S100A1 promotes myocardial wound healing after infarction by regulating monocyte function

S100A1通过调节单核细胞功能促进梗死后心肌伤口愈合

• 批准号: 275166481
• 负责人: Dr. David Rohde
• 金额: --
• 依托单位: Center for Systems Biology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/275166481?language=en
• 关键词: S100A1; promotes; myocardial; wound; healing

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.

心肌梗塞导致功能性心肌组织不可逆地丧失。它是慢性心力衰竭的主要原因。心肌细胞缺血性坏死会引发急性炎症反应，针对驻留心肌细胞以及心脏外组织（如脾脏和骨髓）。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，随后刺激疤痕组织形成并促进血管生成。两个阶段都具有不同的 Mo 表型。它们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会导致心肌损伤扩大和心力衰竭。在我们之前的工作中，我们将小 Ca2+ 结合蛋白 S100A1 描述为一种有利的心脏警报素。从坏死的心肌细胞中释放出来后，间质 S100A1 通过靶向心脏成纤维细胞短暂地引发心肌炎症。循环中的 S100A1 在骨髓中积聚并促进指示祖细胞增殖的标记物的表达。小鼠梗死后，细胞外 S100A1 的中和会导致心肌伤口愈合受损，左心室功能恶化。根据我们的初步结果，该提案旨在检验细胞外 S100A1 通过调节 Mo 功能来应对心肌梗塞来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。