Department of Vascular and Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China.
Department of Vascular and Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China.
Free Radic Biol Med. 2020 Nov 20;160:92-102. doi: 10.1016/j.freeradbiomed.2020.07.026. Epub 2020 Aug 5.
Atherosclerosis (AS) is the fundamental pathological state of many serious vascular diseases, characterized by disorders of lipid metabolism. Ferroptosis is a type of regulated cell death that is mainly mediated by iron-dependent lipid peroxidation. In this study, whether ferroptosis has occurred in AS and the potential effects of ferroptosis on AS were investigated. Ferroptosis inhibitor ferrostatin-1 (Fer-1) was administered to high-fat diet (HFD)-induced AS in ApoE mice. The results showed that Fer-1 could alleviate AS lesion in HFD-fed ApoE mice. Additionally, Fer-1 partially inhibited the iron accumulation, lipid peroxidation and reversed the expressions of ferroptosis indicators SLC7A11 and glutathione peroxidase 4 (GPX4) in HFD-fed ApoE mice. Next, we evaluated the effects of inhibition of ferroptosis on oxidized-low density lipoprotein (ox-LDL)-induced mouse aortic endothelial cells (MAECs). Results showed that Fer-1 increased cell viability and reduced cell death in ox-LDL-treated MAECs. Moreover, Fer-1 decreased iron content and lipid peroxidation and up-regulated the levels of SLC7A11 and GPX4. Additionally, Fer-1 down-regulated the expressions of adhesion molecules and up-regulated eNOS expression. Iron chelator deferoxamine was used to demonstrate ferroptosis could be partially inhibited by iron complexation in ox-LDL-treated MAECs. Our results indicated that ferroptosis might occur during the initiation and development of AS. More importantly, inhibition of ferroptosis could alleviate AS through attenuating lipid peroxidation and endothelial dysfunction in AECs. Our findings might contribute to a deeper understanding regarding the pathological process of AS and provide a therapeutic target for AS.
动脉粥样硬化（AS）是许多严重血管疾病的基本病理状态，其特征是脂质代谢紊乱。铁死亡是一种受铁依赖性脂质过氧化调控的细胞死亡类型。本研究旨在探讨铁死亡是否发生在 AS 中以及铁死亡对 AS 的潜在影响。将铁死亡抑制剂 ferrostatin-1（Fer-1）给予高脂饮食（HFD）诱导的 ApoE 小鼠的 AS 模型。结果表明，Fer-1 可减轻 HFD 喂养的 ApoE 小鼠的 AS 病变。此外，Fer-1 部分抑制了铁积累、脂质过氧化，并逆转了 HFD 喂养的 ApoE 小鼠中铁死亡标志物 SLC7A11 和谷胱甘肽过氧化物酶 4（GPX4）的表达。接下来，我们评估了抑制铁死亡对氧化型低密度脂蛋白（ox-LDL）诱导的小鼠主动脉内皮细胞（MAECs）的影响。结果表明，Fer-1 增加了 ox-LDL 处理的 MAECs 的细胞活力并降低了细胞死亡。此外，Fer-1 降低了铁含量和脂质过氧化，并上调了 SLC7A11 和 GPX4 的水平。此外，Fer-1 下调了黏附分子的表达并上调了 eNOS 的表达。铁螯合剂去铁胺被用于证明铁死亡可被 ox-LDL 处理的 MAECs 中的铁复合物部分抑制。我们的结果表明，铁死亡可能发生在 AS 的起始和发展过程中。更重要的是，抑制铁死亡可通过减轻 AECs 的脂质过氧化和内皮功能障碍来缓解 AS。我们的研究结果可能有助于更深入地了解 AS 的病理过程，并为 AS 提供一个治疗靶点。
