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

作　　者：Zhi-hua Zheng Jiao-jiao Wang Jiu-guo Lin Wei-le Ye Jia-mi Zou Li-yin Liang Ping-lian Yang Wan-lu Qiu Yuan-yuan Li Si-jia Yang Man Zhao Qing Zhou Cheng-zhi Li Min Li Zhuo-ming Li Dong-mei Zhang Pei-qing Liu Zhi-ping Liu 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2024年第9期1879-1897,共19页中国药理学报（英文版）

基　　金：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);National Engineering and Technology Research Center for New Drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004).

摘　　要：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.

关 键 词：CILOSTAZOL STING endothelial cell senescence INFLAMMATION mitochondrial dysfunction atherosclerosis 

分 类 号：R543.5[医药卫生—心血管疾病]