title: Cyclosporin A and cardioprotection: from investigative tool to therapeutic agent.
abstract: Ischaemic heart disease (IHD) is the leading cause of death and disability worldwide. The pathophysiological effects of IHD on the heart most often result from the detrimental effects of acute ischaemia-reperfusion injury (IRI) on the myocardium. Therefore, novel therapeutic targets for protecting the myocardium against acute IRI are required to reduce injury to the heart, preserve cardiac function and improve clinical outcomes in patients with IHD. In this regard, the mitochondrial permeability transition pore (mPTP) has emerged as a critical target for cardioprotection which is readily amenable to intervention at the time of myocardial reperfusion. The formation and opening of the mPTP at the onset of myocardial reperfusion is a major determinant of mitochondrial dysfunction and cardiomyocyte death in the setting of acute IRI. The seminal discovery in the late 1980s that mPTP opening could be pharmacologically inhibited by the immunosuppressive agent, cyclosporin A (CsA), has been fundamental in the elucidation of the critical role of the mPTP as a mediator of acute IRI and, therefore, a viable target for cardioprotection. Its initial role as an investigative tool was used to identify mitochondrial cyclophilin D to be a regulatory component of the mPTP. The mPTP as a viable target for cardioprotection has recently been translated into the clinical setting with CsA reducing myocardial infarct size in patients. In this article, we review the intriguing role of CsA as a tool for investigating the mPTP as a target for cardioprotection and its potential role as a therapeutic agent for patients with IHD.
authors.affiliation: The Hatter Cardiovascular Institute, University College London Hospital & Medical School, London, UK. d.hausenloy@ucl.ac.uk
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Hausenloy
authors.forename: E A
authors.initials: EA
authors.lastname: Boston-Griffiths
authors.forename: D M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine