Inhibition of Wnt signaling in monocytes and its possible role for healing in acute myocardial infarction.

• Applicant: Professor Dr. Florian Leuschner
• Subject Area: Cardiology, Angiology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413533441

Myocardial infarction elicits a sterile immune response that impacts healing and subsequent ventricular function. Monocytes are key players in this inflammatory process. While our understanding of systemic activation of monocytes following cardiac injury has substantially grown in recent years, little is known about the impact of the cardiac microenvironment on these accumulating leukocytes. We have identified a novel role for Wnt signaling in local activation of monocytes and describe cardiomyocyte-secreted Wnt-Inhibitory Factor 1 (WIF1) as a crucial modulator of this process. We now aim to (1) evaluate the effect of systemic administration of recombinant WIF1 and (2) monocyte-specific inhibition of non-canonical Wnt signaling on healing after myocardial infarction. We also aim to further elucidate the impact of Wnt proteins secreted from cardiomyocytes on accumulating monocytes and cardiac healing. To this end, we will analyze (3) small molecule mediated inhibition of Wnt secretion and (4) transgenic mice with an inducible cardiomyocyte-specific deletion of Evi, a receptor essential for the secretion of Wnt molecules. Taken together, the goal of these investigations is to advance our understanding of Wnt signaling following cardiac injury and to identify novel approaches for the modulation of myeloid cell activation to improve healing after myocardial infarction.

• DFG Programme: Research Grants