基于“心-脾”轴免疫网络的芪参颗粒抗心肌缺血的机制研究

Inflammation is a common pathology of coronary heart disease, heart failure and other cardiovascular diseases. The immune network of “cardio-spleen” axis which is crucial mechanism throughout the progress of ischemic heart diseases has influence on the degree of infarct size and ventricular remodeling. So the “cardio-spleen” axis has become a hot spot therapeutic approach for myocardial ischemia, but related affirmative efficacy drugs are rarely produced because ignoring the complexity of immune network. Chinese medicine compound has a remarkable role in immune regulation. Previous research of us indicated that Qishenkeli compound had potential efficacy on AngII-CCR2(spleen)-MCP-1/CCR2(cardio) pathway to treat myocardial ischemic diseases. Therefore, in present study, the immune network of “cardio-spleen” axis is applied as the breakthrough point, mononuclear phagocyte system is focused as a research object, combinations of transcriptomics, molecular biology and bioinformatics are applied to elaborate the mechanism of monocyte mobilization in spleen induced by myocardial ischemia, and the underlying mechanism of the Qishenkeli compounds acting on myocardial injure, repair and remodeling through AngII-CCR2(spleen)-MCP-1/CCR2(cardio) pathway. Meanwhile, the methods of macrophage cultured with bionic myocardial tissue and microfluidic chip system are used to screen the effective component. Our study will provide a new therapeutic approach for the treatment of coronary heart disease, heart failure and other diseases.

炎症反应是目前重大心血管疾病的共同病理表现，“心-脾”轴免疫网络调节是伴随心肌缺血发生、发展，同时影响梗死面积与心室重塑的重要机制与治疗靶向，但目前治疗药物往往因为作用靶标单一而药效不理想。中药复方在免疫调节方面具有多靶点、整体调节的优势，前期研究提示芪参颗粒具有确切的免疫调节作用，其潜在的调控通路为AngII-CCR2(脾)-MCP-1/CCR2(心)。因此，本研究以“心-脾”轴免疫调控为切入点，以单核巨噬细胞为研究对象，针对心肌缺血损伤、修复以及重构的不同疾病阶段，利用转录组学、分子生物学与生物信息学方法，揭示心肌缺血引发脾脏动员单核细胞机制；以AngII-CCR2(脾)-MCP-1/CCR2(心)通路为切入点阐释芪参颗粒的 “心-脾”免疫调控机制；同时，构建巨噬细胞与仿生心肌共培养结合微流控芯片技术的体外模型，用于芪参颗粒中有效成分的筛选，为冠心病、心衰等疾病的治疗提供新的治疗途径。

炎症反应是目前重大心血管疾病的共同病理表现，“心-脾”轴免疫网络调节是伴随心肌缺血发生、发展，同时也是决定梗死面积、心室重塑的重要机制，是心血管疾病治疗的重要靶向。但目前治疗药物往往因为作用靶标单一而药效不理想。中药复方在免疫调节方面具有多靶点、整体调节的优势，前期研究确定了芪参颗粒了有确切的免疫调节作用，且与AngII-CCR2(脾)-MCP-1/CCR2(心)调控通路密切相关。因此，本研究以“心-脾”轴免疫调控为切入点，以单核巨噬细胞为研究对象，针对心肌缺血损伤、修复以及重构的不同疾病阶段，首次明确了芪参颗粒防治大小鼠心肌缺血不同阶段的药效学研究；并且率先阐明了芪参颗粒作用AngII-CCR2(脾)-MCP1/CCR2(心)通路，介导单核/巨噬细胞表型以及在心脏、循环血液、脾脏中的迁移与募集；结合转录组学与分子生物学方法进一步构建并验证心肌缺血状态下“心-脾”免疫调节脾脏动员网络以及芪参颗粒的干预途径，再次佐证了芪参颗粒 “心-脾”轴免疫调控网络的抗心肌缺血机制。同时，通过建立巨噬细胞与三维仿生心肌体外模型，并且基于此体外模型筛选芪参颗粒中的活性成分。其中以丹参酮IIa为代表，进一步阐明了丹参酮IIa能够通过AMPK-mTOR信号转导通路抑制心肌细胞凋亡并促进自噬，促进心肌细胞整体代谢与能量供给进而保护心功能改善心肌损伤与重构，为冠心病、心衰等疾病的治疗提供新的治疗途径。. 本项目严格按照任务书内容执行，依托本项目，已发表相关SCI收录文章17篇，中文核心7篇，其中JCR1区杂志15篇，总影响因子81.585；共培养研究生4名，项目负责人2019年晋升为正高。