Lipotoxicity-induced mtDNA release promotes diabetic cardiomyopathy by activating the cGAS-STING pathway in obesity-related diabetes

• DOI: 10.1007/s10565-021-09692-z
• Publication Date: 2022-03-02T09:02:46Z
• Authors: Xiu Mei Ma; Kang Geng; Betty Yuen-Kwan Law; Peng Wang; Yue Li Pu; Qing Chen; Hui Wen Xu; Xiao Zhen Tan; Zong Zhe Jiang; Yong Xu
• Keywords: IRF3; Sting; Diabetic Cardiomyopathy; Lipotoxicity

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 activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, kidney tissues. However, role mtDNA progression DCM unclear. In this study, with an obesity-related mouse model established feeding db/db mice a high-fat diet (HFD), we observed increased cytosol activated cGAS-STING signaling during DCM, as well downstream targets, IRF3, NF-κB, IL-18, IL-1β. further study palmitic acid (PA)-induced lipotoxic cell H9C2 cells, revealed that was result PA-induced overproduction ROS, which also led activation cGAS/STING system its targets. Notably, treatment extracted alone sufficient activate cultured cells. Besides, both knockdown STING cells inhibition C-176 injection could remarkably block apoptosis cardiomyocytes. conclusion, our elucidated critical mtDNA-induced pathogenesis provided preclinical validation for using inhibitor new potential therapeutic strategy DCM. Graphical abstract