CircUbe3a from M2 macrophage-derived small extracellular vesicles mediates myocardial fibrosis after acute myocardial infarction.
CircUbe3a from M2 macrophage-derived small extracellular vesicles mediates myocardial fibrosis after acute myocardial infarction.
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来自M2巨噬细胞来源的小细胞外囊泡的CircUbe3a介导急性心肌梗死后的心肌纤维化
作者：
Wang Y;Li C;Zhao R;Qiu Z;Shen C;Wang Z;Liu W;Zhang W;Ge J;Shi B
目的：本研究旨在探讨M2巨噬细胞（M2M）来源的小细胞外囊泡（SEV）中的环状RNA（circRNA）在心肌纤维化发展中的作用。方法：在急性心肌梗死小鼠模型中评估 M2M 衍生的细胞外囊泡 (EV) 的调节作用。使用免疫荧光、实时定量 PCR (RT-qPCR)、纳米颗粒跟踪分析、蛋白质印迹分析和电子显微镜来鉴定巨噬细胞、大细胞外囊泡 (LEV) 和 SEV。通过微阵列分析确定 M0 巨噬细胞 (M0Ms) 和 M2Ms 的 circRNA 表达谱。通过生物信息分析、细胞共培养和细胞增殖实验来研究circUbe3a的体外表达、功能和调控机制。采用qPCR、RNA免疫沉淀（RIP）、双荧光素酶报告基因检测、RNA荧光原位杂交（RNA-FISH）、Western blot分析和一系列救援实验来验证circUbe3a、miR-138-5p和RhoC之间的相关性。结果：来自 M2M 衍生 SEV 的 CircUbe3a 引发了心脏成纤维细胞 (CF) 的功能变化。 CircUbe3a 是在心肌梗塞后 M2M 浸润增加期间合成并加载到 SEV 中的。释放的 SEV 与质膜的融合可能导致 circUbe3a 释放到 CF 的胞质溶胶中。沉默或过度表达 circUbe3a 会改变 CF 体外增殖、迁移和表型转化。我们证实，circUbe3a 通过海绵 miR-138-5p，然后在体外翻译抑制 RhoC，在增强 CF 功能变化中发挥着至关重要的作用。在体内，添加M2M衍生的SEV或过度表达circUbe3a会显着加剧急性心肌梗死后的心肌纤维化，而这些效应被circUbe3a特异性shRNA部分消除。结论：我们的研究结果表明，M2M 衍生的含有 circUbe3a 的 SEV 通过直接靶向 miR-138-5p/RhoC 轴促进 CF 的增殖、迁移和表型转化，这也可能加剧急性心肌梗死后的心肌纤维化。
Objective: This study aimed to explore the role of circular RNAs (circRNAs) in M2 macrophage (M2M)-derived small extracellular vesicles (SEVs) in myocardial fibrosis development. Methods: The regulatory role of M2M-derived extracellular vesicles (EVs) was evaluated in a mouse model of acute myocardial infarction. Immunofluorescence, quantitative real-time PCR (RT-qPCR), nanoparticle tracking analysis, Western blot analysis and electron microscopy were used to identify macrophages, large extracellular vesicles (LEVs) and SEVs. The circRNA expression profiles of M0 macrophages (M0Ms) and M2Ms were determined by microarray analysis. Bioinformatic analysis, cell coculture and cell proliferation assays were performed to investigate the expression, function, and regulatory mechanisms of circUbe3a in vitro. qPCR, RNA immunoprecipitation (RIP), dual-luciferase reporter assays, RNA fluorescence in situ hybridization (RNA-FISH), Western blot analysis and a series of rescue experiments were used to verify the correlation among circUbe3a, miR-138-5p and RhoC. Results: CircUbe3a from M2M-derived SEVs triggered functional changes in cardiac fibroblasts (CFs). CircUbe3a was synthesized and loaded into SEVs during increased M2M infiltration after myocardial infarction. The fusion of the released SEVs with the plasma membrane likely caused the release of circUbe3a into the cytosol of CFs. Silencing or overexpressing circUbe3a altered CF proliferation, migration, and phenotypic transformation in vitro. We confirmed that circUbe3a plays a crucial role in enhancing functional changes in CFs by sponging miR-138-5p and then translationally repressing RhoC in vitro. In vivo, the addition of M2M-derived SEVs or overexpression of circUbe3a significantly exacerbated myocardial fibrosis after acute myocardial infarction, and these effects were partially abolished by circUbe3a-specific shRNA. Conclusions: Our findings suggest that M2M-derived circUbe3a-containing SEVs promote the proliferation, migration, and phenotypic transformation of CFs by directly targeting the miR-138-5p/RhoC axis, which may also exacerbate myocardial fibrosis after acute myocardial infarction.
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影响因子：
20.1
作者：
Pinto AR;Ilinykh A;Ivey MJ;Kuwabara JT;D'Antoni ML;Debuque R;Chandran A;Wang L;Arora K;Rosenthal NA;Tallquist MD
通讯作者：
Tallquist MD
来自亚砷酸盐转化细胞的外泌体circRNA_100284通过microRNA-217调节EZH2，通过加速细胞周期和促进细胞增殖参与人肝细胞的恶性转化。
影响因子：
9
作者：
Dai X;Chen C;Yang Q;Xue J;Chen X;Sun B;Luo F;Liu X;Xiao T;Xu H;Sun Q;Zhang A;Liu Q
通讯作者：
Liu Q
影响因子：
3.7
作者：
Lasda E;Parker R
通讯作者：
Parker R
DOI：
10.1016/j.jchromb.2018.10.006
发表时间：
2018-12-01
影响因子：
3
作者：
Ghahari, Sajjad;Ghahari, Somayeh;Nematzadeh, Ghorban Ali
通讯作者：
Nematzadeh, Ghorban Ali
梗塞心脏恶劣的微环境加速移植骨髓间充质干细胞损伤：受损心肌细胞来源的外泌体的作用
影响因子：
9
作者：
Hu M;Guo G;Huang Q;Cheng C;Xu R;Li A;Liu N;Liu S
通讯作者：
Liu S