The role of ferroptosis and endoplasmic reticulum stress in intermittent hypoxia-induced myocardial injury,Sleep and Breathing

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The role of ferroptosis and endoplasmic reticulum stress in intermittent hypoxia-induced myocardial injury
Sleep and Breathing ( IF 2.1 ) Pub Date : 2022-08-11 , DOI: 10.1007/s11325-022-02692-1
Jiefeng Huang ₁ , Hansheng Xie ₁ , Yisong Yang ₁ , Lida Chen ₂ , Ting Lin ₁ , Biying Wang ₁ , Qi-Chang Lin ₁

Affiliation

Purpose

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).

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

铁死亡和内质网应激在间歇性缺氧心肌损伤中的作用

目的

阻塞性睡眠呼吸暂停 (OSA) 与心血管疾病风险增加有关。铁死亡是一种以铁过载为特征的程序性细胞死亡形式，在心肌损伤中起着关键作用。本研究旨在探讨铁死亡在间歇性缺氧 (IH) 诱导的涉及内质网应激 (ERS) 的心肌损伤中的作用。

方法

AC16 人心肌细胞暴露于 IH 或含氧量正常的条件下。小鼠随机分组如下：正常对照 (NC)、IH、ferrostatin-1 + IH (FIH) 和 N-乙酰半胱氨酸 + IH (AIH)。通过qRT-PCR检测AC16细胞中GPX4、xCT、FTH1和FACL4的mRNA水平。Western blot分析检测心肌组织GPX4、xCT、NOX4、ATF4、CHOP、Bcl-2、Bax蛋白水平。

结果

IH组AC16细胞GPX4和xCT mRNA表达水平明显低于NC组。在 IH 小鼠中，心肌组织受损并伴有铁死亡和 ERS 水平升高。铁死亡的抑制和 N-乙酰半胱氨酸的治疗减少了暴露于 IH 的小鼠的 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方面发挥更大的作用。