Hypoxia-primed monocytes/macrophages enhance postinfarction myocardial repair.
Hypoxia-primed monocytes/macrophages enhance postinfarction myocardial repair.
复制标题
缺氧引发的单核细胞/巨噬细胞增强梗死后心肌修复
作者：
Zhu Y;Yang W;Wang H;Tang F;Zhu Y;Zhu Q;Ma R;Jian Z;Xiao Y
背景：心肌梗死（MI）的氧补充仍存在争议。人们普遍认为炎症在心肌修复中发挥核心作用。更好地了解这些过程可能会导致新的战略设计的补充MI治疗。研究方法：为了研究缺氧在急性MI后炎症和心肌修复中的作用，我们将MI小鼠置于可耐受的轻度缺氧（10%O2）室中7天，然后将小鼠转移到环境空气中3周。结果：缺氧条件下MI小鼠的累积存活率明显高于补氧条件下MI小鼠的累积存活率。缺氧促进心肌梗死后心肌修复。重要的是，我们发现缺氧及时调节血液单核细胞从促炎性到促修复性的表型转变，导致随后心肌组织炎症的停止和心肌梗死后心肌修复的促进。具体而言，培养的骨髓源性巨噬细胞（BMDM）在体外缺氧引发表现出改善的修复能力，并通过AMPKα2信号通路与M1和M2巨噬细胞不同。单核/巨噬细胞AMPKα2的缺失阻止了缺氧诱导的表型转化，移植到心肌后不能促进心肌损伤后的修复。结论：总之，我们的工作表明，缺氧通过AMPKα2信号通路及时调节血液单核细胞/巨噬细胞表型从促炎性向促修复性转变，从而促进梗死后心肌修复。缺氧引发可能是一个有吸引力的翻译策略MI治疗通过扩增免疫细胞在早期炎症和随后的决议和修复。
Background: Oxygen supplementation in myocardial infarction (MI) remains controversial. Inflammation is widely believed to play a central role in myocardial repair. A better understanding of these processes may lead to the design of novel strategies complementary to MI treatment. Methods: To investigate the role of hypoxia in inflammation and myocardial repair after acute MI, we placed MI mice in a tolerable mild hypoxia (10% O2) chamber for 7 days and then transferred the mice to ambient air for another 3 weeks. Results: We found that the cumulative survival rate of the MI mice under hypoxia was significantly higher than that under oxygen supplementation. Hypoxia promoted postinfarction myocardial repair. Importantly, we found that hypoxia modulated the phenotypic transition of blood monocytes from pro-inflammatory to pro-reparative in a timely manner, leading to the subsequent discontinuation of inflammation in myocardial tissues and promotion of myocardial repair post-MI. Specifically, cultured bone marrow-derived macrophages (BMDMs) primed by hypoxia in vitro exhibited improved reparative capacities and differed from M1 and M2 macrophages through the AMPKα2 signaling pathway. The deletion of AMPKα2 in monocytes/macrophages prevented the phenotypic transition induced by hypoxia and could not promote myocardial repair after MI when transplanted into the myocardium. Conclusions: Taken together, our work demonstrates that hypoxia promotes postinfarction myocardial repair by modulating the blood monocyte/macrophage phenotypic transition from pro-inflammatory to pro-reparative in a timely manner through the AMPKα2 signaling pathway. Hypoxia priming might be an attractive translational strategy for MI treatment by amplifying immune cells during early inflammation and subsequent resolution and repair.