Abstract | OBJECTIVE:
Atherosclerosis (AS), characterized by cholesterol overloaded-macrophages accumulation and plaque formation in blood vessels, is the major cause of cardiovascular disease. Transactive response DNA-binding protein∼43 kDa (TDP43) has recently been identified as an independent driver of neurodegenerative diseases through triggering inflammatory response. This study investigated whether TDP43 is involved in AS development, especially in macrophages-mediated-foam cell formation and inflammatory responses. METHODS: Transactive response DNA-binding protein∼43 kDa expressions in oxidized low-density lipoprotein ( oxLDL)-treated macrophages and peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD) were detected by real time-polymerase chain reaction (RT-PCR), Western blot, and immunofluorescence. Gene gain or loss of function was used to investigate the effects of TDP43 on macrophages-mediated lipid untake and inflammation with ELISA, protein immunoprecipitation, RT-PCR, Western blot, and immunofluorescence. Macrophage TDP43 specific knockout mice with ApoE-/- background were fed with western diet for 12 weeks to establish AS model, and used to explore the role of TDP43 on AS progression. RESULTS: Transactive response DNA-binding protein∼43 kDa expression increases in oxLDL-treated macrophages and PBMCs from patients with CAD. Furthermore, we find that TDP43 promotes activation of NF-κB to increase inflammatory factor expression in macrophages through triggering mitochondrial DNA release to activate cGAS- STING signaling. Moreover, TDP43 strengthens lipid uptake of macrophages through regulating β- catenin and PPAR-γ complex to promote scavenger receptor gene CD36 transcription. Finally, using macrophage TDP43 specific knockout mice with ApoE-/- background fed with western diet for 12 weeks to establish AS model, we find that specific knockout of TDP43 in macrophages obviously alleviates western diet-induced AS progression in mice. CONCLUSIONS: Transactive response DNA-binding protein∼43 kDa exacerbates atherosclerosis progression by promoting inflammation and lipid uptake of macrophages, suggesting TDP43 as a potential target for developing atherosclerotic drug.
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Authors | Ning Huangfu, Yong Wang, Zhenyu Xu, Wenyuan Zheng, Chunlan Tao, Zhenwei Li, Yewen Hu, Xiaomin Chen |
Journal | Frontiers in cell and developmental biology
(Front Cell Dev Biol)
Vol. 9
Pg. 687169
( 2021)
ISSN: 2296-634X [Print] Switzerland |
PMID | 34291051
(Publication Type: Journal Article)
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Copyright | Copyright © 2021 Huangfu, Wang, Xu, Zheng, Tao, Li, Hu and Chen. |