铁稳态失衡调控血管细胞铁死亡敏感性在血管老化中的作用与机制研究

血管老化是导致多种血管和老年疾病的重要危险因素，但机制尚未阐明。血管细胞持续衰老引起的炎症等病理生理条件改变可加速血管老化。研究报道衰老细胞因铁稳态失衡可降低其铁死亡敏感性，产生铁死亡抵抗以逃避机体清除。申请人前期研究表明衰老血管组织和细胞表现与铁死亡抵抗相关的铁稳态失衡，如铁蛋白Ft积聚和细胞铁利用标记物IRP2上调，提示铁死亡敏感性降低；而具有血管保护作用的HMGCR抑制剂可调控衰老血管细胞的铁稳态。故提出科学假说：铁稳态失衡可使衰老血管细胞产生铁死亡抵抗；调控相应细胞的铁死亡敏感性可减少炎症微环境形成，改善血管老化。本研究拟利用基因沉默技术、流式细胞术、离体血管培养和免疫化学等方法，在细胞和动物水平探讨铁稳态和铁死亡调控在血管细胞衰老和血管老化中的作用与分子机制，为阐明血管老化的内在机制和以铁死亡调控通路为靶点研究血管老化疾病的防治药物提供新的理论依据，具有重要的临床意义和应用价值。

Vascular aging is an important risk factor for the pathogenesis of a variety of vascular or age-related diseases in the elderly but the mechanism has not yet been clarified. Senescence of vascular cells contributes to pathophysiological conditions associated with accelerated vascular aging. It was recently reported that iron homeostasis imbalance of senescent cells reduced the sensitivity to ferroptosis, leading to cellular resistance to ferroptosis and finally escaping from self-clearance. Our previous studies found that the iron homeostasis was imbalanced in vascular tissues and cells of aging animals. There are ferritin accumulation and up-regulation of IRP2 as indicative of decreased cellular iron bioavailability in aging vascular tissues and cells, suggesting reduced sensitivity of ferroptosis. We also found that HMGCR inhibitor, which has vasular protective effects, could regulate iron homeostasis in senescent vascular cells. Therefore, we hypothesize that imbalance of iron homeostasis contributes to ferroptosis resistance of senescent vascular cells; regulating the ferroptosis sensitivity of these cells can reduce the formation of inflammatory microenvironment and improve vascular aging. To verify this hypothesis, we are going to explore the role and mechanism of iron homeostasis and ferroptosis in senescence of vascular cells and vascular aging on cellular and animal tissue’s level, using gene-silencing technology, flow cytometry, in vitro vascular culture and immunochemistry methods. It is of great clinical significance and applied value for this project by helping to interpret the mechanism of vascular aging and laying the foundation of a new theoretical basis for using the ferroptosis regulation pathways as the target to investigate the drugs preventing and treating the vascular aging-related diseases.