Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Fujian Medical University; Fujian Provincial Sleep-Disordered Breathing Clinic Center; Institute of Respiratory Disease, Fujian Medical University, No. 20, Chazhong Road, Taijiang District, Fuzhou, Fujian Province, People's Republic of China, 350005.
Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Xiangcheng, Zhangzhou, 363000, China.
Sleep Breath. 2023 Jun;27(3):1005-1011. doi: 10.1007/s11325-022-02692-1. Epub 2022 Aug 11.
Obstructive sleep apnea (OSA) is related to increased risk of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by iron overload and plays critical roles in myocardial injury. This study aimed to investigate the role of ferroptosis in intermittent hypoxia (IH)-induced myocardial injury involving endoplasmic reticulum stress (ERS).
AC16 human cardiomyocytes were exposed to IH or normoxia conditions. Mice were randomly grouped as follows: normal control (NC), IH, ferrostatin-1 + IH (FIH), and N-acetylcysteine + IH (AIH). The mRNA levels of GPX4, xCT, FTH1, and FACL4 in AC16 cells were detected by qRT-PCR. The protein levels of GPX4, xCT, NOX4, ATF4, CHOP, Bcl-2, and Bax in myocardial tissue were detected by Western blot analysis.
The mRNA expression levels of GPX4 and xCT in AC16 cells were significantly lower in IH group than that of NC group. In IH mice, myocardial tissues were injured accompanied by increased level of ferroptosis and ERS. Inhibition of ferroptosis and treatment of N-acetylcysteine reduced ERS and myocardial injury in mice exposed to IH. In addition, compared to ferrostatin-1, N-acetylcysteine exerted a greater effect in relieving IH-induced myocardial damage and ERS.
Ferroptosis was involved in IH-related myocardial injury accompanied by the activation of ERS. Inhibition of ferroptosis and acetylcysteine treatment alleviated IH-related myocardial injury, which may be a potential target for therapeutic approaches to OSA-induced myocardial injury.
阻塞性睡眠呼吸暂停（OSA）与心血管疾病风险增加有关。铁死亡是一种程序性细胞死亡形式，其特征是铁过载，并在心肌损伤中发挥关键作用。本研究旨在探讨铁死亡在涉及内质网应激（ERS）的间歇性低氧（IH）诱导的心肌损伤中的作用。
AC16 人心肌细胞暴露于 IH 或常氧条件下。将小鼠随机分为以下几组：正常对照组（NC）、IH 组、ferrostatin-1+IH（FIH）组和 N-乙酰半胱氨酸+IH（AIH）组。通过 qRT-PCR 检测 AC16 细胞中 GPX4、xCT、FTH1 和 FACL4 的 mRNA 水平。通过 Western blot 分析检测心肌组织中 GPX4、xCT、NOX4、ATF4、CHOP、Bcl-2 和 Bax 的蛋白水平。
与 NC 组相比，IH 组 AC16 细胞中 GPX4 和 xCT 的 mRNA 表达水平明显降低。在 IH 小鼠中，心肌组织受到损伤，同时伴随着铁死亡和 ERS 水平的增加。抑制铁死亡和 N-乙酰半胱氨酸治疗可减轻 IH 暴露小鼠的 ERS 和心肌损伤。此外，与 ferrostatin-1 相比，N-乙酰半胱氨酸在缓解 IH 诱导的心肌损伤和 ERS 方面具有更大的作用。
铁死亡参与了与 ERS 激活相关的 IH 相关的心肌损伤。抑制铁死亡和乙酰半胱氨酸治疗可减轻 IH 相关的心肌损伤，这可能是治疗 OSA 诱导的心肌损伤的潜在靶点。
