Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, People's Republic of China.
Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, Guangdong, People's Republic of China.
Basic Res Cardiol. 2020 Feb 28;115(2):22. doi: 10.1007/s00395-020-0781-7.
The roles and the underlying mechanisms of M1-type macrophages in angiogenesis and postmyocardial infarction (MI) cardiac repair have remained unclear. In this study, we investigated the role of M1-like macrophage-derived exosomes in a MI microenvironment. We found that the proinflammatory M1-like-type macrophages released an extensive array of proinflammatory exosomes (M1-Exos) after MI. M1-Exos exerted an anti-angiogenic effect and accelerated MI injury. They also exhibited highly expressed proinflammatory miRNAs, such as miR-155. miR-155 was transferred to endothelial cells (ECs), leading to the inhibition of angiogenesis and cardiac dysfunction by downregulating its novel target genes, including Rac family small GTPase 1 (RAC1), p21 (RAC1)-activated kinase 2 (PAK2), Sirtuin 1 (Sirt1), and protein kinase AMP-activated catalytic subunit alpha 2 (AMPKα2). M1-Exos depressed Sirt1/AMPKα2-endothelial nitric oxide synthase and RAC1-PAK2 signaling pathways by simultaneously targeting the five molecule nodes (genes), reduced the angiogenic ability of ECs, aggravated myocardial injury, and restrained cardiac healing. The elucidation of this mechanism provides novel insights into the functional significance of M1 macrophages and their derived exosomes on angiogenesis and cardiac repair. This mechanism can be used as a novel potential therapeutic approach for the prevention and treatment of MI.
M1 型巨噬细胞在血管生成和心肌梗死后（MI）心脏修复中的作用和潜在机制仍不清楚。在这项研究中，我们研究了 M1 样巨噬细胞衍生的外泌体在 MI 微环境中的作用。我们发现，促炎的 M1 样巨噬细胞在 MI 后释放了大量的促炎外泌体（M1-Exos）。M1-Exos 具有抗血管生成作用，并加速 MI 损伤。它们还表现出高度表达的促炎 miRNA，如 miR-155。miR-155 被转移到内皮细胞（ECs）中，通过下调其新型靶基因，包括 Rac 家族小 GTP 酶 1（RAC1）、p21（RAC1）激活激酶 2（PAK2）、Sirtuin 1（Sirt1）和蛋白激酶 AMP 激活的催化亚基 α2（AMPKα2），导致血管生成和心脏功能障碍。M1-Exos 通过同时针对五个分子节点（基因）抑制 Sirt1/AMPKα2-内皮型一氧化氮合酶和 RAC1-PAK2 信号通路，降低 EC 的血管生成能力，加重心肌损伤，抑制心脏愈合。该机制的阐明为 M1 巨噬细胞及其衍生的外泌体在血管生成和心脏修复中的功能意义提供了新的见解。该机制可作为预防和治疗 MI 的一种新的潜在治疗方法。
