趋化因子CXCL16对心肌缺血再灌注后无复流的影响及作用机制研究

No-reflow after cardiac ischemia/reperfusion (I/R) severely demolishes the benefits of coronary revascularization in patients with acute myocardial infarction. Inflammatory response and apoptosis have been suggested to contribute to the myocardial no-reflow. Our preliminary data indicated that the expression of chemokine CXCL16 was elevated in animal myocardial no-reflow model accompanied by increased neutrophil infiltration and apoptosis. Cellular proapoptotic proteins were promoted by administration of recombinant CXCL16 (chemokine domain) in vitro. We therefore propose that myocardial I/R promotes the expression of CXCL16 to recruit neutrophils as well as aggravate local inflammation and induces apoptosis through NF-κB/CXCL16/Caspase3 signaling pathway resulting in no-reflow. In this project, we combine the methods of animal no-reflow model and simulated I/R cell culture. Neutralizing CXCL16 in vivo and RNA interference in vitro to suppress the expression of CXCL16 in I/R are applied to determine the relationship between CXCL16 and no-reflow extent, neutrophil chemotaxis, apoptosis and related signaling pathway. By investigating the mechanism of no-reflow, we sought to provide a theoretical foundation for therapeutic interventions of myocardial I/R-associated no-reflow.

心肌缺血再灌注（I/R）后无复流严重影响了冠心病患者的预后。炎症反应和细胞凋亡对促进无复流起重要作用。我们前期研究显示动物心肌无复流模型中趋化因子CXCL16表达增加，无复流区粒细胞浸润及细胞凋亡明显。重组CXCL16（趋化因子结构域）刺激细胞促凋亡蛋白表达增加。因此提出"心肌I/R促进CXCL16的表达募集中性粒细胞加重局部炎症反应，并通过NF-κB/CXCL16/Caspase3信号转导通路诱导细胞凋亡从而导致无复流"这一假说。本课题应用动物心肌I/R后无复流及体外细胞模拟I/R结合的方法，体内采用特异性中和抗体，体外采用RNA干扰沉默CXCL16在I/R的表达，明确CXCL16与无复流面积、粒细胞趋化、细胞凋亡的关系及信号转导通路。从分子水平、组织水平和动物体内实验，探讨CXCL16介导I/R后无复流的发生机制，旨在为临床防治血管再通后心肌无复流提供理论依据和治疗靶点。

心肌缺血再灌注（I/R）后无复流严重影响了冠心病患者的预后。炎症反应、细胞凋亡、自噬等机制对促进无复流起重要作用。我们的研究显示家兔心肌无复流模型中趋化因子CXCL16表达增加，无复流区粒细胞浸润、细胞凋亡和自噬明显。本课题应用动物心肌I/R后无复流及体外细胞模拟I/R结合的方法，从分子水平、组织水平和动物体内实验，探讨了心肌I/R促进CXCL16的表达募集中性粒细胞加重局部炎症反应，并通过NF-κB信号转导通路诱导细胞凋亡及自噬从而导致无复流的发生机制，为临床防治血管再通后心肌无复流提供理论依据和治疗靶点。