Abstract
Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases.
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Acknowledgements
This work is supported by National Natural Science Foundation of China (82270500, 81870324, 82203304, U21A20419), Guangdong Basic and Applied Basic Research Foundation (2024B1515020113), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093) and National Engineering and Technology Research Center for New Drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004).
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ZHZ, PQL, and ZPL designed the study. ZHZ, JJW, JGL, WLY, JMZ, LYL, PLY, WLQ, YYL, SJY, and MZ performed the experiments and analyzed the data. ZHZ wrote the manuscript. QZ, CZL, ML, ZML, DMZ, PQL and ZPL provided the reagents or materials, participated in designing the experiments, and critically reviewed and revised the manuscript.
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Zheng, Zh., Wang, Jj., Lin, Jg. et al. Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01281-0
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DOI: https://doi.org/10.1038/s41401-024-01281-0