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.

心肌梗塞导致心肌功能组织不可逆转的丧失。它是慢性心力衰竭的主要原因。心肌细胞缺血性坏死引发急性炎症反应，以常驻心肌细胞以及脾、骨髓等心外组织为靶点。单核细胞/巨噬细胞（Mo）在损伤心肌中迅速积聚，首先引发炎症，清除碎片，随后刺激瘢痕组织形成，促进血管生成。这两个阶段的特点是不同的Mo表型。其准确的空间和时间序列是伤口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伤扩张性和心力衰竭。在我们之前的工作中，我们已经将小的Ca2+结合蛋白S100A1描述为一种有利的心脏报警蛋白。从坏死心肌细胞释放后，间质S100A1通过靶向心肌成纤维细胞，瞬间触发心肌炎症。循环中的S100A1在骨髓中积累，并促进祖细胞增殖标志物的表达。细胞外S100A1的中和导致小鼠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，本提案旨在验证细胞外S100A1通过调节心肌梗死时的Mo功能来协调心脏组织修复的假设。该研究可能有助于未来治疗策略的发展，旨在优化损伤心肌的愈合，以预防慢性心力衰竭。