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

Non-enzymatic oxidized metabolite of DHA, 4(RS)-4-F4t-neuroprostane protects the heart against reperfusion injury.

Author information

1
Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France. Electronic address: jerome.roy1902@gmail.com.
2
Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France.
3
IBMM, CNRS UMR 5247, Université de Montpellier, ENSCM, Montpellier, France.
4
INM, INSERM U1051, Université de Montpellier, CHUS Eloi, Montpellier, France.
5
The University of Hong Kong, School of Biological Sciences, Hong Kong SAR.

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

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