活化的血管平滑肌细胞释放的细胞外陷阱促进动脉粥样硬化的进展。

Extracellular traps from activated vascular smooth muscle cells drive the progression of atherosclerosis.

机构信息

Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China.

Biomedical Research Center, Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai, China.

出版信息

Nat Commun. 2022 Dec 6;13(1):7500. doi: 10.1038/s41467-022-35330-1.

DOI:10.1038/s41467-022-35330-1

PMID:36473863

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9723654/

Abstract

Extracellular DNA traps (ETs) represent an immune response by which cells release essential materials like chromatin and granular proteins. Previous studies have demonstrated that the transdifferentiation of vascular smooth muscle cells (VSMCs) plays a crucial role in atherosclerosis. This study seeks to investigate the interaction between CD68 VSMCs and the formation of ETs and highlight its function in atherosclerosis. Here we show that ETs are inhibited, and atherosclerotic plaque formation is alleviated in male Myh11Pad4 mice undergoing an adeno-associated-virus-8 (AAV8) mediating overexpression of proprotein convertase subtilisin/kexin type 9 mutation (PCSK9) injection and being challenged with a high-fat diet. Obvious ETs generated from CD68 VSMCs are inhibited by Cl-amidine and DNase I in vitro. By utilizing VSMCs-lineage tracing technology and single-cell RNA sequencing (scRNA-seq), we demonstrate that the ETs from CD68 VSMCs influence the progress of atherosclerosis by regulating the direction of VSMCs' transdifferentiation through STING-SOCS1 or TLR4 signaling pathway.

摘要

细胞外 DNA 陷阱 (ETs) 代表了一种免疫反应，细胞通过这种反应释放染色质和颗粒状蛋白等重要物质。先前的研究表明，血管平滑肌细胞 (VSMCs) 的转分化在动脉粥样硬化中起着关键作用。本研究旨在探讨 CD68 VSMCs 与 ETs 形成之间的相互作用，并强调其在动脉粥样硬化中的功能。在这里，我们表明，在接受腺相关病毒 8 (AAV8) 介导的前蛋白转化酶枯草溶菌素/凝血酶 9 突变 (PCSK9) 过表达注射并接受高脂肪饮食挑战的雄性 Myh11Pad4 小鼠中，ETs 受到抑制，动脉粥样硬化斑块形成得到缓解。体外实验中，Cl-amidine 和 DNase I 抑制了来自 CD68 VSMCs 的明显 ETs 的形成。通过利用 VSMCs 谱系追踪技术和单细胞 RNA 测序 (scRNA-seq)，我们证明来自 CD68 VSMCs 的 ETs 通过 STING-SOCS1 或 TLR4 信号通路调节 VSMCs 转分化的方向，从而影响动脉粥样硬化的进展。