title: Non-enzymatic oxidized metabolite of DHA, 4(RS)-4-F4t-neuroprostane protects the heart against reperfusion injury.
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.
authors.affiliation: Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France. Electronic address: jerome.roy1902@gmail.com.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Roy
authors.affiliation: Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Fauconnier
authors.affiliation: IBMM, CNRS UMR 5247, Université de Montpellier, ENSCM, Montpellier, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Oger
authors.affiliation: Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Farah
authors.affiliation: INM, INSERM U1051, Université de Montpellier, CHUS Eloi, Montpellier, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Angebault-Prouteau
authors.affiliation: Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thireau
authors.affiliation: Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Bideaux
authors.affiliation: Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Scheuermann
authors.affiliation: IBMM, CNRS UMR 5247, Université de Montpellier, ENSCM, Montpellier, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bultel-Poncé
authors.affiliation: Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Demion
authors.affiliation: IBMM, CNRS UMR 5247, Université de Montpellier, ENSCM, Montpellier, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Galano
authors.affiliation: IBMM, CNRS UMR 5247, Université de Montpellier, ENSCM, Montpellier, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Durand
authors.affiliation: The University of Hong Kong, School of Biological Sciences, Hong Kong SAR.
authors.forename: Jetty Chung-Yung
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Inserm U1046 - UMR CNRS 9214 PHYMEDEX, Université de Montpellier, Montpellier, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Guennec
mesh_terms: D000818:Animals; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D058632:Neuroprostanes / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000235:genetics; D020011:Protective Agents / Q000008:administration & dosage; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D058632:Neuroprostanes; D020011:Protective Agents; D017382:Reactive Oxygen Species; D004281:Docosahexaenoic Acids
keywords: Cardioprotection; Ischemia/reperfusion, n-3 polyunsaturated fatty acids; Mitochondria; Neuroprostanes; mPTP