Investigation of mitochondrial targets for cardioprotection

• Main Author: Dongworth, R. K.
• Published: University College London (University of London) 2013
• Subjects: 616.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.626494

Background Novel therapeutic strategies are required to protect the myocardium against ischaemia- reperfusion injury. Mitochondria are fundamental for the maintenance of cell function and survival in this setting. Although a number of mitochondrial therapeutic targets have been identified, their cardioprotective efficacy in vivo remains unknown. Methods and Results This thesis describes the establishment and validation of an important in vivo murine model of ischaemia-reperfusion injury for the first time within our laboratory. This model was used to investigate the cardioprotective potential of modulating three mitochondrial proteins. In addition, this thesis investigates the use of a novel cardiac MRI sequence to quantify myocardial area-at-risk, an essential pre-requisite for assessing the cardioprotective efficacy of therapeutic interventions. Cyclophilin-D: Cyp-D has been implicated as a critical regulator of cell death by mitochondrial permeability transition pore opening upon ischaemia-reperfusion. Cyp-D genetic ablation evoked cardioprotection against myocardial ischaemia-reperfusion following extended reperfusion; thereby confirming the protective efficacy of this target. Sirtuin-3: Post-translational protein deacetylation by Sirt-3 is an important regulator of mitochondrial biology and cell survival. Sirt-3 genetic ablation did not affect the susceptibility to myocardial infarction upon ischaemia-reperfusion under normal conditions. Fasting-induced Sirt-3 overexpression increased myocardial infarct size; thereby suggesting that Sirt-3 inhibition may be protective under certain conditions. DJ-1: Preservation of mitochondrial function upon oxidative stress by the diverse actions of DJ-1 is critical for cell survival upon cerebral ischaemia-reperfusion. DJ-1 genetic ablation caused increased mitochondrial fragmentation but did not adversely affect cardiac function. DJ-1 knockout mice were more susceptible to myocardial infarction suggesting that this may represent an important target for cardioprotection. Conclusions This thesis confirms the role for CypD as an important target for cardioprotection, and provides experimental evidence implicating Sirt-3 and DJ-1 as novel mitochondrial targets for protecting the heart against ischaemia-reperfusion injury. We also provide initial data that arterial spin labelling cardiac MRI may be an important tool for the future assessment of novel cardioprotective interventions.