EZH2 通过 HMGA2 介导线粒体 PI3K/AKT 信号通路减轻间充质干细胞分泌的外泌体对梗死的心脏保护作用。

EZH2 mitigates the cardioprotective effects of mesenchymal stem cell-secreted exosomes against infarction via HMGA2-mediated PI3K/AKT signaling.

机构信息

Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China.

Department of Cardiac Macrovascular Surgery, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Xinhua District, Shijiazhuang, 050000, Hebei, People's Republic of China.

出版信息

BMC Cardiovasc Disord. 2022 Mar 9;22(1):95. doi: 10.1186/s12872-022-02533-9.

BACKGROUND

Mesenchymal stem cell-derived exosomes (MSC-EXO) have emerged as novel therapeutic strategies for myocardial infarction (MI). However, many questions remain untouched and unanswered regarding their roles in myocardial fibrosis. This study aimed to probe the therapeutic effects of MSC-EXO on myocardial fibrosis after MI and possible mechanisms.

METHODS

Myocardial tissues were obtained from MI rats, and myocardial cell viability, fibrosis, apoptosis, and epithelial-mesenchymal transition (EMT) were detected by immunohistochemistry, Masson's staining, TUNEL, and western blot. Bone marrow-derived MSCs and corresponding EXO were identified, and cardiac function were detected after treatment of MSC-EXO. Bioinformatics analysis and ChIP assay were conducted to detect the downstream genes of EZH2. EZH2 was upregulated alone or with HMGA2 overexpression in myocardial tissues of MI rats upon MSC-EXO treatment, and PI3K/AKT pathway activity in myocardial tissues was detected using western blot.

RESULTS

The proliferative activity in myocardial tissues of MI rats was significantly decreased, along with accentuated fibrosis, increased collagen volume and EMT. MSC-EXO treatment resulted in partial restoration of cardiac function and reduced EZH2 expression in the myocardium of rats. EZH2 inhibited HMGA2 expression by increasing the H3K27me3 modification. PI3K/AKT pathway was altered under the influence of the EZH2/HMGA2 axis. EZH2 inhibited the effect of MSC-EXO on the recovery of cardiac function and accelerated fibrosis, while HMGA2 reversed the effect of EZH2 to reduce fibrosis and enhance cardiac function.

CONCLUSION

MSC-EXO alleviated fibrosis in MI rats via inhibition of EZH2, whereas EZH2 inhibited HMGA2 expression and impaired the PI3K/AKT pathway.

背景

间充质干细胞衍生的外泌体（MSC-EXO）已成为心肌梗死（MI）的新型治疗策略。然而，关于它们在心肌纤维化中的作用仍有许多问题尚未得到解答。本研究旨在探讨 MSC-EXO 对 MI 后心肌纤维化的治疗作用及其可能的机制。

方法

取 MI 大鼠心肌组织，通过免疫组化、Masson 染色、TUNEL 和 Western blot 检测心肌细胞活力、纤维化、凋亡和上皮间质转化（EMT）。鉴定骨髓源性 MSC 和相应的 EXO，并在 MSC-EXO 处理后检测心脏功能。通过生物信息学分析和 ChIP 测定检测 EZH2 的下游基因。单独或与 HMGA2 过表达一起在 MSC-EXO 处理后的 MI 大鼠心肌组织中上调 EZH2，并通过 Western blot 检测心肌组织中 PI3K/AKT 通路的活性。

结果

MI 大鼠心肌组织的增殖活性明显降低，纤维化加重，胶原容积增加，EMT 增强。MSC-EXO 治疗导致大鼠心肌功能部分恢复，EZH2 表达降低。EZH2 通过增加 H3K27me3 修饰抑制 HMGA2 的表达。EZH2/HMGA2 轴改变了 PI3K/AKT 通路。EZH2 抑制 MSC-EXO 对心脏功能恢复和纤维化加速的作用，而 HMGA2 逆转了 EZH2 减少纤维化和增强心脏功能的作用。