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Regulation of the CB1R/AMPK/PGC-1α signaling pathway in mitochondria of mouse hearts and cardiomyocytes with chronic intermittent hypoxia

  • Sleep Breathing Physiology and Disorders • Original Article
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Abstract

Purpose

This study evaluated the effects of chronic intermittent hypoxia (CIH) at different times on the mitochondria of mouse hearts and H9C2 cardiomyocytes to determine the role of the cannabinoid receptor 1 (CB1R)/adenosine 5'-monophosphate–activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) signaling pathway.

Methods

Animal and cellular CIH models were prepared in an intermittent hypoxia chamber at different times. The cardiac function of mice was determined, and heart tissue and ultrastructural changes were observed. Apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential were detected, and MitoTracker™ staining was performed to observe cardiomyocyte mitochondria. Western blot, immunohistochemistry, and cellular immunofluorescence were also performed.

Results

In the short-term CIH group, increases in mouse ejection fraction (EF) and heart rate (HR); mitochondrial division; ROS and mitochondrial membrane potential; and the expression levels of CB1R, AMPK, and PGC-1α were observed in vivo and in vitro. In the long-term CIH group, the EF and HR increased, the myocardial injury and mitochondrial damage were more severe, mitochondrial synthesis decreased, the apoptosis percentage and ROS increased, mitochondrial fragmentation increased, membrane potential decreased, CB1R expression increased, and AMPK and PGC-1α expression levels decreased. Targeted blocking of CB1R can increase AMPK and PGC-1α, reduce damage attributed to long-term CIH in mouse hearts and H9C2 cells, and promote mitochondrial synthesis.

Conclusion

Short-term CIH can directly activate the AMPK/PGC-1α pathway, promote mitochondrial synthesis in cardiomyocytes, and protect cardiac structure and function. Long-term CIH can increase CB1R expression and inhibit the AMPK/PGC-1α pathway, resulting in structural damage, the disturbance of myocardial mitochondria synthesis, and further alterations in the cardiac structure. After targeted blocking of CB1R, levels of AMPK and PGC-1α increased, alleviating damage to the heart and cardiomyocytes caused by long-term CIH.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We wish to thank the Sleep Center of the Second Hospital of Shanxi Medical University and the Shanxi Key Laboratory of Birth Defects and Cell Regeneration for their support of this study.

Funding

Bei Wang provided financial support in the form of the key research and development plan of Shanxi Province Funding (no. 201903D321137) and Shanxi medical key research project (no.2022XM29). Dai Liu provided financial support in the form of the scientific research project of the Shanxi Health and Family Planning Commission Fund (no. 201904). The sponsor had no role in the design or conduct of this research.

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Author notes

  1. Zixuan Hu, Sufang Mu and Li Zhao are contributed equally to this work as co–first authors.

Authors and Affiliations

  1. Basic Medical College, Shanxi Medical University, Taiyuan, China

    Zixuan Hu

  2. Department of the Second Clinical Medicine, Shanxi Medical University, Taiyuan, China

    Sufang Mu, Zhanjun Dou, Peipei Wang, Yuting Duan & Yang Xiong

  3. The Second Hospital of Shanxi Medical University, Taiyuan, China

    Li Zhao & Bei Wang

  4. School of Basic Medicine, Shanxi University of Chinese Medicine, Taiyuan, China

    Junfeng Zhang

  5. Department of Biochemistry and Molecular Biology, Basic Medical College, Shanxi Medical University, Taiyuan, China

    Ning Jin, Xin Lu, Xinrui Xu & Ting Liang

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All authors contributed to the article and approved the submitted version.

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Correspondence to Bei Wang.

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This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of Shanxi Medical University, Shanxi, China.

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Hu, Z., Mu, S., Zhao, L. et al. Regulation of the CB1R/AMPK/PGC-1α signaling pathway in mitochondria of mouse hearts and cardiomyocytes with chronic intermittent hypoxia. Sleep Breath 28, 133–149 (2024). https://doi.org/10.1007/s11325-023-02863-8

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