S100A1 promotes myocardial wound healing after infarction by regulating monocyte function

心肌梗塞导致功能性心肌组织的不可逆损失。它是慢性心力衰竭的主要原因。心肌细胞的缺血性坏死引发急性炎症反应，靶向驻留的心肌细胞以及心外组织如脾和骨髓。单核细胞/巨噬细胞（Mo）在受损心肌中迅速积聚，首先引发炎症并清除碎片，随后刺激瘢痕组织形成并促进血管生成。这两个阶段的特点是不同的钼表型。其准确的空间和时间顺序是伤口充分愈合的关键先决条件。然而，炎症和修复功能的失衡可能导致心肌损害扩大和心力衰竭。在我们以前的工作中，我们的特点是小钙离子结合蛋白S100 A1作为一个有利的心脏alarmin。当从坏死的心肌细胞释放时，间质S100 A1通过靶向心脏成纤维细胞瞬时触发心肌炎症。循环S100 A1在骨髓中积累并促进指示祖细胞增殖的标志物的表达。细胞外S100 A1的中和导致小鼠心肌梗死后心肌伤口愈合受损和左心室功能恶化。基于我们的初步结果，该建议旨在验证细胞外S100 A1通过调节Mo功能来响应心肌梗死而协调心脏组织修复的假设。拟议的研究可能有助于未来治疗策略的发展，旨在优化受损心肌的愈合，以预防慢性心力衰竭。

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.