Nonenzymatic lipid mediators, neuroprostanes, exert the antiarrhythmic properties of docosahexaenoic acid

Free Radic Biol Med. 2015 Sep;86:269-78. doi: 10.1016/j.freeradbiomed.2015.04.014. Epub 2015 Apr 21.

Abstract

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.

Keywords: Antiarrhythmic; Calcium; Cardioprotection; DHA; Free radicals; Neuroprostanes; Oxidative stress; Ryanodine receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / metabolism
  • Calcium Signaling
  • Cells, Cultured
  • Docosahexaenoic Acids / pharmacology*
  • Docosahexaenoic Acids / physiology
  • Heart Ventricles / pathology
  • Lipid Peroxidation
  • Male
  • Mice, Inbred C57BL
  • Myocardial Infarction / metabolism
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Neuroprostanes / physiology*
  • Oxidative Stress
  • Protective Factors

Substances

  • Neuroprostanes
  • Docosahexaenoic Acids