Résumé
The cardioprotective effects through prevention of cardiac arrhythmias of long-chain polyunsaturated fatty acids of the n-3 series (PUFAs) have been demonstrated over the last 40 years. The main n-3 PUFAs are eicosapentaenoic acid (C20:5 n-3, EPA) and docosahexaenoic acid (C22:6 n-3, DHA) and both are highly peroxidable due to the presence of skipped dienes. The effects of n-3 PUFAs on cardiac function are controversial, notably due to lack of information on the mechanisms involved. Particularly, it is not well understood which is the active lipid: the PUFA or one of its oxygenated metabolites. Neuroprostanes are lipid mediators produced by non-enzymatic free radical peroxidation of DHA. Plasmatic 4(RS)-4-F4t-NeuroP concentration is negatively correlated with the risk of atherosclerosis suggesting a beneficial active role in some cardiovascular disease. In this study, we show that oxidized DHA and more specifically the isomers 4(RS)-4-F4t-NeuroP possess strong anti-arrhythmic properties (AAP) in isolated ventricular cardiomyocytes and in vivo in post-myocardial infarcted mice. Calcium imaging and biochemical experiments indicate that arrhythmias are associated with Ca2+ leak from the sarcoplasmic reticulum following oxidation and phosphorylation of the type 2 ryanodine receptor (RyR2) leading to dissociation of the FKBP12.6/ RyR2 complex. DHA per se has no AAP. Oxidized DHA as well as 4(RS)-4- F4t-NeuroP prevented posttranslational modifications of the RyR2 and stabilized the complex FKBP12.6/RyR2 to normalize Ca2+. This effect of 4(RS)- 4-F4t-NeuroP was further associated with the suppression in vitro and in vivo of cardiac arrhythmias. Our findings, demonstrates 4(RS)-4-F4t-NeuroP as a mediator of the AAP that exerts cardioprotective characteristics of DHA.