The role of the mitochondrial permeability transition pore in myocardial protection.

Background- With coronary artery disease set to become the world's leading cause of mortality by 2020, there is an urgent requirement for novel treatment strategies which protect the myocardium against ischaemia-reperfusion injury, in order that patient morbidity and mortality can be improved and the global burden of this disease can be alleviated. This thesis examined the role of the mitochondrial permeability transition pore (mPTP) as a novel target for two major strategies for myocardial protection: (1) Interventions applied at the time of reperfusion, which protect the heart against lethal reperfusion injury, and (2) Myocardial Preconditioning, a process which renders the myocardium more resistant to subsequent ischaemia-reperfusion injury. Methods and Results- Using an isolated perfused rat model of ischaemia-reperfusion injury, we demonstrated that the opening of the mPTP at the time of reperfusion is a critical determinant of myocyte death, and we have shown that inhibiting its opening, by administering pharmacological agents at the time of reperfusion, is cardio-protective. Using experimental models for inducing and detecting mPTP opening in adult rat mitochondria and myocytes, we demonstrated that myocardial preconditioning protects the heart by inhibiting mPTP opening, and that the pro-survival kinases Akt and Erk1/2, may act to mediate the preconditioning- induced inhibition of mPTP opening at the time of reperfusion. Finally, we found that the mPTP may also act as a mediator of the preconditioning signal. In this scenario, transient (low- conductance) opening of the mPTP, which does not lead to cell death, may paradoxically contributed to protective mechanisms recruited by myocardial preconditioning and mitochondrial-uncoupling, indicating a dual role for the mPTP in myocardial preconditioning. Conclusion- We have demonstrated that inhibiting the opening of the mitochondrial permeability transition pore at the time of reperfusion, presents a common target for myocardial protection, irrespective of whether protection is mediated by myocardial preconditioning or by interventions applied solely at the time of reperfusion. Therefore, interventions which target and inhibit mPTP opening, at the time of reperfusion, may improve morbidity and mortality from coronary artery disease, in the clinical settings of ischaemia-reperfusion injury such as thrombolysis following an acute myocardial infarction, heart surgery and percutaneous transluminal coronary angioplasty. Furthermore, we found that transient (low-conductance) opening of the mPTP mediates both preconditioning and mitochondrial uncoupling-induced protection by acting as a channel for the mitochondrial release of reactive oxygen species.