CXCR7在高脂小鼠动脉粥样硬化和心脏缺血再灌注损伤中的作用和机制研究

Atherosclerotic cardiovascular disease is one of the most serious health-threatening diseases. When its acute ischemic event occurred, mostly, the patients had to receive Percutaneous Coronary Intervention (PCI). However, the injury caused by reperfusion, termed as “Ischemia-reperfusion injury (IRI)”, further exacerbates the damage of the cardiac cells, and becomes the main cause of death of the patients who underwent PCI. Thus, it’s badly in need of studies on atherosclerosis and atherosclerosis-related IRI. CXCR7 is a newly identified receptor for the chemokine CXCL12. By Genome-wide association study (GWAS), CXCL12 was found to be related with atherosclerotic coronary disease. However, the role of CXCR7 on atherosclerotic cardiovascular disease remains to be defined. Recently, our studies showed that in normolipidemic mice that suffered from myocardial infarction, endothelial CXCR7 was related to the improvement of heart remodeling, functional recovery and survival rate. However, it’s still not clear whether or not the endothelial CXCR7 could modulate atherosclerotic cardiovascular disease that is characterized by hyperlipoidemia and chronic inflammation. Here, in this study, we hypothesized endothelial CXCR7 ameliorated atherosclerosis and atherosclerosis-related IRI via improving endothelium repair, inhibiting vascular inflammation and ameliorating microcirculation disturbance. As this study focus on endothelial cells, and aims to explore a new mechanism that orchestrated the atherosclerotic cardiovascular disease, it’s of great value on clinical practice and drug development.

动脉粥样硬化性心脏病是危胁人类健康的重大疾病。冠状动脉粥样硬化引起缺血性急症后，经皮血管内介入再通治疗是最常采用的急症治疗，而再通后的心脏缺血再灌注损伤是影响患者预后的关键因素，因此对动脉粥样硬化及其相关心脏缺血再灌注损伤的研究具有重要的意义。CXCR7是新近鉴定的，趋化因子CXCL12的受体。遗传学数据表明CXCL12与冠心病相关。而CXCR7在动脉粥样硬化性心脏病中的作用研究尚少。近期我们的研究显示，内皮细胞CXCR7可改善血脂正常小鼠心梗后的心脏结构与功能损害，提高小鼠生存率。但，内皮CXCR7能否改善具有高血脂、慢性炎症、内皮损伤及微血管改变的动脉粥样硬化及其相关缺血再灌注损伤，仍待进一步研究。本项目假设CXCR7通过调节内皮的增殖与炎症反应及改善微循环，进而改善动脉粥样硬化及其相关心脏缺血再灌注损伤的发生与发展。探讨一个以内皮为核心的改善动脉粥样硬化性心脏病预后的新机制，具有重要的临床及药物研发价值。

动脉粥样硬化是缺血性心脏病、高血压等多种心血管复杂疾病的病理基础。CXCR7是趋化因子CXCL12的新型受体。我们前期工作证实，内皮细胞CXCR7可调控血管损伤后修复，保护心梗后心脏重构。本项目主要阐述了内皮细胞CXCR7对动脉粥样硬化的调控作用及机制。利用CXCR7条件性敲除鼠与LDLR敲除鼠杂交，我们制作了可诱导敲除内皮细胞CXCR7受体的动脉粥样硬化模型小鼠。项目主要研究发现有1）氧化脂质刺激，上调内皮细胞CXCR7表达。2）敲除高脂小鼠内皮细胞CXCR7，抑制小鼠主动脉动脉粥样硬化发生；抑制高脂小鼠颈动脉限流诱导的动脉粥样硬化斑块儿形成。3）敲除高脂小鼠内皮细胞CXCR7，升高循环CXCL12水平；增加外周血白细胞数目；抑制白细胞在血管壁滚动、粘附；降低班块儿内巨噬细胞数目；不影响脂质代谢。4）利用静脉灌注系统提高外周血CXCL12水平，增加外周血白细胞数目。5）给予高脂小鼠股动、静脉缺血再灌注刺激时，敲除内皮CXCR7减少高脂小鼠股血管中白细胞滚动。综上，研究揭示了高脂小鼠内皮细胞CXCR7通过调节血管炎症，而调控动脉粥样硬化的作用与机制。另外，在本项目联合资助下，围绕血管内皮细胞，我们还阐明了1）内皮细胞EP4受体，介导内皮细胞损伤修复，抑制血管损伤后重构的作用与分子机制。2）药物小分子Foskolin，可通过促进内皮细胞修复及抑制血管炎症，而抑制动脉粥样硬化。3）抗癌中药MTE，可通过促进内皮细胞释放一氧化氮，一方面舒张小血管；另一方面抑制肺癌细胞增殖。目前，在项目资助下，共发表SCI论文6篇。仍有少部分工作，正在进一步研究、整理中。