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

  • Sleep Breathing Physiology and Disorders • Original Article
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Abstract

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.

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Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

The work was supported by the National Natural Science Foundation of China (No. 81900090), Natural Science Foundation of Fujian Province (No. 2020J01987), and Youth Research Fund from Health and Family Planning Commission of Fujian Province (No. 2020QNA053).

Author information

Author notes

  1. Jiefeng Huang, Hansheng Xie, and Yisong Yang contributed equally to this article.

Authors and Affiliations

  1. 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

    Jiefeng Huang, Hansheng Xie, Yisong Yang, Ting Lin, Biying Wang & Qi-Chang Lin

  2. Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Xiangcheng, Zhangzhou, 363000, China

    Lida Chen

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  1. Jiefeng Huang
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Contributions

Jiefeng Huang, sequence/data analysis and preparation of the manuscript; Hansheng Xie, study design and preparation of the manuscript; Yisong Yang, PCR and WB; Lida Chen, animal experiments; Biying Wang, manuscript preparation; Gongping Chen, analyzed the data; Qichang Lin, contributed in the experimental design; Jiefeng Huang, Hansheng Xie and Yisong Yang contributed equally to this work. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Qi-Chang Lin.

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Ethics approval

The study protocols were according to the standard ethical guidelines and approved by Xiamen University Animal Care and Use Committee (XMULAC20201002).

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The authors declare no competing interests.

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Huang, J., Xie, H., Yang, Y. et al. The role of ferroptosis and endoplasmic reticulum stress in intermittent hypoxia-induced myocardial injury. Sleep Breath 27, 1005–1011 (2023). https://doi.org/10.1007/s11325-022-02692-1

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  • DOI: https://doi.org/10.1007/s11325-022-02692-1

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