Using Small Molecule Inhibitors to Modulate Wound Healing to Improve Outcomes Following Myocardial Infarction

Keywords: Tissue disease and repair; molecular pathology, ageing and disease, animal models of disease, in vivo imaging, quantitative techniques
Abstract: Ageing increases the risk of myocardial infarction and heart failure. In particular, adverse left ventricular remodelling following acute myocardial infarction (MI) leads to an increased risk of heart failure. In the UK, increased success at opening up the occluded coronary vessel in patients with an acute MI has meant that more patients survive the acute phase, but the numbers of patients living with heart failure is growing. From the available data including the pioneering work of the Nahrendorf laboratory (Harvard), we propose that modulation of wound healing in infarcted myocardium can reduce adverse remodelling and reduce the risk of progression to heart failure. Following MI, circulating monocytes migrate into the injured myocardium, where they differentiate to pro-inflammatory and pro-fibrotic macrophages. It is known that some components of the macrophage response are beneficial whereas others are detrimental. Because of the complexities of the cardiac injury and repair process, we will use a whole organism (mouse) model of MI to investigate the novel hypothesis that targeting selected detrimental macrophage responses with small molecule inhibitors will lead to improved cardiac function. To do this, we will use specific molecular chemokine antagonists in vivo to block initial monocyte recruitment to the injured heart. Importantly we have already shown these inhibitors block monocyte recruitment using in vitro assays. Based on our knowledge of the timing of this process and our established whole organism (mouse) models of myocardial infarction, we will use a temporal approach to optimise the timing of drug delivery to maximise the repair process. We anticipate that this approach will reduce the number of damaging inflammatory macrophage immediately following MI and improve cardiac function in the longer term. Parallel work in vitro will test whether humanised versions of these small molecule inhibitors will also block recruitment of human monocytes in cell adherence and migration assays. The outcomes of this studentship will enhance our understanding of the contribution of recruited monocytes to the healing response following MI. In the longer term this will inform improved strategies to modulate the immune response following MI to achieve optimum wound healing in patients and reduce the risk of progression to heart failure in our ageing population