腺苷A2A受体通过调节单核巨噬细胞迁移起心脏保护作用及机制研究

Heart failure remains a global problem at present, cardiovascular disease is the leading cause of death worldwide for non-communicable diseases. Inflammation is a hallmark of chronic heart failure. Accumulating evidence highlights a critical role for A2A adenosine receptor as a "sensor" of excessive tissue inflammation, which could trigger "OFF" signals in activated immune cells and protect tissue from inflammatory damage. Our preliminary data reveal that A2A deficiency could aggravate Ang II and TAC-induced cardiac remodeling, cardiac dysfunction, aggravate the disorder of splenic histological structure and immune function. Spleen is a secondary lymphoid organ, which contains a monocyte reservoir that mobilizes monocytes in response to stress such as acute myocardial ischemia, hyperlipidemia and so on. Thus, we hypothesize that, in heart failure mice, the immune microenvironment in spleen is more conducive to polarization of M1 macrophage and more likely tends to promote the recruitment of macrophages to heart tissue. This process is governed by A2A adenosine receptor and is macrophage dependent. This project, from the perspective of cardiosplenic axis, researches A2A adenosine receptors’ influence on macrophage migration and polarization, which may offer a promising new immunotherapy target for heart failure.

目前心力衰竭仍是一个全球性问题，心血管疾病占全球非传染性疾病死亡原因的首位。炎症是慢性心衰的一个重要标志，腺苷A2A受体是组织过度炎症的“感受器”,可触发“关闭”开关，终止过度激活的炎症反应以保护组织。我们的前期研究发现，腺苷A2A受体敲除后可显著恶化Ang II及TAC诱导的心室重构、心功能不全、加重脾脏组织学结构及免疫功能的紊乱。脾脏是一个淋巴器官,被视为单核细胞的存储器，可在急性心肌缺血、高脂刺激等应激条件下将单核细胞动员出去，参与心血管疾病的炎症反应。我们提出假设：心衰时，脾脏可促进巨噬细胞向促炎型M1型分化，并促进单核巨噬细胞向心脏迁移，这一过程受腺苷A2A受体调控，并且是单核巨噬细胞依赖性的。本项目从免疫学的角度出发，通过动物实验、细胞实验，研究腺苷A2A受体在脾脏对心脏的调节过程中对巨噬细胞迁移及极化的影响，为心衰疾病的防治提供新的免疫治疗靶点。