Nrf2调控的线粒体质量控制在纳米银内皮细胞毒性和硒保护中的作用

纳米银(AgNP)广泛应用于医疗和技术领域，其心血管损害已受到关注。我们前期研究和最新文献显示线粒体质量控制在AgNP细胞毒性中起重要作用，但其在AgNP血管内皮损伤中的作用及调控的关键靶点尚未阐明。预实验结果显示AgNP激活线粒体凋亡通路，引起线粒体形态改变，下调Nrf2表达，增加线粒体分裂，引起内皮细胞损伤。我们依此提出科学假说：AgNP通过减少Nrf2影响线粒体质量控制使线粒体出现分裂增加、再生减少及功能减退，最终导致内皮细胞死亡。硒通过激活Nrf2，保护线粒体功能，阻止AgNP导致的线粒体质量控制失调和细胞损伤。本课题利用体内外染毒模型，观察AgNP对内皮细胞线粒体质量控制的影响，结合Nrf2敲除/过表达，明确Nrf2是调控线粒体质量控制的主要靶点，并阐明硒的保护机制。研究结果有助于揭示AgNP内皮细胞毒性的新机制，为研究纳米颗粒致动脉粥样硬化奠定基础，并为药物治疗提供理论依据。

Silver nanoparticle (AgNP) has been widely used in medical and technical fields, and its cardiovascular damage has been concerned. Our previous studies and the latest literature show that mitochondrial quality control plays an important role in AgNP cytotoxicity, but its role and regulatory mechanisms have not been elucidated in AgNP -induced vascular endothelial injury. Our preliminary studies suggested that AgNP activated the mitochondrial apoptosis pathway, caused mitochondrial morphological changes, decreased the expression of Nrf2, increased mitochondrial fission, and induced endothelial cell damage. Therefore, we propose the scientific hypothesis: the uncontrolled mitochondrial quality regulated by Nrf2 causes endothelial cytotoxicity induced by AgNP. AgNP affects mitochondrial quality control by reducing Nrf2, leading to the increase of mitochondrial fission, the decrease of mitochondrial biogenesis, and the decline of mitochondrial function, which eventually leads to cell death. Selenium protects mitochondria by activating Nrf2, preventing the changes and cell damage caused by AgNP. In this study, the effects of AgNP on mitochondrial quality control of endothelial cells were observed using in vivo and in vitro toxicity model, and Nrf2 knockout/overexpression was combined to identify Nrf2 as the main regulatory target. The protective mechanism of selenium was also elucidated. The results are helpful to reveal the new mechanism of AgNP endothelial cytotoxicity, lay a foundation for the study of atherosclerosis caused by nanoparticles (ultrafine particles), and provide a theoretical basis for drug therapy.