Circulating extracellular vesicles regulate ELAVL1 by delivering miR-133a-3p which affecting NLRP3 mRNA stability inhibiting PANoptosome formation.

IF 5.7 2区生物学 Q1 BIOLOGY

Biology Direct Pub Date : 2025-03-26 DOI:10.1186/s13062-025-00605-2

Deliang Wang, Zheng Dai, Lu Jiang, Ke Liu

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引用次数: 0

Abstract

Background: In the quest to elucidate novel therapeutic strategies for myocardial injury, recent investigations have underscored the pivotal roles played by circulating extracellular vesicles (EVs) in intercellular communication.

Method: EVs were extracted from individuals who had experienced AMI-EVs and those who were N-EVs. To assess the impact of circulating EVs on cardiomyocyte and endothelial cell proliferation, apoptosis, migration, and tube formation, a range of in vitro assays such as CCK8, EdU assays, flow cytometry, wound healing assays and angiogenesis assays were conducted. Differentially expressed miRNAs in EVs were validated using microarray analysis and real-time PCR. Through bioinformatics analysis, ELAVL1 was identified as a potential downstream target of miR-133a-3p. This finding was further confirmed by conducting dual-luciferase reporter assay and RNA co-immunoprecipitation experiments. To investigate the regulatory effects of circulating EVs from various sources on myocardial injury and PANoptosis, an animal model of ischemia-reperfusion-induced myocardial injury was established.

Result: Our findings revealed that circulating EVs effectively deliver miR-133a-3p to target cells, where it binds to ELAVL1, leading to a decrease in NLRP3 mRNA stability. This reduction in NLRP3 mRNA stability subsequently inhibits the assembly of the PANoptosome, a multi-protein complex implicated in PANoptosis. As a result, we observed a significant mitigation of PANoptosis in our myocardial injury models, demonstrating the protective role of miR-133a-3p against excessive cell death.

Conclusion: The present study underscores the regulatory role of circulating EV-delivered miR-133a-3p in modulating PANoptosis through ELAVL1-mediated NLRP3 mRNA stabilization. This mechanism represents a potential therapeutic target for attenuating myocardial injury by suppressing PANoptosis.

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循环细胞外囊泡通过传递miR-133a-3p来调节ELAVL1， miR-133a-3p影响NLRP3 mRNA的稳定性，抑制PANoptosome的形成。

背景：为了阐明心肌损伤的新治疗策略，最近的研究强调了循环细胞外囊泡（EVs）在细胞间通讯中的关键作用。方法：分别从ami - ev患者和n - ev患者中提取ev。为了评估循环ev对心肌细胞和内皮细胞增殖、凋亡、迁移和管形成的影响，进行了一系列体外实验，如CCK8、EdU实验、流式细胞术、伤口愈合实验和血管生成实验。通过微阵列分析和实时PCR验证ev中差异表达的mirna。通过生物信息学分析，ELAVL1被确定为miR-133a-3p的潜在下游靶点。双荧光素酶报告基因实验和RNA共免疫沉淀实验进一步证实了这一发现。为了研究各种来源的循环ev对心肌损伤和PANoptosis的调节作用，我们建立了缺血再灌注心肌损伤动物模型。结果：我们的研究结果表明，循环ev有效地将miR-133a-3p传递到靶细胞，在那里它与ELAVL1结合，导致NLRP3 mRNA稳定性降低。NLRP3 mRNA稳定性的降低随后抑制PANoptosome的组装，PANoptosome是一种与PANoptosis有关的多蛋白复合物。因此，我们在心肌损伤模型中观察到PANoptosis的显著缓解，证明了miR-133a-3p对过度细胞死亡的保护作用。结论：本研究强调了循环ev传递的miR-133a-3p通过elavl1介导的NLRP3 mRNA稳定调节PANoptosis的调节作用。这一机制代表了通过抑制PANoptosis来减轻心肌损伤的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biology Direct 生物-生物学

CiteScore

6.40

自引率

10.90%

发文量

审稿时长

7 months

期刊介绍： Biology Direct serves the life science research community as an open access, peer-reviewed online journal, providing authors and readers with an alternative to the traditional model of peer review. Biology Direct considers original research articles, hypotheses, comments, discovery notes and reviews in subject areas currently identified as those most conducive to the open review approach, primarily those with a significant non-experimental component.