补体C3a在心肌梗死后心脏重塑中的作用机制研究

Cardiac remodeling after myocardial infarction includes the replacement of the necrotic area with extracellular matrix secreted by activated cardiac fibroblasts and the clearance of necrotic cells and matrix debris. Cardiac inflammation micro-environment regulates the balance of synthesis and degradation of extracellular matrix. Complement component C3a, as the regulator of cell function, participated in the development of inflammatory diseases. We have previously found that the expression of C3aR increased in infarct heart, there were increased cardiac rupture and decreased survival ratio in C3aR deficiency heart, accompanied with more infiltrated neutrophils, but the regulation mechanism is still unknown. In this study, we will use the C3aR deficiency mice to determine the role of C3a-C3aR pathway in inflammation environment and cardiac remodeling, use bone marrow transplantation, neutrophils depletion and in vitro cell co-culture experiments to clarify the key molecular regulation mechanism of cardiac remodeling after myocardial infarction, which will provide novel target to the prevention of fatal complications such as cardiac rupture.

冠心病心肌梗死后，活化的肌成纤维细胞产生细胞外基质替代梗死心肌完成心室重塑，心脏炎症微环境可调控细胞外基质合成和降解的平衡维持心脏功能。补体C3a通过受体C3aR调节多种细胞功能参与炎症性疾病的病理生理过程。前期研究发现，梗死心脏中C3aR表达增加，C3aR缺失导致梗死早期室壁破裂率增加和生存率下降，心脏中中性粒细胞浸润增加，但其具体调控机制尚不清楚。据此，提出科学假设：补体C3a-C3aR相关信号通路抑制中性粒细胞的动员和招募，避免其对细胞外基质的降解，在心梗早期心脏重塑中发挥保护作用。我们拟以前降支结扎复制小鼠心肌梗死，使用C3aR敲除小鼠探讨补体C3a-C3aR通路对梗死后心脏重塑和炎症微环境的影响，结合骨髓移植实验、中性粒细胞祛除实验和体外细胞共培养等方法明确补体C3a调控的炎症微环境在心梗后心脏重塑中的分子机制，从而发现心肌梗死室壁破裂等致死性并发症的预防治疗靶点。

冠心病心肌梗死后，活化的肌成纤维细胞产生细胞外基质替代梗死心肌完成心室重塑，心脏炎症微环境可调控细胞外基质合成和降解的平衡维持心脏功能。补体系统调控炎症微环境，但其对心脏重构的影响尚不清楚。本研究通过使用C3aR 敲除小鼠探讨补体C3a-C3aR 通路对梗死后心脏重塑和炎症微环境的影响，结合转录组测序分析、骨髓移植实验、中性粒细胞祛除实验和体外细胞共培养等方法明确补体C3a调控的炎症微环境在心梗后心脏重塑中的分子机制。本研究发现了补体分子C3a可以通过C3aR/AKT/FOXO1信号通路的活化减少心肌细胞的死亡，从而减少中性粒细胞的招募，进而发挥抑制心肌梗死后心脏重塑和心力衰竭的保护性作用；发现了可减轻心肌梗死后心脏重塑和心力衰竭的新分子-精胺；探索了AKT/FOXO1信号通路在心力衰竭导致骨骼肌萎缩形成过程中的活性变化；并明确了补体分子C3a通过骨髓来源巨噬细胞表面的C3aR调控巨噬细胞的活化和招募从而促进骨骼肌损伤修复避免骨骼肌萎缩的分子机制。我们的一系列发现为心梗后心脏破裂和心力衰竭以及骨骼肌萎缩等致死性并发症的预防和治疗提供新靶点和新思路。