骨间充质干细胞来源的外泌体中 miR-183-5p 的过表达通过靶向 FOXO1 保护心肌缺血/再灌注损伤。
MiR-183-5p overexpression in bone mesenchymal stem cell-derived exosomes protects against myocardial ischemia/reperfusion injury by targeting FOXO1.
机构信息
Department of Cardiovascular Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, China.
Department of Critical Care Medicine, Yantai City Yantai Mountain Hospital, Yantai, Shandong 264001, China.
出版信息
Immunobiology. 2022 May;227(3):152204. doi: 10.1016/j.imbio.2022.152204. Epub 2022 Mar 7.
OBJECTIVE
Exosomes have been suggested to serve as possible drug delivery vehicles due to their nanometer-size range and capability of transferring biological materials to recipient cells. Thus, whether miR-183-5p-overexpressing bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) could protect against myocardial ischemia/reperfusion (MI/R) injury by targeting FOXO1 was investigated.
METHODS
Exosomes were isolated from rat BMSCs, and ischemia/reperfusion (I/R) rat models were established. I/R rats were treated with Exo/NC-Exo/miR-183-5p-Exo/anti-miR-183-5p-Exo. Cardiac function, serum biochemical indices, apoptosis, myocardial infarction size, and the expression of miR-183-5p, FOXO1 and cleaved caspase 3 were assessed. Primary cardiomyocytes were isolated to establish hypoxia/reoxygenation (H/R) models to observe the function of miR-183-5p-Exo in vitro.
RESULTS
Rats in the I/R group exhibited a decreased left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS) and left ventricular systolic pressure (LVSP) but an increased left ventricular end-diastolic pressure (LVEDP), myocardial infarct size and apoptosis index (AI). In addition, in I/R rats, miR-183-5p expression was decreased, but FOXO1 and cleaved caspase 3 expression was increased. Both Exo and miR-183-5p-Exo improved the above indices in I/R rats, but miR-183-5p-Exo showed better effects. However, anti-miR-183-5p-Exo reversed the protective effect of Exo. FOXO1 was a target gene of miR-183-5p. Experiments in vitro revealed that Exo and miR-183-5p-Exo suppressed apoptosis and oxidative stress injury in H/R-induced cardiomyocytes, whereas overexpressed FOXO1 reversed the protective role of miR-183-5p-Exo.
CONCLUSION
BMSC-derived exosomal miR-183-5p could target FOXO1 to reduce apoptosis and oxidative stress in I/R cardiomyocytes and improve cardiac function, thereby protecting against MI/R injury.
目的
由于外泌体的纳米尺寸范围及其将生物材料传递给受体细胞的能力，它们被认为是潜在的药物传递载体。因此，研究了过表达 miR-183-5p 的骨髓间充质干细胞源性外泌体（BMSC-Exos）是否可以通过靶向 FOXO1 来保护心肌缺血/再灌注（MI/R）损伤。
方法
分离大鼠 BMSCs 的外泌体，并建立缺血/再灌注（I/R）大鼠模型。用 Exo/NC-Exo/miR-183-5p-Exo/anti-miR-183-5p-Exo 处理 I/R 大鼠。评估心功能、血清生化指标、细胞凋亡、心肌梗死面积以及 miR-183-5p、FOXO1 和 cleaved caspase 3 的表达。分离原代心肌细胞建立缺氧/复氧（H/R）模型，观察 miR-183-5p-Exo 的体外功能。
结果
I/R 组大鼠左心室射血分数（LVEF）、左心室短轴缩短率（LVFS）和左心室收缩压（LVSP）降低，左心室舒张末期压（LVEDP）、心肌梗死面积和凋亡指数（AI）增加。此外，在 I/R 大鼠中，miR-183-5p 的表达降低，但 FOXO1 和 cleaved caspase 3 的表达增加。Exo 和 miR-183-5p-Exo 均改善了 I/R 大鼠的上述指标，但 miR-183-5p-Exo 效果更好。然而，anti-miR-183-5p-Exo 逆转了 Exo 的保护作用。FOXO1 是 miR-183-5p 的靶基因。体外实验表明，Exo 和 miR-183-5p-Exo 抑制 H/R 诱导的心肌细胞凋亡和氧化应激损伤，而过表达 FOXO1 则逆转了 miR-183-5p-Exo 的保护作用。
结论
BMSC 来源的外泌体 miR-183-5p 可通过靶向 FOXO1 减少 I/R 心肌细胞的凋亡和氧化应激，改善心功能，从而保护心肌免受 MI/R 损伤。
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