Role of the MPTP in conditioning the heart - translatability and mechanism.

S‐B Ong,H A Cabrera‐Fuentes,R K Dongworth,D J Hausenloy

doi:10.1111/bph.13013

Abstract

Mitochondria have long been known to be the gatekeepers of cell fate. This is particularly so in the response to acute ischaemia‐reperfusion injury (IRI). Following an acute episode of sustained myocardial ischaemia, the opening of the mitochondrial permeability transition pore (MPTP) in the first few minutes of reperfusion, mediates cell death. Preventing MPTP opening at the onset of reperfusion using either pharmacological inhibitors [such as cyclosporin A (CsA) ] or genetic ablation has been reported to reduce myocardial infarct (MI) size in animal models of acute IRI. Interestingly, the endogenous cardioprotective intervention of ischaemic conditioning, in which the heart is protected against MI by applying cycles of brief ischaemia and reperfusion to either the heart itself or a remote organ or tissue, appears to be mediated through the inhibition of MPTP opening at reperfusion. Small proof‐of‐concept clinical studies have demonstrated the translatability of this therapeutic approach to target MPTP opening using CsA in clinical settings of acute myocardial IRI. However, given that CsA is a not a specific MPTP inhibitor, more novel and specific inhibitors of the MPTP need to be discovered – the molecular identification of the MPTP should facilitate this. In this paper, we review the role of the MPTP as a target for cardioprotection, the potential mechanisms underlying MPTP inhibition in the setting of ischaemic conditioning, and the translatability of MPTP inhibition as a therapeutic approach in the clinical setting.Linked ArticlesThis article is part of a themed section on Conditioning the Heart – Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐8

Highlights

The mitochondria are crucial determinants of cardiomyocyte fate following an episode of acute myocardial ischaemiareperfusion injury (IRI)
A more recent study has suggested that glycogen synthase kinase (GSK)-3β inhibition, allows the dephosphorylation of the outer mitochondrial membrane (OMM) protein, voltage-dependent anion channel (VDAC), which prevents the entry of adenine nucleotides into mitochondria, which would be expected to facilitate mitochondrial depolarization and reduce mitochondrial calcium accumulation and reactive oxygen species (ROS) production during myocardial ischaemia thereby preventing mitochondrial permeability transition pore (MPTP) opening at the time of reperfusion (Das et al, 2008)
We have recently found that administering a single dose of cyclosporin A (CsA) prior to coronary artery bypass graft (CABG) surgery reduced the extent of perioperative myocardial injury (PMI) in CABG surgery patients (Hausenloy et al, 2014)

Summary

Tables of Links

These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http:// www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al, 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (a,b,cAlexander et al, 2013a,b,c)

Introduction

Findings

Summary and conclusions