Grant: Project Grant

Ischemic heart disease leading to myocardial infarction (MI, heart attack) is a leading cause of death worldwide. Although many patients reach hospitals in a timely manner and undergo post-ischemia reperfusion (mI/R), this triggers a profound inflammatory response termed "reperfusion injury" leading to infarct expansion and adverse cardiac remodelling. Studies using broad approaches to reduce inflammation fail to show clinical effectiveness because they act on both beneficial and deleterious immune pathways involved in infarct healing. Specific targets are needed instead. We recently showed that the circadian system is an important mechanism regulating immunocyte recruitment to infarcted myocardium. However, direct targeting of the circadian mechanism to reduce reperfusion injury and benefit treatment of clinically relevant mI/R has not yet been pursued, in large part because we lacked the pharmacology to do so. In this grant we will investigate direct pharmacological targeting of the circadian mechanism factor REV-ERB to reduce reperfusion injury and benefit healing after mI/R in murine models. We will use genetic circadian models to investigate the specificity of this approach. We will also demonstrate that this strategy is vital using a pre-clinical model and state-of-the-art imaging relevant to humans. This is a unique and direct pharmacological approach to limit infarct expansion and remodelling after mI/R, can be given alongside conventional therapies, and is effective for improving outcomes.