JC
Lee
INSERM U1046-UMR 9214, Centre National de la Recherche Scientifique, Physiologie et Médecine Expérimentale du Coeur et des Muscles, Université de Montpellier, 34295 Montpellier Cedex 5, France.
Alain
A
Lacampagne
Institut des Biomolécules Max Mousseron, UMR 5247, Centre National de la Recherche Scientifique, Université de Montpellier, ENSCM, Montpellier, France.
Jean-Marie
JM
Galano
Institut des Biomolécules Max Mousseron, UMR 5247, Centre National de la Recherche Scientifique, Université de Montpellier, ENSCM, Montpellier, France.
Thierry
T
Durand
INSERM U1046-UMR 9214, Centre National de la Recherche Scientifique, Physiologie et Médecine Expérimentale du Coeur et des Muscles, Université de Montpellier, 34295 Montpellier Cedex 5, France. Electronic address: Jean-Yves.Le-Guennec@Inserm.Fr.
Jean-Yves
JY
Le Guennec
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000494:pharmacology* / Q000502:physiology; D006352:Heart Ventricles / Q000473:pathology; D015227:Lipid Peroxidation; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D058632:Neuroprostanes / Q000502:physiology*; D018384:Oxidative Stress; D065840:Protective Factors
D058632:Neuroprostanes; D004281:Docosahexaenoic Acids
Antiarrhythmic; Calcium; Cardioprotection; DHA; Free radicals; Neuroprostanes; Oxidative stress; Ryanodine receptor