Lipotoxicity-induced mtDNA release promotes diabetic cardiomyopathy by activating the cGAS-STING pathway in obesity-related diabetes.
Lipotoxicity-induced mtDNA release promotes diabetic cardiomyopathy by activating the cGAS-STING pathway in obesity-related diabetes.
复制标题
DOI：
10.1007/s10565-021-09692-z
复制
发表时间：
2023-02
影响因子：
6.1
通讯作者：
中科院分区：
文献类型：
--
作者：
糖尿病心肌病（DCM）的特点是脂质蓄积、线粒体功能障碍和无菌性炎症激活。据报道，线粒体来源的胞质 DNA 可通过激活脂肪、肝脏和肾脏组织中的环 GMP-AMP 合酶 (cGAS)/干扰素基因刺激剂 (STING) 途径来诱导炎症。然而，胞质 mtDNA 在 DCM 进展中的作用尚不清楚。在这项研究中，通过用高脂饮食（HFD）喂养db/db小鼠建立了肥胖相关的DCM小鼠模型，我们观察到DCM期间细胞质中mtDNA增加并激活cGAS-STING信号通路，以及下游靶标IRF3、NF-κB、IL-18和IL-1β。在对 H9C2 细胞中建立的棕榈酸 (PA) 诱导的脂毒性细胞模型的进一步研究中，我们发现胞质 mtDNA 是 PA 诱导线粒体 ROS 过量产生的结果，这也导致 cGAS/STING 系统及其下游靶标的激活。值得注意的是，仅对提取的线粒体 DNA 进行处理就足以激活培养的 H9C2 细胞中的 cGAS-STING 信号通路。此外，在PA诱导的H9C2细胞中敲低STING以及在DCM小鼠模型中注射C-176抑制STING都可以显着阻断心肌细胞的炎症和凋亡。总之，我们的研究阐明了胞质 mtDNA 诱导的 cGAS-STING 激活在肥胖相关 DCM 发病机制中的关键作用，并为使用 STING 抑制剂作为治疗 DCM 的新的潜在治疗策略提供了临床前验证。在线版本包含可在 10.1007/s10565-021-09692-z 获取的补充材料。线粒体来源的胞质 DNA 是高脂血症诱导的线粒体功能障碍和 DCM 发病机制之间的关键链接。 cGAS-STING 通路通过感知释放的胞质 mtDNA 介导脂毒性诱导的心肌功能障碍。 STING被确定为治疗DCM的新的潜在治疗靶点。在线版本包含可在 10.1007/s10565-021-09692-z 获取的补充材料。
Diabetic cardiomyopathy (DCM) is characterized by lipid accumulation, mitochondrial dysfunction, and aseptic inflammatory activation. Mitochondria-derived cytosolic DNA has been reported to induce inflammation by activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, and kidney tissues. However, the role of cytosolic mtDNA in the progression of DCM is unclear. In this study, with an obesity-related DCM mouse model established by feeding db/db mice with a high-fat diet (HFD), we observed increased mtDNA in the cytosol and activated cGAS-STING signaling pathway during DCM, as well as the downstream targets, IRF3, NF-κB, IL-18, and IL-1β. In a further study with a palmitic acid (PA)-induced lipotoxic cell model established in H9C2 cells, we revealed that the cytosolic mtDNA was the result of PA-induced overproduction of mitochondrial ROS, which also led to the activation of the cGAS/STING system and its downstream targets. Notably, treatment of extracted mtDNA alone was sufficient to activate the cGAS-STING signaling pathway in cultured H9C2 cells. Besides, both knockdown of STING in PA-induced H9C2 cells and inhibition of STING by C-176 injection in the DCM mouse model could remarkably block the inflammation and apoptosis of cardiomyocytes. In conclusion, our study elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation for using a STING inhibitor as a new potential therapeutic strategy for the treatment of DCM. The online version contains supplementary material available at 10.1007/s10565-021-09692-z. Mitochondria-derived cytosolic DNA acts as a critical linker between hyperlipidemia-induced mitochondrial dysfunction and pathogenesis of DCM. cGAS-STING pathway mediates the lipotoxicity-induced myocardial dysfunction through sensing released cytosolic mtDNA. STING was identified as a new potential therapeutic target for the treatment of DCM. The online version contains supplementary material available at 10.1007/s10565-021-09692-z.
登录
查看更多内容
影响因子：
4.6
作者：
Isfort, Michael;Stevens, Sarah C. W.;Schaffer, Stephen;Jong, Chian Ju;Wold, Loren E.
通讯作者：
Wold, Loren E.
影响因子：
15.9
作者：
Marinho FV;Benmerzoug S;Oliveira SC;Ryffel B;Quesniaux VFJ
通讯作者：
Quesniaux VFJ
靶向先天免疫 cGAS–STING–TBK1 信号通路的小分子
DOI：
10.1016/j.apsb.2020.03.001
发表时间：
2020-12
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Ding C;Song Z;Shen A;Chen T;Zhang A
通讯作者：
Zhang A
影响因子：
64.8
作者：
Morehouse BR;Govande AA;Millman A;Keszei AFA;Lowey B;Ofir G;Shao S;Sorek R;Kranzusch PJ
通讯作者：
Kranzusch PJ
影响因子：
20.1
作者：
Chen YR;Zweier JL
通讯作者：
Zweier JL