Department of Cardiovascular Surgery, Key Laboratory for Cardiovascular Disease of Yunnan Province, Clinical Medicine Center for Cardiovascular Disease of Yunnan Province, Yan'an Hospital Affiliated to Kunming Medical University, Kunming 650051, China.
Department of Cardiovascular Surgery, Key Laboratory for Cardiovascular Disease of Yunnan Province, Clinical Medicine Center for Cardiovascular Disease of Yunnan Province, Yan'an Hospital Affiliated to Kunming Medical University, Kunming 650051, China.
J Mol Cell Cardiol. 2024 Nov;196:71-83. doi: 10.1016/j.yjmcc.2024.09.001. Epub 2024 Sep 7.
The prevalence of coronary heart disease (CHD) has increased significantly with the aging population worldwide. It is unclear whether ferroptosis occurs during CHD. Hence, we aimed to investigate the potential mechanisms associated with ferroptosis in CHD. Bioinformatics was used to characterize differentially expressed genes (DEGs) in CHD-related datasets (GSE21610 and GSE66360). There were 76 and 689 DEGs in the GSE21610 and GSE66360, respectively, and they predominantly associated with immune and inflammatory responses. DDX3Y, EIF1AY, KDM5D, RPS4Y1, SGK1, USP9Y, and NSG1 were intersecting DEGs of GSE21610 and GSE66360. Their expression pattern in circulating endothelial cells (ECs) derived from healthy individuals and CHD patients are consistent with the results of bioinformatics analysis, especially SGK1. In vitro, SGK1 knockdown alleviated the Erastin-induced downregulation of SLC7A11, GPX4, GSH, and GSSG, as well as the upregulation of lipid peroxidation, Fe accumulation, and mitochondrial damage in mouse aortic ECs (MAECs). Notably, SGK1 may interact with NEDD4L according to the String database. Moreover, SGK1 promoted NEDD4L and p-P65 expression in MAECs. Interestingly, the effect of SGK1 knockdown on ferroptosis in MAECs was rescued by overexpression of NEDD4L or PMA (NF-κB pathway activator). In vivo, SGK1 knockdown facilitated the recovery of body weight, blood lipids, and aortic tissue structure in CHD animal models. Furthermore, SGK1 knockdown alleviated Fe accumulation in the aorta and inactivated the NEDD4L-NF-κB pathway. In conclusion, SGK1 contributes to EC ferroptosis by regulating the NEDD4L-NF-κB pathway. SGK1 could be recognized as a therapeutic target related to ferroptosis in CHD.
冠心病（CHD）的患病率随着全球人口老龄化而显著增加。目前尚不清楚铁死亡是否发生在 CHD 中。因此，我们旨在研究与 CHD 相关的铁死亡潜在机制。使用生物信息学方法对 CHD 相关数据集（GSE21610 和 GSE66360）中的差异表达基因（DEGs）进行特征描述。GSE21610 和 GSE66360 中分别有 76 个和 689 个 DEGs，主要与免疫和炎症反应有关。DDX3Y、EIF1AY、KDM5D、RPS4Y1、SGK1、USP9Y 和 NSG1 是 GSE21610 和 GSE66360 的交集 DEGs。它们在来自健康个体和 CHD 患者的循环内皮细胞（EC）中的表达模式与生物信息学分析的结果一致，特别是 SGK1。在体外，SGK1 敲低减轻了 Erastin 诱导的 SLC7A11、GPX4、GSH 和 GSSG 的下调，以及脂质过氧化、Fe 积累和线粒体损伤在小鼠主动脉 EC（MAECs）中的上调。值得注意的是，根据 String 数据库，SGK1 可能与 NEDD4L 相互作用。此外，SGK1 促进了 MAECs 中 NEDD4L 和 p-P65 的表达。有趣的是，SGK1 敲低对 MAECs 中铁死亡的影响可通过 NEDD4L 或 PMA（NF-κB 途径激活剂）的过表达得到挽救。在体内，SGK1 敲低促进了 CHD 动物模型体重、血脂和主动脉组织结构的恢复。此外，SGK1 敲低减轻了主动脉中的 Fe 积累并使 NEDD4L-NF-κB 途径失活。总之，SGK1 通过调节 NEDD4L-NF-κB 途径促进 EC 铁死亡。SGK1 可被视为与 CHD 中铁死亡相关的治疗靶点。
