S100A1 promotes myocardial wound healing after infarction by regulating monocyte function

心肌梗死会导致功能性心肌组织不可逆转的丧失。它是慢性心力衰竭的主要原因。心肌细胞的缺血性坏死会引发急性炎症反应，以常驻心肌细胞以及心外组织如脾和骨髓为靶点。单核/巨噬细胞(Mo)在受损心肌中迅速聚集，首先引发炎症和清除碎片，然后刺激疤痕组织形成和促进血管生成。这两个相都具有不同的Mo表型。它们准确的空间和时间序列是伤口充分愈合的关键前提。然而，炎症和修复功能的失衡可能导致扩大的心肌损害和心力衰竭。在我们之前的工作中，我们已经将小钙结合蛋白S100A1表征为一种有利的心脏警报蛋白。当从坏死的心肌细胞中释放出来时，间质S100A1通过靶向心脏成纤维细胞短暂地触发心肌炎症。循环中的S100A1积聚在骨髓中，并促使祖细胞增殖的标志物表达。细胞外S100A1的中和导致心肌损伤愈合受损，并使小鼠心肌梗死后左心功能恶化。根据我们的初步结果，这一建议旨在检验细胞外S100A1通过调节Mo功能来协调心肌组织修复的假说。这项拟议的研究可能有助于开发未来的治疗策略，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.