Extracellular Vesicle Packaged TDP43 Derived From ECs Exacerbates Cigarette Tar-Related Atherosclerosis Progression via Enhancing Macrophage Extracellular Traps.

Authors

Xinxin Zhu, Yuwu Chen, Wei Meng, Biyi Xu, Junke Mou, Xiaolin Liu, Mengyang Wang, Qishuo Gu, Qianhui Sun, Man Li, Chen Zhao, Ming Zeng, Ying Lv, Boling Yi, Sheng Qu, Xiaoxuan Bai, Ji Li, Xing Luo, Sining Hu, Bo Yu, Haibo Jia

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e78001. Sep 27, 2026. Epub Sep 27, 2026.

Abstract

Smoking acts as a critical risk factor for atherosclerosis (AS), but the precise molecular mechanisms remain unclear. We performed in vivo experiments with TAR-injected ApoE^-/- mice and in vitro co-culture of macrophages with extracellular vesicles (EVs) from TAR-treated endothelial cells (ECs). Single-cell RNA sequencing were used to explore the regulatory effects and molecular pathways of ECs-derived EVs in smoke-related AS. Cigarette TAR significantly stimulated ECs EV secretion and aggravated atherosclerotic plaques, while the EV inhibitor GW4869 alleviated these lesions. RNA-seq indicated TAR facilitated AS by increasing macrophage extracellular traps (METs) formation. Combined in vivo and in vitro proteomics showed TDP43 was highly enriched in circulating EVs from smoking patients, TAR-treated mice, and stimulated ECs. TDP43 knockdown alleviated TAR-induced AS, accompanied by suppressed METs and inflammatory responses. Mechanistically, EV-delivered TDP43 bound macrophage VDAC1 to induce mitochondria-associated membranes (MAMs), triggering Ca²⁺ overload/METs; 2-APB and BAPTA blocked this process. Retinoic acid (RA) might bind with TDP43 to inhibit MAMs, thereby reducing METs and mitigating smoke-related AS. Cigarette TAR accelerates ASthrough EC EV-packaged TDP43 partly, which binds VDAC1 to induce MAMs, calcium overload, METs, and inflammation. RA may serve as a putative protective molecule for the progression of smoking-related atherosclerotic plaques.

PMID:
42801562
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.