Non-enzymatic oxidized metabolite of DHA, 4(RS)-4-F 4t-neuroprostane protects the heart against reperfusion injury

Free Radic Biol Med. 2017 Jan;102:229-239. doi: 10.1016/j.freeradbiomed.2016.12.005. Epub 2016 Dec 5.

Abstract

Acute myocardial infarction leads to an increase in oxidative stress and lipid peroxidation. 4(RS)-4-F4t-Neuroprostane (4-F4t-NeuroP) is a mediator produced by non-enzymatic free radical peroxidation of the cardioprotective polyunsaturated fatty acid, docosahexaenoic acid (DHA). In this study, we investigated whether intra-cardiac delivery of 4-F4t-NeuroP (0.03mg/kg) prior to occlusion (ischemia) prevents and protects rat myocardium from reperfusion damages. Using a rat model of ischemic-reperfusion (I/R), we showed that intra-cardiac infusion of 4-F4t-NeuroP significantly decreased infarct size following reperfusion (-27%) and also reduced ventricular arrhythmia score considerably during reperfusion (-41%). Most notably, 4-F4t-NeuroP decreased ventricular tachycardia and post-reperfusion lengthening of QT interval. The evaluation of the mitochondrial homeostasis indicates a limitation of mitochondrial swelling in response to Ca2+ by decreasing the mitochondrial permeability transition pore opening and increasing mitochondria membrane potential. On the other hand, mitochondrial respiration measured by oxygraphy, and mitochondrial ROS production measured with MitoSox red® were unchanged. We found decreased cytochrome c release and caspase 3 activity, indicating that 4-F4t-NeuroP prevented reperfusion damages and reduced apoptosis. In conclusion, 4-F4t-NeuroP derived from DHA was able to protect I/R cardiac injuries by regulating the mitochondrial homeostasis.

Keywords: Cardioprotection; Ischemia/reperfusion, n-3 polyunsaturated fatty acids; Mitochondria; Neuroprostanes; mPTP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Docosahexaenoic Acids / administration & dosage*
  • Docosahexaenoic Acids / metabolism
  • Heart / drug effects
  • Heart / physiopathology
  • Humans
  • Lipid Peroxidation / genetics
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / pathology
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / physiopathology
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Neuroprostanes / administration & dosage*
  • Oxidative Stress / genetics
  • Protective Agents / administration & dosage
  • Rats
  • Reactive Oxygen Species / metabolism
  • Tachycardia, Ventricular / drug therapy
  • Tachycardia, Ventricular / metabolism
  • Tachycardia, Ventricular / pathology

Substances

  • Neuroprostanes
  • Protective Agents
  • Reactive Oxygen Species
  • Docosahexaenoic Acids