School of Medicine, Zhumadian Key Laboratory of Chronic Disease Research and Translational Medicine, Huanghuai University, Zhumadian, People's Republic of China.
Department of Scientific Research Section, Zhumadian Central Hospital, Affiliated Hospital of Huanghuai University, Zhumadian, People's Republic of China.
J Liposome Res. 2024 Sep;34(3):452-463. doi: 10.1080/08982104.2023.2293844. Epub 2023 Dec 25.
This study focused on investigating the mechanism of the astragaloside IV-induced bone marrow mesenchymal stem cell exosome (AS-IV-MSC-exo)/microRNA(miR)-411/HIF-1α axis in affecting vascular neovascularization and protecting cardiac function in myocardial infarction (MI) mice. Exosomes (MSC-exo and AS-IV-MSC-exo) were separated by differential centrifugation and then characterized. MI mouse models were established by left anterior descending coronary artery ligation. Echocardiography was used to evaluate cardiac function. HE staining and Masson staining were performed to observe myocardial histopathology. Capillary density in the myocardium immunohistochemistry and quantified the expression of vascular endothelial growth factor (VEGF) RT-qPCR. The expression of miR-411 and HIF-1α was tested by RT-qPCR and western blot and the targeting relationship of miR-411 and HIF-1α was verified by bioinformatics website and dual luciferase reporter gene assay. Exosomes with lipid bi-layer membrane structure, expressing exosomal surface marker proteins, and being taken up by cardiomyocytes could be successfully isolated utilizing ultracentrifugation. Intramyocardial injection of MSC-exo could restore cardiac function, decrease myocardial pathological changes and collagen deposition, and promote neovascularization in MI mice; the effect of AS-IV-MSC-exo was more significant. The ability of AS-IV-MSC-exo to restore cardiac function, lower myocardial pathological changes and collagen deposition, and promote neovascularization in MI mice was diminished when miR-411 expression in AS-IV-MSC-exo was reduced. Mechanistically, miR-411 was found to target and inhibit HIF-1α expression. Overexpression of HIF-1α impaired the impact of AS-IV-MSC-exo on improving cardiac function and promoting neovascularization in MI mice. AS-IV-MSC-exo improves cardiac function and promoted neovascularization the miR-411/HIF-1α axis, thereby ameliorating MI.
这项研究旨在探讨黄芪甲苷 IV 诱导的骨髓间充质干细胞外泌体（AS-IV-MSC-exo）/microRNA（miR）-411/缺氧诱导因子-1α（HIF-1α）轴在影响心肌梗死后（MI）小鼠血管新生和保护心功能中的作用机制。通过差速离心分离外泌体（MSC-exo 和 AS-IV-MSC-exo），并对其进行鉴定。通过左前降支冠状动脉结扎建立 MI 小鼠模型。使用超声心动图评估心功能。进行 HE 染色和 Masson 染色观察心肌组织病理学变化。免疫组织化学检测心肌组织中毛细血管密度并定量检测血管内皮生长因子（VEGF）的表达。采用 RT-qPCR 检测 miR-411 和 HIF-1α的表达，采用 Western blot 检测 miR-411 和 HIF-1α的表达，通过生物信息学网站和双荧光素酶报告基因检测验证 miR-411 和 HIF-1α的靶向关系。利用超速离心成功分离出具有脂质双层膜结构、表达外泌体表面标志物蛋白、并被心肌细胞摄取的外泌体。心肌内注射 MSC-exo 可恢复 MI 小鼠的心功能，减轻心肌病理变化和胶原沉积，促进血管新生；AS-IV-MSC-exo 的作用更显著。当 AS-IV-MSC-exo 中的 miR-411 表达减少时，AS-IV-MSC-exo 恢复 MI 小鼠心功能、降低心肌病理变化和胶原沉积、促进血管新生的能力减弱。机制上，miR-411 被发现靶向并抑制 HIF-1α的表达。过表达 HIF-1α 会损害 AS-IV-MSC-exo 改善 MI 小鼠心功能和促进血管新生的作用。AS-IV-MSC-exo 通过 miR-411/HIF-1α 轴改善心功能和促进血管新生，从而改善 MI。
