Unacylated ghrelin analog prevents myocardial reperfusion injury independently of permeability transition pore

http://crossmark.crossref.org/dialog/?doi=10.1007/s00395-016-0595-9&domain=pdf

Web End = Basic Res Cardiol (2017) 112:4 DOI 10.1007/s00395-016-0595-9

http://crossmark.crossref.org/dialog/?doi=10.1007/s00395-016-0595-9&domain=pdf

Web End = ORIGINAL CONTRIBUTION

Unacylated ghrelin analog prevents myocardial reperfusion injury independently of permeability transition pore

Rania Harisseh1,2 Bruno Pillot1,2 Abdallah Gharib1,2 Lionel Augeul1,2

Noelle Gallo-Bona1,2 Ren Ferrera1,2 Joseph Loufouat1,2 Thomas Delale5

Soraya Allas5 Thierry Abribat5 Claire Crola Da Silva1,2 Michel Ovize1,2,3,4

Received: 20 April 2016 / Accepted: 9 December 2016 / Published online: 19 December 2016 Springer-Verlag Berlin Heidelberg 2016

Abstract Reperfusion injury is responsible for an important part of myocardial infarct establishment due notably to triggering cardiomyocytes death at the rst 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

H2O2 production, 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.

Keywords In vivo IschemiaReperfusion Bax/Caspase 3

apoptosis Oxidative stress Cardiomyocyte

Mitochondria Unacylated ghrelin

Introduction

Over the last decades, there has been major progress in the management of acute myocardial infarction (AMI) patients resulting in a signicant reduction of cardiovascular mortality and morbidity [39]. Mortality, heart failure, and recurrent ischemic events remain, however, unacceptably frequent in the post-infarction period [35]. Experimental evidence indicates that the nal damage to the heart is not only related to the ischemic insult, but also to an irreversible injury that occurs after reow, namely, reperfusion injury [6]. While much progress has been done to re-open the culprit coronary artery and prevent its re-occlusion (i.e., to treat ischemia injury),...