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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2022-03-02

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

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 More... »

PAGES

1-23

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10565-021-09692-z

DOI

http://dx.doi.org/10.1007/s10565-021-09692-z

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https://app.dimensions.ai/details/publication/pub.1145980784

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/35235096


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23 DNA
24 Further studies
25 GMP-AMP synthase
26 H9c2 cells
27 IL-18
28 IL-1β
29 IRF3
30 NF-κB
31 PA
32 ROS
33 STING inhibitor
34 accumulation
35 acid
36 activation
37 adipose
38 apoptosis
39 apoptosis of cardiomyocytes
40 cGAS-STING
41 cGAS-STING activation
42 cGAS-STING pathway
43 cardiomyocytes
44 cell model
45 cells
46 conclusion
47 critical role
48 cultured H9c2 cells
49 cyclic GMP-AMP synthase
50 cytosol
51 cytosolic DNA
52 cytosolic mtDNA
53 db mice
54 db/db mice
55 diabetes
56 diet
57 downstream targets
58 dysfunction
59 gene pathways
60 high-fat diet
61 inflammation
62 inflammatory activation
63 inhibition
64 inhibition of STING
65 inhibitors
66 injection
67 interferon genes (STING) pathway
68 kidney tissue
69 knockdown
70 knockdown of STING
71 lipid accumulation
72 liver
73 mice
74 mitochondria
75 mitochondrial ROS
76 mitochondrial dysfunction
77 model
78 mouse model
79 mtDNA
80 mtDNA release
81 new potential therapeutic strategy
82 obesity-related diabetes
83 overproduction
84 palmitic acid
85 pathogenesis
86 pathway
87 potential therapeutic strategy
88 preclinical validation
89 progression
90 progression of DCM
91 release
92 results
93 results of PA
94 role
95 stimulator
96 stings
97 strategies
98 study
99 synthase
100 system
101 target
102 therapeutic strategies
103 tissue
104 treatment
105 treatment of DCM
106 validation
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