Characterisation of the role of RUNX1 in the context of myocardial ischaemia-reperfusion injury

Coronary artery disease is the leading cause of death and disability worldwide and is typically caused by atherosclerotic narrowing of the coronary arteries, which impairs blood flow (ischaemia) to heart. In severe cases atherosclerotic plaques destabilise and rupture, resulting in complete occlusion of the coronary artery and progressive ischaemic necrosis (myocardial infarction, MI). The optimal treatment is to restore the patency of the coronary artery using primary percutaneous coronary intervention (PPCI) to reperfuse the ischaemic myocardium and limit necrosis. However, paradoxically, the full efficacy of PPCI is limited by additional injury initiated by reperfusion that causes cell death and contributes to contractile dysfunction. The collective injury caused by ischaemia and reperfusion, termed ischaemia-reperfusion (I/R) injury, leaves patients vulnerable to adverse cardiac remodelling and the development of heart failure, a hugely debilitating condition with high mortality rates. As such, there is a pressing, unmet need for novel therapeutic strategies that can be used as an adjunctive to reperfusion therapy to limit contractile dysfunction and adverse remodelling post-MI and prevent heart failure development. Previous work has highlighted RUNX1 as a promising therapeutic target for the management of I/R injury and adverse cardiac remodelling. RUNX1 belongs to the RUNX family of transcription factors and is upregulated in border zone cardiomyocytes following MI. Using mice with a cardiomyocyte specific deficiency in Runx1 (Runx1∆/∆ mice) it was previously shown that RUNX1 is detrimental to contractility and contributes to adverse cardiac remodelling in experimental models of MI and I/R injury. It was subsequently demonstrated that increased contractility of Runx1∆/∆ hearts at 2 weeks post-MI was explained by improved cardiomyocyte calcium handling, caused by a decrease in protein phosphatase 1 (PP1) expression, increased phosphorylation of phospholamban (PLB) and the relief of sarcoplasmic reticulum calcium ATPase (SERCA) inhibition. This thesis aimed to further investigate the role of RUNX1 in the context of myocardial I/R injury. Specifically, it aimed to study potential triggers for Runx1 mRNA that may arise in the infarct and border zone including I/R injury and stretch. It also aimed to explore whether Runx1 deficiency offers acute (