微小RNA-21在血清外泌体保护心肌缺血再灌注损伤中的作用及机制研究

Exosomes are involved in the physiological and pathological process of heart, while the mechanisms are still unclear. We have found that serum exosomes could protect against myocardial apoptosis induced by oxygen glucose deprivation/ reperfusion (OGD/R). Previous studies have indicated that miR-21 could protect cardiomyocytes from apoptosis. However, whether exosomes protect against myocardial apoptosis by increasing miR-21 is unclear..Based on our findings, this project will firstly identify the roles of miR-21 in the protective effects of exosomes in myocardial apoptosis by both in vitro (OGD/R model) and in vivo (acute ischemia reperfusion injury model, IRI) bases on both loss-of-function and gain-of-function experiments. After that, based on the target genes PTEN and PDCD4, in vivo and in vitro rescue experiments will be performed to identify whether these targets mediate the role of miR-21 in exosomes’ protective effects in reducing myocardial apoptosis..This project will reveal the roles and molecular mechanisms of miR-21 in protecting against myocardial apoptosis by exosomes and unearth one or more new targets for treatment of myocardial ischemia reperfusion injury.

外泌体参与心脏的一些生理病理过程，但其发挥作用的具体机制还不明确。我们发现血清外泌体可以抵抗缺糖缺氧再复糖复氧（OGD/R）诱导的心肌细胞凋亡，而有报道表明增加微小RNA-21可以抵抗心肌细胞凋亡，但是外泌体是否经由微小RNA-21发挥其保护心肌细胞凋亡的作用尚不清楚。本项目拟在细胞水平（OGD/R）和动物整体水平（急性缺血再灌注）结合功能缺失性（微小RNA-21敲除大鼠）和获得性实验（微小RNA-21转基因大鼠）来明确微小RNA-21在血清外泌体抵抗心肌细胞凋亡中的作用。基于靶基因PTEN和PDCD4，进行细胞和动物整体水平的挽救实验，阐明微小RNA-21介导血清外泌体抵抗心肌细胞凋亡的分子机制。本项目将揭示血清外泌体通过微小RNA-21抵抗心肌细胞凋亡的作用及分子机制，发掘出一种或多种治疗心肌缺血再灌注损伤的新靶点。

急性心肌梗死（AMI）是世界范围内发病率和死亡率升高的主要原因。细外泌体（EVs）被认为是一种很有前途的抗心肌梗死治疗方法。血清是外泌体的丰富来源，它运输各种microRNAs（miRNAs，miRs）。血清外泌体对缺血再灌注损伤有保护作用，但其在AMI中的作用尚不清楚。此外，miRNA是否可能与血清EVs的抗肿瘤作用有关AMI尚未确定。在这里，我们证明血清外泌体在细胞和小鼠急性心肌梗死模型中显著减少心肌细胞凋亡，并显著减轻急性心肌梗死后小鼠心脏的梗死面积。抑制miR-21的表达可降低血清外泌体抑制心肌细胞凋亡的保护作用。AMI后小鼠心脏miR-21水平降低，血清外泌体水平升高。此外，程序性细胞死亡4（PDCD4）的表达被确定为一个靶点miR-21基因。因此，本研究揭示了血清外泌体对AMI的保护作用，为AMI的治疗提供了新的策略。