高表达Tie2的巨噬细胞在小鼠心肌缺血-再灌注损伤中的作用及其机制研究

Coronary heart disease and the acute myocardial infarction caused by it are currently a serious threat to human health. Reconstruction of the coronary artery in patients with myocardial infarction can improve cardiac function, but reperfusion itself can also cause myocardial damage. Evidence from both clinical and animal studies suggests that inflammatory response is one of the important mechanisms of myocardial ischemia/reperfusion injury. After myocardial infarction, macrophages chemotaxis and infiltrate into ischemic myocardial tissue, showing two different effects: proinflammatory (M1) and anti-inflammatory (M2). The process of balancing macrophages from M1 to M2 can improve myocardial repair after MI and regulate cardiac remodeling. Angiogenesis plays an important role in M2 macrophage-mediated tissue repair. Our previous study found for the first time that macrophages in peripheral blood of patients with myocardial infarction express high levels of Tie2, and that Tie2-expressing macrophages (TEM) showed similar functions to M2 cells: Sorted TEM can promote vascular endothelial cell sprouting; knocking out Tie2 on macrophages can inhibit angiogenesis and promote cardiomyocyte apoptosis. These results suggest that Tie2 molecules may play an important role in the MI repair process. In the following, we will use a variety of molecular biology methods to study 1) TEM phenotype and function in IRI process; 2) TEM effect on cardiac function of IRI model mice; 3) molecular mechanism downstream of TEM, thus to understand the pathogenesis of myocardial ischemia/reperfusion injury, and to provide a new way for the treatment of this disease.

为治疗心肌梗死（MI）而进行心肌再灌注的过程本身亦能造成心肌损伤（缺血-再灌注损伤，IRI），大量证据表明，再灌注后趋化、浸润至缺血区心肌组织的巨噬细胞表现出促炎（M1型）与抑炎（M2型）的双重作用，平衡巨噬细胞从M1转向M2这一过程可以改善MI后的心肌修复和功能，并调节心脏重塑。我们的前期研究首次发现人心肌梗死患者外周血中有巨噬细胞高表达Tie2分子，并发现表达Tie2的巨噬细胞(TEM) 表现出与M2型细胞类似的功能：分选出的TEM可以促进血管内皮细胞出芽；敲除巨噬细胞上的Tie2分子则可抑制血管新生并促进心肌细胞凋亡。上述结果提示TEM可能在MI修复过程中发挥重要作用。本课题将继续研究①TEM在IRI过程中的表型和功能；②TEM对IRI模型小鼠心脏功能的影响；③TEM下游的分子机制，以深化理解心肌缺血/再灌注损伤的发病机理，为该疾病的治疗提供新的途径。

巨噬细胞在心肌梗死（MI）后的损伤修复过程中起关键作用，负责协调心脏重塑过程中的每个阶段，包括坏死组织吞噬，炎症和血管生成。其中，MI后的血管修复和重塑不仅能补充缺血区域的血液，还能挽救心肌细胞的坏死，促进心脏功能的恢复。髓系细胞的原血管生成亚群，即表达tie2的单核/巨噬细胞(TEMs)，由于对肿瘤血管生成和脑卒中后血管重塑的重要作用而受到特别关注。在这里，我们发现，在急性心肌梗死小鼠模型中，骨髓(BM)来源的表达tie2的单核/巨噬细胞(TEMs)进入梗死心肌的缺血性病变处，并通过促进内源性血运重建和发挥“愈合”功能。MTie2小鼠脑血管阻塞区Angpt2、Crp、Csf3、Cxclf12、Mmp9和Mrc1基因表达升高，Cxcr4和Tie2基因表达减弱，提示TEMs促进血管生成并具有免疫调控作用。对急性心肌梗死患者的研究表明，心肌梗死患者的外周血中TEMs的表达水平显著升高。这些数据可能有助于了解心肌梗死后巨噬细胞调控血管新生的模式，并提示了外源性TEMs应用于急性心肌梗死治疗的良好前景。