Macrophage ferroptosis in myocardial infarction
Acute myocardial infarction (MI) and the subsequent development of heart failure (HF) remain leading causes of global morbidity and mortality. Despite advances in therapy, the incidence of post-MI HF remains unacceptably high. This highlights an urgent need for novel strategies that reduce infarct size and prevent adverse cardiac remodelling. MI-induced ischemia results in extensive cell death, forming a necrotic core surrounded by an area at risk that delineates damaged from viable myocardium. While considerable progress has been made in understanding cardiomyocyte (CM) death, the role of innate immune cell death under hypoxic conditions and its impact on remodelling trajectories of damaged tissue has been relatively overlooked. Our recent work demonstrated that CM necrosis during MI is mediated by ferroptosis, consistent with reports that ferroptosis inhibitors reduce myocardial injury, limit infarct size, and preserve cardiac function. Thus, pharmacological inhibition of ferroptosis following MI presents a promising therapeutic avenue. However, translation to clinical settings remains challenging due to emerging evidence of context-dependent effects of ferroptosis within the complex tissue microenvironment. We build our objectives based on the hypothesis that regulation of ferroptosis during MI represents a crucial point with a dichotomous face - while excessive CM ferroptosis leads to detrimental tissue necrosis, ferroptosis suppression could interfere with beneficial innate immune responses. Therefore, we will investigate how ferroptosis influences survival and activation of innate immune cells, especially macrophages, and how it shapes the overall innate immune response at the different post-MI phases, aiming to provide new insights into the pathophysiology of myocardial infarction and enable precision therapeutic interventions. A spatial molecular map of the injured myocardium will provide functional insights into the identity of various cell types and their susceptibility to ferroptotic cell death across the different post-MI phases (invasive, destructive, reparative). Cell-(sub)type-resolved lipotyping will be integrated with mechanistic studies of ferroptosis regulation in distinct macrophage subsets, including pro- and anti-inflammatory populations. Translationally, the impact of macrophage-targeted modulation of ferroptosis on post-MI cardiac outcomes will be testedin a murine MI model. Altogether, it will allow to establish the “window of opportunity” for the application of ferroptosis inhibitors as pharmacological strategy in patients with acute MI.
Participating persons
Applicants
Professorin Maria Fedorova Ph.D. • Dresden TU, Centre for Membrane Biochemistry and Lipid Research
Professor Dr. Andreas Linkermann • Dresden TU, Nephrology
Dr. Wulff Tonnus • Dresden TU, Nephrology