Pei Xueliang, Cui Facai, Chen Yu, Yang Zhiyuan, Xie Zhouliang, Wen Yongjin
Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, Zhengzhou, Henan, People's Republic of China.
Clinical Laboratory, Henan Provincial People's Hospital, Zhengzhou, Henan, People's Republic of China.
J Inflamm Res. 2025 Mar 17;18:3937-3950. doi: 10.2147/JIR.S507076. eCollection 2025.
Atherosclerosis (AS) is a chronic inflammatory disease caused by the dysregulation of lipid metabolism. It has been established that oxidized low-density lipoprotein (ox-LDL)-induced macrophage inflammation and ferroptosis play important roles in AS. However, the mechanism by which ox-LDL induces inflammation in macrophages requires further investigation.
A foam cell model derived from ox-LDL-induced macrophages was constructed to study its mechanism of action. The levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were evaluated using an Enzyme-Linked Immunosorbent Assay (ELISA). Oil Red O staining was used to detect intracellular lipid accumulation levels. Lactate dehydrogenase (LDH), malondialdehyde (MDA), reactive oxygen species (ROS), and Fe levels were assessed. Dual-luciferase and RNA-binding protein immunoprecipitation (RIP) experiments validated the binding relationship between microRNA (miR)-214-3p and glutathione peroxidase 4 (GPX4).
The levels of IL-6, IL-1β, and TNF-α were significantly increased in ox-LDL-induced macrophages, accompanied by increased lipid accumulation, indicating the promotion of foam cell formation. Additionally, ox-LDL increased LDH, MDA, ROS, and Fe. The expression of miR-214-3p positively correlated with ox-LDL concentration in macrophages. Treatment with an miR-214-3p inhibitor reduces lipid accumulation, inflammatory responses, and ferroptosis in macrophages. Dual-luciferase and RIP experiments confirmed that miR-214-3p regulates GPX4 transcription. Silenced GPX4 reversed the inflammatory effects of the miR-214-3p inhibitor on ox-LDL-induced macrophages. Low GPX4 expression also increased lipid accumulation and ferroptosis in macrophages.
miR-214-3p promotes macrophage ferroptosis and inflammation induced by ox-LDL. This mechanism may be associated with miR-214-3p-induced GPX4 expression, which underscores the therapeutic significance of targeting macrophage inflammation and ferroptosis in addressing AS.
动脉粥样硬化（AS）是一种由脂质代谢失调引起的慢性炎症性疾病。已证实氧化型低密度脂蛋白（ox-LDL）诱导的巨噬细胞炎症和铁死亡在AS中起重要作用。然而，ox-LDL诱导巨噬细胞炎症的机制仍需进一步研究。
构建ox-LDL诱导的巨噬细胞来源的泡沫细胞模型以研究其作用机制。采用酶联免疫吸附测定（ELISA）评估白细胞介素（IL）-6、IL-1β和肿瘤坏死因子（TNF）-α的水平。用油红O染色检测细胞内脂质积累水平。评估乳酸脱氢酶（LDH）、丙二醛（MDA）、活性氧（ROS）和铁水平。双荧光素酶和RNA结合蛋白免疫沉淀（RIP）实验验证了微小RNA（miR）-214-3p与谷胱甘肽过氧化物酶4（GPX4）之间的结合关系。
ox-LDL诱导的巨噬细胞中IL-6、IL-1β和TNF-α水平显著升高，同时脂质积累增加，表明促进了泡沫细胞形成。此外，ox-LDL增加了LDH、MDA、ROS和铁。巨噬细胞中miR-214-3p的表达与ox-LDL浓度呈正相关。用miR-214-3p抑制剂处理可减少巨噬细胞中的脂质积累、炎症反应和铁死亡。双荧光素酶和RIP实验证实miR-214-3p调节GPX4转录。沉默GPX4可逆转miR-214-3p抑制剂对ox-LDL诱导的巨噬细胞的炎症作用。低GPX4表达也增加了巨噬细胞中的脂质积累和铁死亡。
miR-214-3p促进ox-LDL诱导的巨噬细胞铁死亡和炎症。该机制可能与miR-214-3p诱导的GPX4表达有关，这突出了靶向巨噬细胞炎症和铁死亡在解决AS中的治疗意义。
