title: Mitochondrial permeability transition in cardiac ischemia-reperfusion: whether cyclophilin D is a viable target for cardioprotection?
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.
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR 00936-5067, Puerto Rico. sabzali.javadov@upr.edu.
authors.forename: Sabzali
authors.initials: S
authors.lastname: Javadov
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR 00936-5067, Puerto Rico.
authors.forename: Sehwan
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR 00936-5067, Puerto Rico.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Parodi-Rullán
authors.affiliation: Cincinnati Children's Research Foundation, University of Cincinnati, 240 Albert Sabin Way, Cincinnati, OH, 54229, USA.
authors.forename: Zaza
authors.initials: Z
authors.lastname: Khuchua
authors.affiliation: Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kuznetsov
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055808:Drug Discovery; D004734:Energy Metabolism / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D058990:Molecular Targeted Therapy; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D021983:Cyclophilins; D002118:Calcium
keywords: Cardioprotection; Cyclophilin D; Ischemia–reperfusion injury; Mitochondrial permeability transition pores; Oxidative stress