Malat1 通过与 EZH2 结合增加 PPAR-γ 甲基化从而促进急性心肌梗死中巨噬细胞相关炎症。

Malat1 promotes macrophage-associated inflammation by increasing PPAR-γ methylation through binding to EZH2 in acute myocardial infarction.

机构信息

School of Medicine, Shandong University, Jinan 250012, China.

Department of Cardiology, Yantai Yuhuangding Hospital, Yantai 264000, China.

出版信息

Int Immunopharmacol. 2023 Oct;123:110695. doi: 10.1016/j.intimp.2023.110695. Epub 2023 Aug 15.

DOI:10.1016/j.intimp.2023.110695

PMID:37591118

Abstract

The inflammatory microenvironment of macrophage plays an important role in acute myocardial infarction (AMI), but the regulatory mechanism is unknown. Here, we aimed to investigate the role of Malat1 on inflammation microenvironment of macrophage in AMI. Our study found that Malat1 expression was increased in AMI, which mainly expressed in macrophages. Malat1 inhibition improved collagen deposition and inflammation in infarcted heart. In vitro, Malat1 inhibition evidently reduced macrophage-associated inflammation. The results from ribonucleic acid pull-down (RNA pull-down) and RNA Immunoprecipitation (RIP) assay demonstrated that Malat1 directly binds to EZH2. Malat1 and EZH2 complex could increase histone H3K27me3 expression and further inhibit the production of PPAR-γ. In vivo, inhibition of Malat1 also leaded to the down-regulation of both EZH2 and H3K27me3, as well as up-regulation of PPAR-γ in infarcted heart. Therefore, these findings demonstrate a novel mechanism of Malat1 on inflammation microenvironment of macrophage in AMI, which provide a new target for its treatment.

摘要

巨噬细胞的炎症微环境在急性心肌梗死（AMI）中起着重要作用，但调控机制尚不清楚。在这里，我们旨在研究 Malat1 在 AMI 中对巨噬细胞炎症微环境的作用。我们的研究发现，Malat1 在 AMI 中表达增加，主要在巨噬细胞中表达。Malat1 抑制可改善梗死心脏的胶原沉积和炎症。在体外，Malat1 抑制明显减少了与巨噬细胞相关的炎症。RNA 下拉（RNA pull-down）和 RNA 免疫沉淀（RIP）实验的结果表明，Malat1 可直接与 EZH2 结合。Malat1 和 EZH2 复合物可增加组蛋白 H3K27me3 的表达，进而抑制 PPAR-γ 的产生。在体内，Malat1 的抑制也导致了梗死心脏中 EZH2 和 H3K27me3 的下调以及 PPAR-γ 的上调。因此，这些发现表明 Malat1 在 AMI 中对巨噬细胞炎症微环境具有新的作用机制，为其治疗提供了新的靶点。