Abstract | BACKGROUND: METHODS: RESULTS: In the chronic DIC model, we observed significant activation of the cGAS- STING pathway in cardiac ECs. Global cGAS, Sting, and Irf3 deficiency all markedly ameliorated DIC. EC-specific Sting deficiency significantly prevented DIC and endothelial dysfunction. Mechanistically, doxorubicin activated the cardiac EC cGAS- STING pathway and its target, IRF3, which directly induced CD38 expression. In cardiac ECs, the cGAS- STING pathway caused a reduction in NAD levels and subsequent mitochondrial dysfunction via the intracellular NAD glycohydrolase ( NADase) activity of CD38. Furthermore, the cardiac EC cGAS- STING pathway also regulates NAD homeostasis and mitochondrial bioenergetics in cardiomyocytes through the ecto- NADase activity of CD38. We also demonstrated that pharmacological inhibition of TANK-binding kinase 1 or CD38 effectively ameliorated DIC without compromising the anticancer effects of doxorubicin. CONCLUSIONS: Our findings indicate a critical role of the cardiac EC cGAS- STING pathway in DIC. The cGAS- STING pathway may represent a novel therapeutic target for preventing DIC.
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Authors | Wei Luo, Xiaoyi Zou, Yidan Wang, Zheng Dong, Xinyu Weng, Zhiqiang Pei, Shuai Song, Yongchao Zhao, Zilun Wei, Rifeng Gao, Beijian Zhang, Liwei Liu, Peiyuan Bai, Jin Liu, Xiang Wang, Tingwen Gao, Yang Zhang, Xiaolei Sun, Hang Chen, Kai Hu, Shisuo Du, Aijun Sun, Junbo Ge |
Journal | Circulation research
(Circ Res)
Vol. 132
Issue 11
Pg. e223-e242
(05 26 2023)
ISSN: 1524-4571 [Electronic] United States |
PMID | 37154056
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- NAD
- Nucleotidyltransferases
- Doxorubicin
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Topics |
- Mice
- Animals
- Signal Transduction
- Cardiotoxicity
- NAD
(metabolism)
- Nucleotidyltransferases
(genetics, metabolism)
- Doxorubicin
(toxicity)
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