TDP43 Exacerbates Atherosclerosis Progression by Promoting Inflammation and Lipid Uptake of Macrophages.
TDP43 Exacerbates Atherosclerosis Progression by Promoting Inflammation and Lipid Uptake of Macrophages.
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DOI：
10.3389/fcell.2021.687169
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发表时间：
2021
影响因子：
5.5
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Huangfu N;Wang Y;Xu Z;Zheng W;Tao C;Li Z;Hu Y;Chen X
动脉粥样硬化（AS）是心血管疾病的主要原因，其特征是胆固醇超负荷-巨噬细胞积聚和斑块形成。近年来，反式反应DNA结合蛋白TDP 43（Transactive response DNA binding protein TDP 43）被认为是神经退行性疾病的一个独立驱动因子，它通过引发炎症反应而发挥作用。本研究探讨了TDP 43是否参与AS的发展，特别是在巨噬细胞介导的泡沫细胞形成和炎症反应。采用真实的时间-聚合酶链反应（RT-PCR）、免疫印迹和免疫荧光法检测冠心病（CAD）患者巨噬细胞和外周血单个核细胞（PBMC）经氧化低密度脂蛋白（oxLDL）处理后的转录反应DNA结合蛋白（DNA-binding protein，DNA-binding protein）的表达。采用ELISA、蛋白质免疫沉淀、RT-PCR、Western blot和免疫荧光等方法，研究TDP 43对巨噬细胞介导的脂质摄取和炎症的影响。采用ApoE-/-背景的巨噬细胞TDP 43特异性基因敲除小鼠，以西式饲料喂养12周建立AS模型，探讨TDP 43在AS进展中的作用。CAD患者oxLDL处理的巨噬细胞和PBMC中的反式反应DNA结合蛋白43 kDa表达增加此外，我们发现TDP 43通过触发线粒体DNA释放来激活cGAS-STING信号，从而促进NF-κB的活化，从而增加巨噬细胞中炎症因子的表达。此外，TDP 43通过调节β-catenin和PPAR-γ复合物促进清道夫受体基因CD 36的转录，增强巨噬细胞的脂质摄取。最后，我们利用ApoE-/-背景的巨噬细胞TDP 43特异性敲除小鼠，通过饲喂西方饮食建立AS模型12周，发现巨噬细胞中TDP 43的特异性敲除明显延缓了西方饮食诱导的小鼠AS进展。反式反应DNA结合蛋白TDP 43 kDa通过促进巨噬细胞的炎症和脂质摄取而加剧动脉粥样硬化进展，这表明TDP 43是开发动脉粥样硬化药物的潜在靶点。
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. 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. 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. 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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影响因子：
16.8
作者：
Koltsova EK;Ley K
通讯作者：
Ley K
影响因子：
37.8
作者：
Go AS;Mozaffarian D;Roger VL;Benjamin EJ;Berry JD;Blaha MJ;Dai S;Ford ES;Fox CS;Franco S;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Huffman MD;Judd SE;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Mackey RH;Magid DJ;Marcus GM;Marelli A;Matchar DB;McGuire DK;Mohler ER 3rd;Moy CS;Mussolino ME;Neumar RW;Nichol G;Pandey DK;Paynter NP;Reeves MJ;Sorlie PD;Stein J;Towfighi A;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
巨噬细胞中铁的积累促进泡沫细胞的形成和动脉粥样硬化的发展
影响因子：
7.5
作者：
Cai J;Zhang M;Liu Y;Li H;Shang L;Xu T;Chen Z;Wang F;Qiao T;Li K
通讯作者：
Li K
影响因子：
82.9
作者：
Kerur N;Fukuda S;Banerjee D;Kim Y;Fu D;Apicella I;Varshney A;Yasuma R;Fowler BJ;Baghdasaryan E;Marion KM;Huang X;Yasuma T;Hirano Y;Serbulea V;Ambati M;Ambati VL;Kajiwara Y;Ambati K;Hirahara S;Bastos-Carvalho A;Ogura Y;Terasaki H;Oshika T;Kim KB;Hinton DR;Leitinger N;Cambier JC;Buxbaum JD;Kenney MC;Jazwinski SM;Nagai H;Hara I;West AP;Fitzgerald KA;Sadda SR;Gelfand BD;Ambati J
通讯作者：
Ambati J
DOI：
10.1038/nri3520
发表时间：
2013-10
期刊：
Nature reviews. Immunology
影响因子：
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作者：
通讯作者：
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