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SIRT6 Protects Against Myocardial Ischemia–Reperfusion Injury by Attenuating Aging-Related CHMP2B Accumulation

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Abstract

Impaired autophagic flux induces aging-related ischemia vulnerability, which is the hallmark pathology in cardiac aging. Our previous work has confirmed that the accumulation of charged multivesicular body protein 2B (CHMP2B), a subunit of the ESCRT-III complex, in the heart can impair autophagy flux. However, whether CHMP2B accumulation contributes to aging-related intolerance to ischemia/reperfusion (I/R) injury and the regulatory mechanism for CHMP2B in aged heart remain elusive. The cardiac CHMP2B level was significantly higher in aged human myocardium than that in young myocardium. Increased CHMP2B were shown to inhibit autophagic flux leading to the deterioration of MI/R injury in aged mice hearts. Interestingly, a negative correlation was observed between SIRT6 and CHMP2B expression in human heart samples. Specific activation of SIRT6 suppressed CHMP2B accumulation and ameliorated autophagy flux in aged hearts. Using myocardial-specific SIRT6 heterozygous knockout mice and recovery experiments confirmed that SIRT6 regulated myocardial CHMP2B levels. Finally, activation of SIRT6 decreased acetylation of FoxO1 to promote its transcriptional function on Atrogin-1, a muscle-specific ubiquitin ligase, which subsequently enhanced the degradation of CHMP2B by Atrogin-1. This is a novel mechanism for SIRT6 against aging-related myocardial ischemia vulnerability, particularly by preventing excessive accumulation of autophagy key factors.

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Acknowledgements

The authors wish to thank Dr Tian Li from the Fourth Military Medical University for his help in this research.

Funding

This study was financially supported by the National Natural Science Foundation of China (82070261, 91749108 to H. Ma; 81803053 and 82170251 to N. Mu), the Science and Technology Research and Development Program of Shaanxi Province, China (2018SF-270, 2015KW-050, 2018SF-101). The Youth Innovation Team of Shaanxi Universities (to H. Ma). The Seed Foundation of Innvation and Creation for Graduate Students in Northwestern Polytechnical University (CX202065 to Jiang WH).

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Author notes

  1. Heng Ma, Nan Mu and Haiyan Wang contributed equally.

Authors and Affiliations

  1. Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, No. 1 Xinsi Rd, Xi’an, China

    Xiaokang Li & Haiyan Wang

  2. Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, No. 1 Xinsi Rd, Xi’an, 710032, China

    Lin Liu

  3. Institute of Medical Research, Northwestern Polytechnical University, Xi’an, China

    Wenhua Jiang

  4. Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, No. 169 Changle West Rd, Xi’an, China

    Manling Liu, Yishi Wang, Heng Ma & Nan Mu

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  1. Xiaokang Li
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Correspondence to Heng Ma, Nan Mu or Haiyan Wang.

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All the procedures in this study were in accordance with the Helsinki Declaration of 1975, as revised in 2000, and were approved by the ethical review board of Fourth Military Medical University (IACUC-20200602). Informed consents were obtained from all study participants. Institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.

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Associate Editor Junjie Xiao oversaw the review of this article

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Li, X., Liu, L., Jiang, W. et al. SIRT6 Protects Against Myocardial Ischemia–Reperfusion Injury by Attenuating Aging-Related CHMP2B Accumulation. J. of Cardiovasc. Trans. Res. 15, 740–753 (2022). https://doi.org/10.1007/s12265-021-10184-y

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