Department of Cardiovascular Medicine, Cangzhou Central Hospital, Cangzhou, Hebei, China.
Eur Rev Med Pharmacol Sci. 2020 Oct;24(20):10619-10631. doi: 10.26355/eurrev_202010_23420.
Pulmonary embolism (PE) is a primary clinical manifestation of venous thromboembolism (VTE). It has been demonstrated that pulmonary endothelial cells (PECs) are apoptotic-resistant in PE.
In this study, PECs were collected from PE patients and mouse models. Western blot, RT-PCR, flow cytometry, H&E and TUNEL assay, confocal and TEM microscopy, and Luciferase reporter assay were performed to determine the effects of miR-28-3p on PECs apoptosis and if exosomes can act as the shuttle to transport miR-28-3p to PECs.
The results revealed that apoptosis and miR-28-3p were downregulated in PECs of PE. The miR-28-3p mimics and inhibitor enhanced and further inhibited apoptosis in PECs, respectively. Both miR-28-3p-modified adipose tissue-derived mesenchymal stem cells (AMSCs) and AMSC-derived exosomes upregulated miR-28-3p expression in PECs, leading to elevated apoptosis of PECs. Apoptosis inhibitor 5 (API5) was a direct target gene of miR-28-3p, and the overexpression of API5 in miR-28-3p-modified PECs further suppressed apoptosis. Furthermore, the administration of miR-28-3p-modified exosomes to PE mouse model promoted apoptosis in PECs.
Exosomal miR-28-3p could ameliorate PE-associated apoptosis-resistance in PECs through targeting API5 in vitro and in vivo. Therefore, AMSCs-derived exosome is a promising way to deliver functioning miRNA to PECs, providing insight into novel therapy of PE.
肺栓塞（PE）是静脉血栓栓塞症（VTE）的主要临床表现。已有研究表明，PE 患者的肺血管内皮细胞（PEC）具有抗凋亡特性。
本研究从 PE 患者和小鼠模型中收集 PEC。采用 Western blot、RT-PCR、流式细胞术、H&E 和 TUNEL 检测、共聚焦和透射电镜以及荧光素酶报告基因检测，以确定 miR-28-3p 对 PEC 凋亡的影响，以及外泌体是否可以作为将 miR-28-3p 转运至 PEC 的载体。
结果显示，PE 患者的 PEC 中凋亡和 miR-28-3p 表达下调。miR-28-3p 模拟物和抑制剂分别增强和进一步抑制 PEC 凋亡。miR-28-3p 修饰的脂肪组织来源的间充质干细胞（AMSCs）和 AMSC 衍生的外泌体均能上调 PEC 中的 miR-28-3p 表达，导致 PEC 凋亡增加。凋亡抑制剂 5（API5）是 miR-28-3p 的直接靶基因，miR-28-3p 修饰的 PEC 中 API5 的过表达进一步抑制了凋亡。此外，向 PE 小鼠模型中给予 miR-28-3p 修饰的外泌体可促进 PEC 中的凋亡。
外泌体 miR-28-3p 可通过在体外和体内靶向 API5 改善 PE 相关的 PEC 凋亡抵抗。因此，AMSCs 衍生的外泌体是一种有前途的向 PEC 输送功能 miRNA 的方法，为 PE 的新型治疗提供了思路。
