Abstract
ObjectiveAtherosclerosis (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.MethodsTransactive 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.ResultsTransactive 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.ConclusionsTransactive 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.
Highlights
Atherosclerosis (AS), which is a chronic immune-inflammatory disease characterized by cholesterol overloaded-macrophages accumulation and plaque formation in blood vessels, is the major cause of cardiovascular disease, such as coronary artery disease (CAD), and stroke (Go et al, 2013; Writing Group Members et al, 2016)
We find that Transactive response deoxyribonucleic acid (DNA)-binding protein∼43 kDa (TDP43) promotes activation of NF-κB to increase inflammatory factor expression in macrophages through triggering mitochondrial DNA release to activate cyclic GMP-AMP synthase (cGAS)-stimulator of type interferon gene (STING) signaling
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
Summary
Atherosclerosis (AS), which is a chronic immune-inflammatory disease characterized by cholesterol overloaded-macrophages accumulation and plaque formation in blood vessels, is the major cause of cardiovascular disease, such as coronary artery disease (CAD), and stroke (Go et al, 2013; Writing Group Members et al, 2016). Macrophages, as the primary immune cells present in plaque, have been reported to play essential roles in the development of AS through formation of foam cells and production of inflammatory factors (Hansson and Hermansson, 2011; Moore et al, 2013). Illuminating the underlying mechanism of macrophage-mediated foam cell formation and inflammatory responses in atherosclerosis will deeper our understanding of disease and provide potential targets for developing novel drugs for AS therapy. Mis-localization and aggregation of TDP43 in the cytoplasm has been considered as an independent driver of neurodegenerative diseases, including Alzheimer’s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis (Uryu et al, 2008; Yarchoan et al, 2012; Nag et al, 2015; Yu L. et al, 2020). Whether TDP43 is involved in atherosclerosis development, especially in macrophagesmediated-foam cell formation and inflammatory responses is still unclear
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