Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
Biomolecules. 2024 Jul 22;14(7):879. doi: 10.3390/biom14070879.
This study sought to explore potential roles of endothelial ferroptosis in radiation-associated atherosclerosis (RAA) and molecular mechanisms behind this phenomenon. Here, an in vivo RAA mouse model was used and treated with ferroptosis inhibitors. We found that the RAA group had a higher plaque burden and a reduction in endothelial cells with increased lipid peroxidation compared to the control group, while ameliorated by liproxstatin-1. In vitro experiments further confirmed that radiation induced the occurrence of ferroptosis in human artery endothelial cells (HAECs). Then, proteomics analysis of HAECs identified domain-containing protein 2 (DDHD2) as a co-differentially expressed protein, which was enriched in the lipid metabolism pathway. In addition, the level of lipid peroxidation was elevated in DDHD2-knockdown HAECs. Mechanistically, a significant decrease in the protein and mRNA expression of glutathione peroxidase 4 (GPX4) was observed in HAECs following DDHD2 knockdown. Co-immunoprecipitation assays indicated a potential interaction between DDHD2 and nuclear factor erythroid 2-related factor 2 (Nrf2). The downregulation of Nrf2 protein was also detected in DDHD2-knockdown HAECs. In conclusion, our findings suggest that radiation-induced endothelial ferroptosis accelerates atherosclerosis, and DDHD2 is a potential regulatory protein in radiation-induced endothelial ferroptosis through the Nrf2/GPX4 pathway.
本研究旨在探讨内皮细胞铁死亡在放射性相关动脉粥样硬化（RAA）中的潜在作用及其背后的分子机制。本研究构建了 RAA 小鼠模型，并采用铁死亡抑制剂进行干预。结果显示，与对照组相比，RAA 组斑块负荷更高，内皮细胞减少，脂质过氧化增加，而脂氧素类似物 liproxstatin-1 可改善上述现象。体外实验进一步证实，辐射可诱导人动脉内皮细胞（HAECs）发生铁死亡。随后，对 HAECs 的蛋白质组学分析鉴定出结构域包含蛋白 2（DDHD2）为共差异表达蛋白，其在脂质代谢途径中富集。此外，DDHD2 敲低的 HAECs 中脂质过氧化水平升高。机制研究表明，DDHD2 敲低后，HAECs 中谷胱甘肽过氧化物酶 4（GPX4）的蛋白和 mRNA 表达显著下降。免疫共沉淀实验表明，DDHD2 与核因子红细胞 2 相关因子 2（Nrf2）之间存在潜在的相互作用。DDHD2 敲低的 HAECs 中 Nrf2 蛋白表达也下调。综上所述，本研究结果表明，辐射诱导的内皮细胞铁死亡加速了动脉粥样硬化的发生，DDHD2 可能通过 Nrf2/GPX4 通路成为辐射诱导内皮细胞铁死亡的潜在调控蛋白。
