| First Author | Huangfu N | Year | 2021 |
| Journal | Front Cell Dev Biol | Volume | 9 |
| Pages | 687169 | PubMed ID | 34291051 |
| Mgi Jnum | J:321256 | Mgi Id | MGI:6730653 |
| Doi | 10.3389/fcell.2021.687169 | Citation | Huangfu N, et al. (2021) TDP43 Exacerbates Atherosclerosis Progression by Promoting Inflammation and Lipid Uptake of Macrophages. Front Cell Dev Biol 9:687169 |
| abstractText | 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 approximately 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 approximately 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 approximately 43 kDa expression increases in oxLDL-treated macrophages and PBMCs from patients with CAD. Furthermore, we find that TDP43 promotes activation of NF-kappaB 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 beta-catenin and PPAR-gamma 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 approximately 43 kDa exacerbates atherosclerosis progression by promoting inflammation and lipid uptake of macrophages, suggesting TDP43 as a potential target for developing atherosclerotic drug. |
