趋化因子-受体信号通路调控心力衰竭的发病机制

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.

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。

免疫细胞特别是单核/巨噬细胞聚集是启动心血管炎症反应和心血管重构的早期事件。趋化因子及其受体信号是介导免疫细胞动员和在心血管组织聚集活化的关键通路。但是，那些趋化因子信号在心衰中发坏关键的作用及分子机制不清楚。本课题主要阐明了趋化因子-受体信号通路调控心力衰竭的发病机”研究主要成果如下：.1、明确了高血压因素（Ang II或压力超负荷）上调趋化因子及其受体表达的动态特征；发现（1）Ang II处理小鼠1天后，心室、心房和血管中CXCL1和表达水平升高最显著；其受体CXCR2 表达及CXCR2+ 单核/巨噬细胞水平呈时间依赖性增高；（2）病人血液中CXCL1水平及CXCR2+单核细胞数量比正常对照组显著增高，且与高血压、心衰及房颤的发生率之间呈明显正相关。.2、阐明趋化因子CXCL1调节CXCR2+单核/巨噬细胞聚集和活化，促进高血压及心衰的发病机理；（1）Ang II或DOCA-salt灌注野生小鼠后导致血压明显增高、心脏收缩和血管舒张功能障碍、心脏病理生重构包括肥厚、纤维化、氧化应激以及 CXCR2+巨噬细胞聚集；（2）在基因敲除和骨髓移植小鼠中，发现CXCR2敲除明显抑制心脏和血管CXCR2+ 单核/巨噬细胞聚集和炎症因子的表达，降低高血压、改善心脏和血管结构和功能障碍的发生，进而抑制高血压、心衰及房颤的发生发展。.3、发现CXCL1和CXCR2可作为干预高血压、心衰及房颤发生的新靶点：（1）应用CXCL1中和抗体和处理小鼠可抑制心脏组织中单核/巨噬细胞聚集和活化，进而降低Ang II引起的心功能障碍和心脏重构。（2）应用CXCR2抑制剂SB225002 处理小鼠可抑制心脏和血管中单核/巨噬细胞的聚集，进而降低Ang II、DOCA-salt引起的高血压, 血管功能障碍和心脏重构的发生发展；（3）这些作用自发性高血压大鼠得到验证。这些结果提示CXCL1或CXCR2可作为干预这些心血管疾病发生的新靶点。