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Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol

Acta Pharmacologica Sinica (2024)Cite this article

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.

A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

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Fig. 1: Upregulation of the STING signaling pathway in various aging models, both in vitro and in vivo.
Fig. 2: Intervention with STING through knockdowns or inhibitors significantly alleviates EC inflammation and senescence.
Fig. 3: dsDNA and mtDNA are the true triggers that activate STING and lead to endothelial senescence.
Fig. 4: Age-related endothelial inflammation is exacerbated by STING activating the SASP process within the senescent microenvironment.
Fig. 5: EC-specific Sting deficiency significantly alleviates vascular endothelial aging.
Fig. 6: Significant improvement in paraquat-induced acute vascular inflammation and senescence in Sting-/- mice.
Fig. 7: Significant reduction in the D-gal-induced chronic vascular inflammation and senescence in Sting-/- mice.
Fig. 8: Identification of Cilostazol as a negative regulator of STING and EC inflammation and senescence induced by STING activation.
Fig. 9: EC-specific Sting knockdown reduced the development of atherosclerosis in Apoe−/− mice.
Fig. 10

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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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  1. These authors contributed equally: Zhi-hua Zheng, Jiao-jiao Wang.

Authors and Affiliations

  1. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China

    Zhi-hua Zheng, Jiao-jiao Wang, Jiu-guo Lin, Wei-le Ye, Jia-mi Zou, Ping-lian Yang, Wan-lu Qiu, Yuan-yuan Li, Dong-mei Zhang & Zhi-ping Liu

  2. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China

    Zhi-hua Zheng, Jiao-jiao Wang, Jiu-guo Lin, Wei-le Ye, Jia-mi Zou, Ping-lian Yang, Yuan-yuan Li, Dong-mei Zhang & Zhi-ping Liu

  3. Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

    Zhi-hua Zheng, Li-yin Liang, Min Li, Zhuo-ming Li & Pei-qing Liu

  4. National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

    Zhi-hua Zheng, Min Li & Pei-qing Liu

  5. Department of Ophthalmology, the First Affiliated Hospital, Jinan University, Guangzhou, 510006, China

    Wan-lu Qiu & Qing Zhou

  6. Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China

    Si-jia Yang

  7. School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen, 518060, China

    Man Zhao

  8. Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen, 518060, China

    Man Zhao

  9. Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510006, China

    Cheng-zhi Li

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Contributions

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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Correspondence to Pei-qing Liu or Zhi-ping Liu.

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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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