CXCR2受体介导血管紧张素II诱导的心房纤维化的分子机制研究

心房纤维化是心房颤动（房颤）发生和维持的重要机制。炎症反应参与心房纤维化的发生，CXCR2激活是炎性细胞聚集的重要信号。我们前期实验发现在高血压患者外周血单核细胞和血管紧张素II（AngII）处理的小鼠心房组织中CXCR2及其配体CXCL1明显增高，巨噬细胞聚集和心房纤维化明显增加；而应用CXCR2抑制剂可显著改善Ang II诱导的纤维化。但是，在Ang II刺激的模型中CXCR2促进心房纤维化的分子机制不清楚。本项目拟应用CXCR2抑制剂处理的小鼠、CXCR2敲除小鼠、骨髓移植小鼠及体外细胞共培养体系，采用流式细胞、qPCR等技术，研究AngII上调巨噬细胞CXCR2表达的分子机理；明确CXCR2对AngII诱导的心房炎性细胞聚集、炎症因子表达及纤维化；在体外进一步明确巨噬细胞中CXCR2促进心房纤维母细胞增殖和活化的分子机制，为阐明房颤发生的病理生理机制和寻找治疗新靶点提供新理论依据。

Atrial fibrosis is a major substrate for occurrence and maintenance of atrial fibrillation (AF). Inflammation plays an important role in atrial fibrosis, and activation of CXCR2 receptor is an important signaling pathway that causes the accumulation of inflammatory cells. Our previous experiments found that angiotensin II (Ang II) treatment significantly increased the expression of CXCL1 (a CXCR2 ligands), macrophage accumulation and atrial fibrosis in atrial tissue, whereas administration of CXCR2 inhibitor can significantly attenuate Ang II-induced Atrial fibrosis. However, the role of CXCR2 receptor in modulating atrial fibrosis and the molecular mechanism remain unclear. In the present study, using CXCR2 inhibitor treated mice, CXCR2 knockout mice, bone marrow transplantation in mice and in vitro cell co-culture system, we aim to investigate the molecular mechanism of CXCR2 receptor in regulating angiotensin II-induced atrial fibrosis in macrophage, and clarify the role of CXCR2 on atrial inflammatory cell infiltration, expression of cytokines and atrial fibrosis. In addition, we will explore the molecular mechanism of CXCR2 in macrophage activates cardiac fibrosis.This study will provide a new theoretical basis for elucidating the pathophysiology of atrial fibrillation and finding new therapeutic targets.