S100A1 promotes myocardial wound healing after infarction by regulating monocyte function

• Applicant: Dr. David Rohde
• Subject Area: Cardiology, Angiology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 275166481

Myocardial infarction results in the irreversible loss of functional heart muscle tissue. It is the leading cause of chronic heart failure. Ischemic necrosis of cardiomyocytes initiates an acute inflammatory reaction, targeting resident myocardial cells as well as extra-cardiac tissues like spleen and bone marrow. Monocytes/macrophages (Mo) rapidly accumulate in the injured myocardium, first triggering inflammation and removing debris, later stimulating scar tissue formation and promoting angiogenesis. Both phases are characterized by distinct Mo phenotypes. Their accurate spatial and temporal sequence represents a critical prerequisite for adequate wound healing. However, imbalance of inflammatory and reparative Mo functions may lead to expanded myocardial damage and heart failure. In our previous work, we have characterized the small Ca2+-binding protein S100A1 as a favourable cardiac alarmin. Upon release from necrotic cardiomyocytes, interstitial S100A1 transiently triggers myocardial inflammation by targeting cardiac fibroblasts. Circulating S100A1 accumulates in bone marrow and prompts expression of markers indicating progenitor cell proliferation. Neutralization of extracellular S100A1 results in impaired myocardial wound healing and worsened left ventricular function after infarction in mice. Based on our preliminary results, this proposal is designed to test the hypothesis that extracellular S100A1 orchestrates cardiac tissue repair by regulating Mo function in response to myocardial infarction. The proposed research could potentially contribute to the development of future therapeutic strategies, aiming at optimized healing of injured myocardium in order to prevent chronic heart failure.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Matthias Nahrendorf