干扰素基因刺激剂
内部收益率3
刺
线粒体
糖尿病性心肌病
脂毒性
胞浆
细胞生物学
炎症
细胞凋亡
线粒体DNA
信号转导
生物
药理学
内科学
内分泌学
医学
心肌病
糖尿病
心力衰竭
生物化学
胰岛素抵抗
基因
先天免疫系统
受体
酶
航空航天工程
工程类
作者
Xiu Mei,Kang Geng,Betty Yuen‐Kwan Law,Peng Wang,Yue Li Pu,Qing Chen,Haibo Xu,Xiao Zhen Tan,Zong Zhe Jiang,Yong Xu
标识
DOI:10.1007/s10565-021-09692-z
摘要
Abstract 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. Graphical abstract
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