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Angiotensin II receptor blocker irbesartan attenuates sleep apnea–induced cardiac apoptosis and enhances cardiac survival and Sirtuin 1 upregulation

  • Sleep Breathing Physiology and Disorders • Original Article
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Abstract

Background

The purpose of this study was to investigate whether or not angiotensin II type 1 receptor blocker irbesartan (ARB) with a partial agonist of PPAR-γ could protect against chronic nocturnal intermittent hypoxia (CIH)–induced cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis.

Methods

Sprague–Dawley rats were in a normoxic control group (CON-G), or rats were in a chronic nocturnal intermittent hypoxia group (HP-G, from 3 to 7% oxygen versus 21% oxygen per forty seconds cycle, nocturnally 8 h per day for 1 month), or rats were in a chronic nocturnal intermittent hypoxia group pretreated with ARB (50 mg/kg/day, S.C.) (ARB-HP-G). Echocardiography, H&E staining, TUNEL staining, and Western blotting were measured in the left ventricle.

Results

Hypoxia-induced SIRT1 degradation, Fas receptors, FADD, active caspase-8 and caspase-3 (Fas/FasL apoptotic pathway) and Bax, tBid, active caspase-9 and -3 (mitochondrial apoptotic pathway) and TUNEL-positive apoptosis were reduced in ARB-HP-G when compared with HP-G. IGF-I, IGF1 receptor, p-PI3k, p-Akt, Bcl2, and Bcl-XL (IGF1/PI3K/AKT pro-survival pathway) were increased in ARB-HP-G compared to HP-G.

Conclusions

Our findings suggest that the ARB may prevent cardiac Fas/FasL to mitochondrial apoptotic pathways and enhance cardiac IGF1/PI3K/AKT pro-survival pathway in the sleep apnea model associated with JNK de-activation and SIRT1 upregulation. ARB prevents chronic sleep apnea–enhanced cardiac apoptosis via enhancing survival pathways.

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Acknowledgements

We would like to thank Michael Burton for proofreading the manuscript.

Funding

This study was partially supported by Asia University and China Medical University (Asia-106-CMUH-05) as well as Ministry of Science and Technology (MOST 107–2314-B-468–002-MY3). This study was partially supported by National Taipei University of Nursing and Health Science, Taiwan; Weifang Medical University, China.

Author information

Author notes

  1. Pei-Ying Pai and Yi-Yuan Lin; Chih-Yang Huang and Shin-Da Lee share equal contribution.

Authors and Affiliations

  1. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

    Pei-Ying Pai & Ching-Yuang Lin

  2. Division of Cardiology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan

    Pei-Ying Pai & Yi-Fan Liou

  3. Department of Exercise and Health Science, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan

    Yi-Yuan Lin

  4. College of Rehabilitation, Shandong University of Traditional Chinese Medicine, Shandong, China

    Shao-Hong Yu

  5. Clinical Immunology Center, China Medical University Hospital, Taichung, Taiwan

    Ching-Yuang Lin

  6. Department of Rehabilitation, Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Xu-Bo Wu & Shin-Da Lee

  7. School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Xu-Bo Wu & Shin-Da Lee

  8. Department of Cardiology, Asia University Hospital, Taichung, Taiwan

    James K. S. Wong

  9. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan

    Chih-Yang Huang

  10. Department of Biotechnology, Asia University, Taichung, Taiwan

    Chih-Yang Huang

  11. Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

    Chih-Yang Huang

  12. Department of Physical Therapy, Asia University, Taichung, Taiwan

    Shin-Da Lee

  13. Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taichung, 40402, Taiwan

    Shin-Da Lee

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  1. Pei-Ying Pai
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Contributions

C.Y.H and S.D.L were responsible for conceptualization; P.Y.P.,Y.Y.L., and Y.F.L. were responsible for data curation and methodology; S.H.Y., C. Y. L., X.B.W., K.S.H., and J.KS.W were responsible for funding acquisition; P.Y.P.,Y.Y.L., C.Y.H., and S.D.L. were responsible for visualization; P.Y.P., Y.Y.L., S.H.Y., C. Y. L., K.S.H., X.B.W., J.KS.W., C.Y.H., and S.D.L were responsible for final version of the manuscript.

Corresponding author

Correspondence to Shin-Da Lee.

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Ethical approval

All experiments were performed in accordance with National Institutes of Health guidelines. The protocols were approved by the Standing Committee on Ethics and Animal Experimentation at China Medical University. The animal experiments were performed after approval from the Standing Committee on Ethics and Animal Experimentation at China Medical University.

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The authors declare no competing interests.

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Pai, PY., Lin, YY., Yu, SH. et al. Angiotensin II receptor blocker irbesartan attenuates sleep apnea–induced cardiac apoptosis and enhances cardiac survival and Sirtuin 1 upregulation. Sleep Breath 26, 1161–1172 (2022). https://doi.org/10.1007/s11325-021-02499-6

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  • DOI: https://doi.org/10.1007/s11325-021-02499-6

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