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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.

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Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France. Electronic address:
Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France.
IBMM, CNRS UMR 5247, Université de Montpellier, ENSCM, Montpellier, France.
INM, INSERM U1051, Université de Montpellier, CHUS Eloi, Montpellier, France.
The University of Hong Kong, School of Biological Sciences, Hong Kong SAR.


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.


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

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