炎症反应是促进心肌重构及心力衰竭发生的重要机制。趋化因子/受体是招募免疫细胞和启动炎症反应的关键信号通路。我们前期研究发现血管紧张素II（Ang II）灌注可明显上调心肌中趋化因子CXCL1、13和其受体CXCR2、5的表达。应用中和抗体或抑制剂后可明显改善心肌重构。但是这些趋化因子/受体通路如何调节免疫炎症反应及心衰的发病机制不清楚。本项目将应用基因敲除、骨髓移植及抑制剂处理的小鼠以及体外细胞共培养体系，在AngII灌注和主动脉结扎（TAC）诱导的心衰模型中，阐明AngII和TAC刺激心肌CXCL1、13及CXCR2、5表达的分子机制；明确CXCL1/CXCR2、CXCL13/CXCR5分别招募单核/巨噬细胞和B淋巴细胞迁移和活化，促进心肌细胞肥大、凋亡和纤维化，导致心肌重构及心衰发生的病理生理机制。最后阐明趋化因子/受体信号启动和调控心衰的发病机制，为临床心衰的防治提供新的药物靶点。

Immune inflammation is a main mechanism to promote cardiac remodeling and heart failure. Chemonkine/receptor signaling pathways plays critical roles in recruiting immune cells and initiating inflammation. Our prelimirary results suggest that angiotension II infusion the expression of myocardial chemokines CXCL1/13 and receptors CXCR2/5 was significantly upregulated in the process of cardiac remodeling induced by angiotension II infusion. Conversely, treatment of the heart with CXCL1 neutralizing antibody or CXCR2 inhibitor markedly inhibited cardiac remodeling and heart failure. However, the role of these chemokien/receptor pairs in the regulating heart failure and the underlying mechanisms remains unclear. In this study, we will use the flow cytometry, microarray, physiological and pathological examinations, knockout mice, inhibitor-treated mice or bone marrow transplantation, and Ang II or aortic banding (TAC)-induced cardiac remodeling and heart failure models to investigate: (1) How Ang II and TAC up-regulate the expression of myocardial CXCL1 and CXCL13; (2) How these chemokines and receptors modulate recruitment differentiation of immune cells such as monocytes/macrophages, B cells in the damaged heart, which cause cardiac hypertrophy, apoptosis, and activation of myofibroblasts and fibrosis formation resulting in cardiac remodeling and heart failure. Together, these results will provide novel evidence for understanding the pathogenesis and progression of heart failure and potential therapeutic target for the treatment and prevention of heart failure.