The regulation of inflammation in ventricular remodelling after myocardial infarction

Heart failure (HF) is when the heart is unable to pump with enough force to meet the demands of the body. It frequently results from a heart attack (myocardial infarction or MI) causing impaired heart function. Despite current treatments, HF after MI causes significant morbidity and mortality. Inflammation, the body's response to harmful stimuli that is largely mediated by circulating white blood cells, is an important response to MI. However, there is compelling evidence implicating excessive inflammation in the development of post-MI HF. Certain types of inflammatory cells, called monocytes and macrophages, appear especially important. Blocking the influx of monocytes and macrophages after MI may prevent HF. This project aims to study the behaviour and molecular signalling of these cells after MI by manipulating a molecule called Nrf2, which is known to mitigate inflammation after a heart attack. It is hoped that these studies will identify new treatment targets with the ultimate aim of developing new ways of treating patients after MI to alleviate the development of HF.

Despite timely reperfusion, myocardial infarction (MI) is the commonest cause of heart failure (HF). MI results in ventricular remodelling, which is characterised by ventricular dilatation and progressive functional deterioration. This early adverse remodelling, over weeks, sets the scene for longer-term HF, and mortality for such patients remains high. Inflammation after MI is vital to activate reparative mechanisms and the balance between inflammatory and reparative leucocyte subsets appears crucial as there is compelling evidence implicating excessive inflammation in remodelling. scRNA-seq studies have identified cardiac resident subsets as important mediators of the inflammatory response to cardiac injury, but it is not clear how signalling in these cells is regulated.

Impeding excessive leucocyte recruitment to the infarct zone in the inflammatory phase and/or promoting a switch to reparative phenotypes (proliferative phase) can mitigate adverse ventricular remodelling, with the timing of such intervention likely to be critical. The transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) impedes transcriptional upregulation of pro-inflammatory cytokines and its deletion enhances inflammation in various murine models. Recent data suggest that Nrf2 expression, possibly in cardiac resident macrophages, may play an important role after MI, but its precise functions are unknown. Importantly, studies suggest the timing of Nrf2 expression is crucial, with most indicating a protective effect acutely but harmful consequences at later timepoints, although the timing and mechanism of this switch is not known.

This project aims to delineate signalling in leucocytes after MI using models of Nrf2 loss-of-function and gain-of-function. Taken together, these studies will provide invaluable knowledge on the regulation of inflammation after MI and will identify potential therapeutic targets to alleviate progression to HF.