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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

Zhi-hua Zheng1,2,3,4, Jiao-jiao Wang1,2, Jiu-guo Lin1,2, Wei-le Ye1,2, Jia-mi Zou1,2, Li-yin Liang3, Ping-lian Yang1,2, Wan-lu Qiu1,5, Yuan-yuan Li1,2, Si-jia Yang6, Man Zhao7,8, Qing Zhou5, Cheng-zhi Li9, Min Li3,4, Zhuo-ming Li3, Dong-mei Zhang1,2, Pei-qing Liu3,4, Zhi-ping Liu1,2
1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
2 Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
3 Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
4 National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
5 Department of Ophthalmology, the First Affiliated Hospital, Jinan University, Guangzhou 510006, China
6 Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
7 School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518060, China
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
9 Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510006, China
Correspondence to: Pei-qing Liu: liupq@mail.sysu.edu.cn, Zhi-ping Liu: liuzhiping@jnu.edu.cn,
DOI: 10.1038/s41401-024-01281-0
Received: 19 December 2023
Accepted: 28 March 2024
Advance online: 30 April 2024

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.
Keywords: cilostazol; STING; endothelial cell senescence; inflammation; mitochondrial dysfunction; atherosclerosis

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