title: Unacylated ghrelin analog prevents myocardial reperfusion injury independently of permeability transition pore.
abstract: Reperfusion injury is responsible for an important part of myocardial infarct establishment due notably to triggering cardiomyocytes death at the first minutes of reperfusion. AZP-531 is an optimized analog of unacylated ghrelin currently in clinical development in several metabolic diseases. We investigated a potential cardioprotective effect of AZP-531 in ischemia/reperfusion (IR) and the molecular underlying mechanism(s) involved in this protection. In vivo postconditioning with AZP-531 in C57BL6 mouse IR model decreased infarct size. Western blot analysis on areas at risk from the different mouse groups showed that AZP-531 activates Akt, ERK1-2 as well as S6 and 4EBP1, mTORC1 effectors. We also showed an inhibition of caspase 3 cleavage and Bax translocation to the mitochondria. AZP-531 also stimulated the expression of antioxidants and was capable of decreasing mitochondrial H2O2production, contributing to the reduction of ROS accumulation. AZP-531 exhibits cardioprotective effect when administrated for postconditioning in C57BL6 mouse IR model. Treatment with AZP-531 rescued the myocardium from cell death at early reperfusion by stimulating protein synthesis, inhibiting Bax/caspase 3-induced apoptosis as well as ROS accumulation and oxidative stress-induced necrosis. AZP-531 may prove useful in the treatment of IR injury.
authors.affiliation: CarMeN laboratory, INSERM U1060, INRA U1397, Univ Lyon, Université Claude Bernard Lyon1, Groupement Hospitalier Est, Bâtiment B13, 59 boulevard Pinel, Insa-Lyon, 69500, Bron, France. rania.harisseh@gmail.com.|IHU OPERA, Cardioprotection Laboratory, Hospices Civils de Lyon, CIC, 69500, Bron, France. rania.harisseh@gmail.com.
authors.forename: Rania
authors.initials: R
authors.lastname: Harisseh
authors.affiliation: CarMeN laboratory, INSERM U1060, INRA U1397, Univ Lyon, Université Claude Bernard Lyon1, Groupement Hospitalier Est, Bâtiment B13, 59 boulevard Pinel, Insa-Lyon, 69500, Bron, France.|IHU OPERA, Cardioprotection Laboratory, Hospices Civils de Lyon, CIC, 69500, Bron, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pillot
authors.affiliation: CarMeN laboratory, INSERM U1060, INRA U1397, Univ Lyon, Université Claude Bernard Lyon1, Groupement Hospitalier Est, Bâtiment B13, 59 boulevard Pinel, Insa-Lyon, 69500, Bron, France.|IHU OPERA, Cardioprotection Laboratory, Hospices Civils de Lyon, CIC, 69500, Bron, France.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Gharib
authors.affiliation: CarMeN laboratory, INSERM U1060, INRA U1397, Univ Lyon, Université Claude Bernard Lyon1, Groupement Hospitalier Est, Bâtiment B13, 59 boulevard Pinel, Insa-Lyon, 69500, Bron, France.|IHU OPERA, Cardioprotection Laboratory, Hospices Civils de Lyon, CIC, 69500, Bron, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Augeul
authors.affiliation: CarMeN laboratory, INSERM U1060, INRA U1397, Univ Lyon, Université Claude Bernard Lyon1, Groupement Hospitalier Est, Bâtiment B13, 59 boulevard Pinel, Insa-Lyon, 69500, Bron, France.|IHU OPERA, Cardioprotection Laboratory, Hospices Civils de Lyon, CIC, 69500, Bron, France.
authors.forename: Noelle
authors.initials: N
authors.lastname: Gallo-Bona
authors.affiliation: CarMeN laboratory, INSERM U1060, INRA U1397, Univ Lyon, Université Claude Bernard Lyon1, Groupement Hospitalier Est, Bâtiment B13, 59 boulevard Pinel, Insa-Lyon, 69500, Bron, France.|IHU OPERA, Cardioprotection Laboratory, Hospices Civils de Lyon, CIC, 69500, Bron, France.
authors.forename: René
authors.initials: R
authors.lastname: Ferrera
authors.affiliation: CarMeN laboratory, INSERM U1060, INRA U1397, Univ Lyon, Université Claude Bernard Lyon1, Groupement Hospitalier Est, Bâtiment B13, 59 boulevard Pinel, Insa-Lyon, 69500, Bron, France.|IHU OPERA, Cardioprotection Laboratory, Hospices Civils de Lyon, CIC, 69500, Bron, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Loufouat
authors.affiliation: Alizé Pharma, 69130, Ecully, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Delale
authors.affiliation: Alizé Pharma, 69130, Ecully, France.
authors.forename: Soraya
authors.initials: S
authors.lastname: Allas
authors.affiliation: Alizé Pharma, 69130, Ecully, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Abribat
authors.affiliation: CarMeN laboratory, INSERM U1060, INRA U1397, Univ Lyon, Université Claude Bernard Lyon1, Groupement Hospitalier Est, Bâtiment B13, 59 boulevard Pinel, Insa-Lyon, 69500, Bron, France.|IHU OPERA, Cardioprotection Laboratory, Hospices Civils de Lyon, CIC, 69500, Bron, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Crola Da Silva
authors.affiliation: CarMeN laboratory, INSERM U1060, INRA U1397, Univ Lyon, Université Claude Bernard Lyon1, Groupement Hospitalier Est, Bâtiment B13, 59 boulevard Pinel, Insa-Lyon, 69500, Bron, France.|IHU OPERA, Cardioprotection Laboratory, Hospices Civils de Lyon, CIC, 69500, Bron, France.|Faculté de médecine Lyon Est, Université Lyon 1, 69373, Lyon, France.|Service d'Explorations Fonctionnelles Cardiovasculaires et CIC de Lyon, Hôpital Louis Pradel, Hospices Civils de Lyon, 69677, Lyon, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Ovize
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D054439:Ghrelin / Q000031:analogs & derivatives / Q000494:pharmacology*; D057775:Ischemic Postconditioning / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*
chemical_list: D054439:Ghrelin; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C581708:cyclic des-acyl ghrelin (6-13)
keywords: Bax/Caspase 3 apoptosis; Cardiomyocyte; In vivo Ischemia–Reperfusion; Mitochondria; Oxidative stress; Unacylated ghrelin