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

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.