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The Role of the Mitochondrial Permeability Transition Pore in Cardioprotection

Hendry, C; (2012) The Role of the Mitochondrial Permeability Transition Pore in Cardioprotection. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Myocardial infarction is the largest cause of morbidity and mortality worldwide. Despite optimal treatment, patients have a mortality which approaches 12% at six months. Reperfusion of the ischaemic myocardium is essential to salvage myocardium. However, reperfusion itself is harmful, with up to 40% of myocardial necrosis occurring at this time. This is known as “Lethal Reperfusion Injury”. Opening of the mitochondrial permeability transition pore (MPTP), a channel situated in the inner mitochondrial membrane is central to this process. In its quiescent state, the MPTP remains closed, but once open it becomes non-selectively permeable to solutes of up to 1.5 kDa, resulting in rapidly advancing necrotic cell death. The molecular structure of the MPTP has not yet been fully determined, although cyclophilin D (Cyp D) has been shown to be essential to its function. Genetic ablation of Cyp D has been shown to result in delayed opening of the MPTP and resistance to myocardial damage after acute ischaemia-reperfusion injury. MPTP inhibition is cardioprotective, and may be achieved by a variety of means including ischaemic pre- and post-conditioning, and by pharmacological agents. The aim of this thesis is to investigate the role of the MPTP (cyclophilin D) in cardioprotection from acute ischaemia-reperfusion injury. In chapter 4 we investigate whether it is possible to protect the heart in mice deficient of cyclophilin D by applying a stronger ischaemic preconditioning stimulus to that previously investigated in vivo. We found that there was a non-statistically significant trend towards a protective effect in cyclophilin D deficient mice which were subjected to a stronger IPC stimulus than that previously studied in vivo. Chapter 5 explores whether it is possible to protect the heart whilst avoiding the deleterious extra-cardiac effects of cyclosporin A by sub-cellular targeting of cyclosporin A (CsA) to mitochondria in the first in vivo testing of a mitochondrial-specific form of CsA (mtCsA). We demonstrated that mtCsA administered at reperfusion did not protect the heart of wild type mice from ischaemia- reperfusion. Chapter 6 examines the possibility of achieving cardioprotection independent of cyclophilin D. In this chapter, the effects of the matrix metalloproteinase inhibitor, Ilomastat, are studied. We confirmed that MMP inhibition was cardioprotective in wild type mice and also showed for the first time in vivo that administration of ilomastat can protect the heart from ischaemia- reperfusion in mice deficient in cyclophilin D. In summary our data supports the hypothesis that it is possible to protect the heart from ischaemia – reperfusion in cyclophilin D deficiency by administration of an MMP inhibitor at reperfusion. We also showed a trend towards cardioprotection in cyclophilin D deficiency by administration of an increased IPC stimulus. Together, these data may suggest that necrotic cell death may not all be mediated by the MPTP, or possibly, that the MPTP may exhibit a threshold effect which is surmountable by an increase in inhibitory action of combined pharmacology or increase in IPC stimulus.

Type: Thesis (Doctoral)
Title: The Role of the Mitochondrial Permeability Transition Pore in Cardioprotection
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
URI: http://discovery.ucl.ac.uk/id/eprint/1370643
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