Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou 215123, Jiangsu, China.
Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou 215123, Jiangsu, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
Sci Total Environ. 2024 Apr 15;921:171177. doi: 10.1016/j.scitotenv.2024.171177. Epub 2024 Feb 23.
Vascular endothelial cell senescence plays a pivotal role in the development of atherosclerosis. Recent studies have demonstrated that ambient fine particulate matter (PM) induces stress-induced premature senescence (SIPS) in vascular endothelial cells. However, the precise mechanisms underlying this process remain to be fully elucidated. Cellular senescence is closely associated with reactive oxygen species (ROS), and emerging research has established a strong connection between the SIRT1/PGC-1α/SIRT3 signaling pathway and the antioxidant system in vascular endothelial cells. In this study, we aimed to investigate the impact of PM on vascular endothelial cell senescence and to elucidate the underlying mechanisms. Our findings revealed that PM exposure led to an increase in senescence-associated β-galactosidase (SA-β-gal) activity and the expression of the cell cycle-blocking proteins P53/P21 and P16 in human umbilical vein endothelial cells (HUVECs). Flow cytometry analysis demonstrated an elevated proportion of cells arrested in the G0/G1 phase after PM exposure. In addition, PM-induced cellular senescence was attributed to the disruption of the cellular antioxidative defense system through the SIRT1/PGC-1α/SIRT3 signaling pathway. The expression of cellular senescence markers was reduced after targeted scavenging of mitochondrial ROS using MitoQ. Moreover, treatment with SRT1720, a SIRT1-specific activator, upregulated the SIRT1/PGC-1α/SIRT3 signaling pathway, restored the antioxidant system, and attenuated the expression of cellular senescence markers. Taken together, our results suggest that PM downregulates the SIRT1/PGC-1α/SIRT3 signaling pathway, resulting in impaired antioxidant defenses in HUVECs. This, in turn, allows for the accumulation of ROS, leading to inhibition of endothelial cell cycle progression and the onset of stress-induced senescence in HUVECs.
血管内皮细胞衰老在动脉粥样硬化的发生发展中起着关键作用。最近的研究表明，环境细颗粒物（PM）可诱导血管内皮细胞产生应激诱导的早衰（SIPS）。然而，这一过程的确切机制仍有待充分阐明。细胞衰老与活性氧（ROS）密切相关，新兴研究已经在血管内皮细胞中建立了 SIRT1/PGC-1α/SIRT3 信号通路与抗氧化系统之间的紧密联系。在这项研究中，我们旨在研究 PM 对血管内皮细胞衰老的影响，并阐明其潜在机制。我们的研究结果表明，PM 暴露导致人脐静脉内皮细胞（HUVEC）中衰老相关β-半乳糖苷酶（SA-β-gal）活性和细胞周期阻滞蛋白 P53/P21 和 P16 的表达增加。流式细胞术分析表明，PM 暴露后，G0/G1 期停滞的细胞比例升高。此外，PM 诱导的细胞衰老归因于 SIRT1/PGC-1α/SIRT3 信号通路通过破坏细胞抗氧化防御系统而发生。使用 MitoQ 靶向清除线粒体 ROS 后，细胞衰老标志物的表达减少。此外，SIRT1 特异性激活剂 SRT1720 的处理上调了 SIRT1/PGC-1α/SIRT3 信号通路，恢复了抗氧化系统，并减弱了细胞衰老标志物的表达。综上所述，我们的研究结果表明，PM 下调了 SIRT1/PGC-1α/SIRT3 信号通路，导致 HUVEC 抗氧化防御受损。这反过来又允许 ROS 的积累，导致内皮细胞周期进程受阻，并在 HUVEC 中引发应激诱导的衰老。
