间充质干细胞衍生的细胞外囊泡转运的 microRNA-302d-3p 抑制急性心肌梗死后的炎症和心脏重构。

Mesenchymal Stem Cell-Derived Extracellular Vesicle-Shuttled microRNA-302d-3p Represses Inflammation and Cardiac Remodeling Following Acute Myocardial Infarction.

机构信息

Clinical Laboratory, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, 161000, People's Republic of China.

The Fifth Ward of Cardiovascular Medicine, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, 161000, People's Republic of China.

出版信息

J Cardiovasc Transl Res. 2022 Aug;15(4):754-771. doi: 10.1007/s12265-021-10200-1. Epub 2022 Feb 22.

DOI:10.1007/s12265-021-10200-1

PMID:35194734

Abstract

Our research intended to investigate the roles of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in acute myocardial infarction (AMI) via delivery of microRNA (miR)-302d-3p. AMI mouse models were established. EVs isolated from MSCs with miR-302d-3p mimic were injected near the infarct area or co-cultured with hypoxic cardiomyocytes to evaluate their effects. The expression of NF-κB pathway-related genes and inflammatory factors was determined. AMI mice exhibited downregulated miR-302d-3p and elevated MD2 and BCL6 levels. BCL6 was negatively targeted by miR-302d-3p and could bind to MD2 promoter to upregulate MD2 expression. MSCs-EVs, MSCs-EVs carrying miR-302d-3p, or BCL6 or MD2 silencing inactivated the NF-κB pathway and alleviated infarcted area, myocardial fibrosis, inflammation, apoptosis, and cardiac dysfunction in AMI mice. Besides, MSCs-EVs, MSCs-EVs carrying miR-302d-3p, or BCL6 or MD2 silencing diminished viability and inflammation but augmented apoptosis of hypoxic cardiomyocytes. Conclusively, MSCs-EVs carrying miR-302d-3p repressed inflammation and cardiac remodeling after AMI via BCL6/MD2/NF-κB axis.

摘要

我们的研究旨在通过递送 microRNA（miR）-302d-3p 来研究间充质干细胞（MSC）衍生的细胞外囊泡（EVs）在急性心肌梗死（AMI）中的作用。建立了 AMI 小鼠模型。用 miR-302d-3p 模拟物分离的 EVs 被注射到梗死区域附近或与缺氧心肌细胞共培养，以评估它们的作用。测定 NF-κB 途径相关基因和炎症因子的表达。AMI 小鼠表现出 miR-302d-3p 下调和 MD2 和 BCL6 水平升高。BCL6 是 miR-302d-3p 的负靶向物，可与 MD2 启动子结合以上调 MD2 表达。MSC-EVs、携带 miR-302d-3p 的 MSC-EVs 或 BCL6 或 MD2 沉默均可使 NF-κB 通路失活，并减轻 AMI 小鼠的梗死面积、心肌纤维化、炎症、凋亡和心功能障碍。此外，MSC-EVs、携带 miR-302d-3p 的 MSC-EVs 或 BCL6 或 MD2 沉默均可减少缺氧心肌细胞的活力和炎症，但增加其凋亡。总之，携带 miR-302d-3p 的 MSC-EVs 通过 BCL6/MD2/NF-κB 轴抑制 AMI 后炎症和心脏重塑。