Non-enzymatic oxidized metabolite of DHA, 4(RS)-4-F-neuroprostane protects the heart against reperfusion injury.
Free Radic Biol Med. 2017 01 ;102:229-239. Epub 2016 Dec 5. PMID: 27932075
Acute myocardial infarction leads to an increase in oxidative stress and lipid peroxidation. 4(RS)-4-F-Neuroprostane (4-F-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-F-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-F-NeuroP significantly decreased infarct size following reperfusion (-27%) and also reduced ventricular arrhythmia score considerably during reperfusion (-41%). Most notably, 4-F-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 Caby 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-F-NeuroP prevented reperfusion damages and reduced apoptosis. In conclusion, 4-F-NeuroP derived from DHA was able to protect I/R cardiac injuries by regulating the mitochondrial homeostasis.