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SIRT1 regulates mitochondrial fission to alleviate high altitude hypoxia inducedcardiac dysfunction in rats via the PGC-1α-DRP1/FIS1/MFF pathway

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Abstract

High-altitude exposure has been linked to cardiac dysfunction. Silent information regulator factor 2-related enzyme 1 (sirtuin 1, SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase, plays a crucial role in regulating numerous cardiovascular diseases. However, the relationship between SIRT1 and cardiac dysfunction induced by hypobaric hypoxia (HH) remains unexplored. This study aims to assess the impact of SIRT1 on HH-induced cardiac dysfunction and delve into the underlying mechanisms, both in vivo and in vitro. In this study, we have demonstrated that exposure to HH results in cardiomyocyte injury, along with the downregulation of SIRT1 and mitochondrial dysfunction. Upregulating SIRT1 significantly inhibits mitochondrial fission, improves mitochondrial function, reduces cardiomyocyte injury, and consequently enhances cardiac function in HH-exposed rats. Additionally, HH exposure triggers aberrant expression of mitochondrial fission-regulated proteins, with a decrease in PPARγ coactivator 1 alpha (PGC-1α) and mitochondrial fission factor (MFF) and an increase in mitochondrial fission 1 (FIS1) and dynamin-related protein 1 (DRP1), all of which are mitigated by SIRT1 upregulation. Furthermore, inhibiting PGC-1α diminishes the positive effects of SIRT1 regulation on the expression of DRP1, MFF, and FIS1, as well as mitochondrial fission. These findings demonstrate that SIRT1 alleviates HHinduced cardiac dysfunction by preventing mitochondrial fission through the PGC-1α-DRP1/FIS1/MFF pathway.

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Funding

This work was partially supported by a grant from the foundation [grant number 2019CXTD01]. The funding bodies played no role in the design of the study, the collection, analysis, or interpretation of data or in writing the manuscript.

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Author notes

  1. Hongbao Xu, Xiaona Song and Xiaoru Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine, Tianjin, China

    Hongbao Xu, Xiaona Song, Guangrui Wang, Xiaoling Cheng, Ling Zhang, Zirou Wang, Ran Li, Chongyi Ai, Xinxing Wang, Lingling Pu, Zhaoli Chen & Weili Liu

  2. State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China

    Xiaoru Zhang

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  1. Hongbao Xu
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Contributions

Conception and design: W.L Liu, Z.L Chen and L.L Pu; Acquisition of data: H.B Xu, X.N Song, X.R Zhang, G.R Wang, X.L Cheng, L Zhang; Analysis and interpretation of data including statistical analysis, biostatistics, and computational analysis: W.L Liu, H.B Xu, X.N Song, X.R Zhang, Z.RR Wang, R Li, C.Y Ai, X.X Wang; Writing, review, and/or revision of the manuscript: W.L Liu, H.B Xu, X.N Song and X.R Zhang; Administrative, technical, or material support including reporting or organizing data: W.L Liu, H.B Xu, X.N Song, X.R Zhang, Z.L Chen and L.L Pu; Study supervision: W.L Liu, Z.L Chen and L.L Pu.

Corresponding authors

Correspondence to Lingling Pu, Zhaoli Chen or Weili Liu.

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All animal experiments were performed in accordance with the NIH guidelines and were approved by the Institutional Animal Care and Use Committee of Environmental and Operational Medicine Research Department.

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Xu, H., Song, X., Zhang, X. et al. SIRT1 regulates mitochondrial fission to alleviate high altitude hypoxia inducedcardiac dysfunction in rats via the PGC-1α-DRP1/FIS1/MFF pathway. Apoptosis (2024). https://doi.org/10.1007/s10495-024-01954-5

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