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Melatonin Alleviates Cardiac Dysfunction Via Increasing Sirt1-Mediated Beclin-1 Deacetylation and Autophagy During Sepsis

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Abstract

Cardiac dysfunction is a major cause leading to multiple organ failure in sepsis. Beclin-1-dependent autophagy has been evidenced to exert protective effects on hearts in sepsis. However, the mechanisms on how Beclin-1 and autophagy are regulated remains enigmatic. To explore the detailed mechanisms controlling Beclin-1-dependent autophagy in septic heart and whether melatonin could protect against sepsis via regulating cardiac autophagy, adult Sprague-Dawley (SD) rats were subjected to cecal ligation and puncture (CLP) to induce sepsis. Rats were intraperitoneally administrated with 30 mg/kg melatonin within 5-min post-CLP surgery. Our data showed that sepsis induced Becline-1 acetylation and inhibited autophagy in hearts, resulting in impaired cardiac function. However, melatonin treatment facilitated Beclin-1 deacetylation and increased autophagy in septic hearts, thus improved cardiac function. Moreover, melatonin increased the expression and activity of Sirtuin 1 (Sirt1), and inhibition of Sirt1 abolished the protective effects of melatonin on Beclin-1 deacetylation and cardiac function. In conclusion, increased Beclin-1 acetylation was involved in impaired autophagy in septic hearts, while melatonin contributed to Beclin-1 deacetylation via Sirt1, leading to improved autophagy and cardiac function in sepsis. Our study sheds light on the important role of Beclin-1 acetylation in regulating autophagy in sepsis and suggests that melatonin is a potential candidate drug for the treatment of sepsis.

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Acknowledgments

All authors make significant contributions to this work.

Funding

This research was funded by the National Natural Science foundation of China (NSFC81700320), Chongqing Science and Technical Commission Basic Research Funding (CSTC 2019JCY-MSXMX0827) and Basic Research Training Project of the First Affiliated Hospital of Chongqing Medical University (PyJJ2017-11).

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Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Qiang-Zhong Pi

  2. Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Xiao-Wen Wang, Dan Chen, Cheng Zhang & Qing-Chen Wu

  3. Department of Cardiothoracic Surgery, Shanghai Jiao Tong University School of Medicine Xinhua Hospital, Shanghai, 200233, China

    Zhao-Lei Jian

  4. Centre for Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK

    Dan Chen & Cheng Zhang

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Contributions

Conceptualization, Xiao-Wen Wang; methodology, Qiang-Zhong Pi, Xiao-Wen Wang, Zhao-Lei Jian, Dan Chen; formal analysis, Xiao-Wen Wang, Qing-Chen Wu; investigation, Qiang-Zhong Pi, Xiao-Wen Wang, Zhao-Lei Jian, Dan Chen; writing—original draft preparation, Qiang-Zhong Pi; writing—review and editing, Xiao-Wen Wang; supervision, Qing-Chen Wu; funding acquisition, Xiao-Wen Wang. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Xiao-Wen Wang.

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The ethics review board of Chongqing Medical University approved the study protocol. All animal experiments comply with the ethical requirements of the animal council. No human data were included in this study.

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Pi, QZ., Wang, XW., Jian, ZL. et al. Melatonin Alleviates Cardiac Dysfunction Via Increasing Sirt1-Mediated Beclin-1 Deacetylation and Autophagy During Sepsis. Inflammation 44, 1184–1193 (2021). https://doi.org/10.1007/s10753-021-01413-2

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