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Mitochondrial permeability transition in cardiac ischemia–reperfusion: whether cyclophilin D is a viable target for cardioprotection?

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Abstract

Growing number of studies provide strong evidence that the mitochondrial permeability transition pore (PTP), a non-selective channel in the inner mitochondrial membrane, is involved in the pathogenesis of cardiac ischemia–reperfusion and can be targeted to attenuate reperfusion-induced damage to the myocardium. The molecular identity of the PTP remains unknown and cyclophilin D is the only protein commonly accepted as a major regulator of the PTP opening. Therefore, cyclophilin D is an attractive target for pharmacological or genetic therapies to reduce ischemia–reperfusion injury in various animal models and humans. Most animal studies demonstrated cardioprotective effects of PTP inhibition; however, a recent large clinical trial conducted by international groups demonstrated that cyclosporine A, a cyclophilin D inhibitor, failed to protect the heart in patients with myocardial infarction. These studies, among others, raise the question of whether cyclophilin D, which plays an important physiological role in the regulation of cell metabolism and mitochondrial bioenergetics, is a viable target for cardioprotection. This review discusses previous studies to provide comprehensive information on the physiological role of cyclophilin D as well as PTP opening in the cell that can be taken into consideration for the development of new PTP inhibitors.

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Abbreviations

ANT:

Adenine nucleotide translocase

CRC:

Ca2+ retention capacity

CsA:

Cyclosporine A

CypD:

Cyclophilin D

ETC:

Electron transport chain

FAO:

Fatty acid oxidation

Hsp60:

Heat-shock protein 60

IFM:

Interfibrillar mitochondria

IMM:

Inner mitochondrial membrane

IR:

Ischemia–reperfusion

KO:

Knockout

ΔΨm :

Mitochondrial membrane potential

MEFs:

Mouse embryonic fibroblasts

MI:

Myocardial infarction

mtDNA:

Mitochondrial DNA

NO:

Nitric oxide

PCI:

Percutaneous coronary intervention

Pi :

Inorganic phosphate

PiC:

Phosphate carrier

PPARα:

Peroxisome proliferator-activated receptor alpha

PPIase:

Peptidyl-prolyl cis-trans isomerase

Ppif :

CypD gene

PTM:

Post-translational modification

PTP:

Permeability transition pore

ROS:

Reactive oxygen species

SfA:

Sanglifehrin A

SPG7:

Spastic paraplegia 7

SSM:

Subsarcolemmal mitochondria

TCA:

Tricarboxylic acid

TRAP1:

Tumor necrosis factor receptor-associated protein 1

VDAC:

Voltage-dependent anion channel

WT:

Wild type

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Acknowledgements

The authors apologize that they could not cite all important studies in this field due to space restriction. This study was supported by the NHLBI NIH Grants SC1HL118669 (to SJ).

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR 00936-5067, Puerto Rico

    Sabzali Javadov, Sehwan Jang & Rebecca Parodi-Rullán

  2. Cincinnati Children’s Research Foundation, University of Cincinnati, 240 Albert Sabin Way, Cincinnati, OH, 54229, USA

    Zaza Khuchua

  3. Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria

    Andrey V. Kuznetsov

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  1. Sabzali Javadov
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Javadov, S., Jang, S., Parodi-Rullán, R. et al. Mitochondrial permeability transition in cardiac ischemia–reperfusion: whether cyclophilin D is a viable target for cardioprotection?. Cell. Mol. Life Sci. 74, 2795–2813 (2017). https://doi.org/10.1007/s00018-017-2502-4

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