骨髓来源CXCR2阳性细胞促进心力衰竭的病理生理机制

Inflammation promotes cardiac remodeling and heart failure. Recruiting the inflammatory cells into the heart is the key process of initiating the inflammation. However, which chemokine-receptor signal participates in the recruiting process and heart failure is still unknown. Our previous experiments found that in the early phase of Angiotensin II (Ang II)-induced cardiac remodeling, the expression of CXCL1 and its receptor CXCR2 elevated the most significantly, moreover the bone marrow-derived CXCR2 positive cells also obvious increased. Applying the CXCR2 inhibitor can alleviate Ang II-induced cardiac hypertrophy, inflammation and fibrosis. Intensive study of how bone marrow-derived CXCR2 positive cells promote heart failure and illuminating the underlying pathophysiologic mechanism is necessary. Our study will creat the Ang II/TAC-induced heart failure model in the CXCR2-knockout mice, the CXCR2 inhibitor-treated mice and the bone marrow-chimera-mice to further illuminate the pathophysiologic mechanism of how bone marrow-derived CXCR2 positive cells induce cardiac hypertrophy, apoptosis, inflammation, fibrosis and heart failure. By the cell-co-culture system, we can illuminate the molecular mechanism of how the bone marrow-derived CXCR2 positive cells regulate the activation of cardiomyocytes and fibroblasts. Finally we can propose the new experimental basis to explain the mechanism of how CXCR2 inducing heart failure.

炎症反应是促进心肌重塑及心力衰竭（心衰）的重要机制，免疫细胞被招募到心脏中是启动早期炎症反应的关键，但是哪种趋化因子-受体信号参与该过程并在心衰中起关键作用仍不明确。我们发现在血管紧张素II（Ang II）诱导的心肌重塑早期，CXCL1及其受体CXCR2表达增高最显著，心脏中骨髓来源CXCR2阳性细胞明显增多，应用CXCR2抑制剂可显著减轻Ang II诱导的心肌肥厚、炎性和纤维化。但是仍需要深入研究骨髓来源CXCR2阳性细胞促进心肌重塑及心衰的病理生理机制。本课题拟应用CXCR2基因敲除、抑制剂处理及骨髓移植小鼠，在Ang II和主动脉缩窄诱导的心衰模型上，深入阐明骨髓来源CXCR2阳性细胞调控心肌肥厚、凋亡、炎症反应、纤维化及心衰的病理生理机制；并在体外共培养体系中明确骨髓来源CXCR2阳性细胞调节心肌细胞和成纤维细胞活化的分子机制，为阐明CXCR2促进心衰的病理生理机制提供实验依据。

当心脏损伤发生时，炎症细胞向心脏组织中趋化浸润是心肌重塑心脏炎症过程的始动环节。然而，哪种趋化因子/受体信号通路介导心肌重塑免疫炎症细胞的趋化，目前仍不清楚。该研究首先通过基因芯片发现血管紧张素II灌注第1天，心脏组织中趋化因子CXCL1表达水平明显升高，并进一步证实了CXCR2阳性细胞向心脏组织中的浸润亦明显增多。应用CXCL1中和抗体、CXCR2基因敲除与应用CXCR2抑制剂均可明显减轻血管紧张素II引起的血压升高、心脏功能异常、心肌肥厚、心脏炎症及纤维化；将CXCR2基因敲除骨髓移植到野生小鼠体内可明显减轻血管紧张素II引起的心肌肥厚、心脏炎症及纤维化；同时，体外共培养实验进一步证实CXCR2敲除的单核巨噬细胞趋化及活化能力下降，并且显著减轻血管紧张素II引起的心肌细胞肥大及成纤维细胞转分化。研究进一步发现在心衰患者血液中CXCL1水平较正常人明显升高，同时心衰患者血液中CXCR2阳性细胞较正常人亦明显增多。本研究的临床价值是抑制趋化因子CXCL1及其受体CXCR2可作为减轻心肌重塑新的治疗靶点。