Rossello Lozano, Francisco Javier; (2017) The role of PI3Kα in cardioprotection. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

BACKGROUND: Ischaemic preconditioning (IPC) is an endogenous cardioprotective phenomenon, which can limit infarct size following ischaemia-reperfusion injury (IRI) through the activation of intracellular signalling pathways, such as the PI3K kinase cascade. Little is known about the individual roles of PI3K isoforms in IRI. This thesis aimed to elucidate the role of PI3Kα in cardioprotection. METHODS AND RESULTS. Initial studies focussed on establishing the Langendorff-perfused isolated heart model of mouse IRI, and the relative contribution of different lengths of ischemia and reperfusion to myocardial infarction was rigorously determined. The PI3K signalling cascade and its interaction with other pathways were also dissected before evaluating the role of PI3Kα. PI3Kα was shown to be critical in mediating IPC-induced heart protection against IRI. Using the ex vivo model of myocardial infarction, we showed that PI3Kα is required during the IPC reperfusion phase to reduce myocardial infarct size, whilst not mediating the effect during the trigger phase. These findings were confirmed in an in vivo setting. Using insulin as a canonical activator of PI3K, we also demonstrated that this isoform is not only necessary for IPC to confer cardioprotection, but sufficient for its specific activator to promote myocardial salvage against IRI. PI3Kα activation mediates its effect through the end-effector namely the mitochondrial permeability transition pore, as demonstrated by delaying its opening in primary isolated cardiomyocytes. Importantly, the PI3Kα protein levels are comparable between mouse and human heart tissue, and its activation can be modulated in both tissues. These last observations highlights the potential ability of PI3Kα to be translated into the clinical setting. CONCLUSIONS. These studies have clearly demonstrated that PI3Kα plays a crucial role at reperfusion. This suggests that strategies specifically enhancing the α isoform of PI3K, at reperfusion, could provide a direct target for clinical treatment of IRI.

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