State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China.
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
Acta Pharmacol Sin. 2024 Sep;45(9):1879-1897. doi: 10.1038/s41401-024-01281-0. Epub 2024 Apr 30.
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.
内皮衰老、与衰老相关的炎症和线粒体功能障碍是血管衰老的突出特征，并导致与衰老相关的血管疾病的发展。越来越多的证据表明，衰老血管细胞，特别是内皮细胞 (ECs) 中会发生 DNA 损伤。然而，EC 衰老的机制尚未完全阐明，迄今为止，临床上尚无专门用于治疗 EC 衰老和血管衰老的药物。在这里，我们表明，各种衰老刺激会在内皮细胞中诱导核 DNA 和线粒体损伤，从而促进细胞质游离 DNA (cfDNA) 的释放，进而激活 DNA 感应衔接蛋白 STING。STING 的激活导致与衰老相关的分泌表型 (SASP)，从而释放促衰老细胞因子和 cfDNA，进一步加剧线粒体损伤和 EC 衰老，从而形成恶性循环，所有这些都可以通过 STING 敲低或抑制来抑制。通过下一代 RNA 测序，我们证明 STING 的激活刺激，而 STING 的抑制破坏与细胞衰老和 SASP 相关的途径。体内研究表明，内皮特异性 Sting 缺失可减轻与衰老相关的内皮炎症和线粒体功能障碍，并防止小鼠动脉粥样硬化的发展。通过筛选 FDA 批准的血管保护药物，我们发现 Cilostazol 是一种新的 STING 抑制剂，可在体外和体内减轻与衰老相关的内皮炎症。我们证明 Cilostazol 通过靶向 STING 的 S162 和 S243 残基，显著抑制 STING 激活时从内质网到高尔基体的易位。这些结果揭示了 cfDNA-STING-SASP-cfDNA 恶性循环对 EC 衰老和动脉粥样形成的有害影响，并表明 STING 途径是血管衰老相关疾病的有前途的治疗靶点。提出的模型说明了 STING 在介导 cfDNA-STING-SASP-cfDNA 恶性循环以加剧与年龄相关的内皮炎症和线粒体损伤中的核心作用。
