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SUV39H1 mediated SIRT1 trans-repression contributes to cardiac ischemia–reperfusion injury

  • Guang Yang
  • Xinjian Zhang
  • Xinyu Weng
  • Peng Liang
  • Xin Dai
  • Sheng Zeng
  • Huihui Xu
  • Hailin Huan
  • Mingming Fang
  • Yuehua Li
  • Dachun XuEmail author
  • Yong XuEmail author
Original Contribution

Abstract

Ischemic reperfusion (I/R) contributes to deleterious cardiac remodeling and heart failure. The deacetylase SIRT1 has been shown to protect the heart from I/R injury. We examined the mechanism whereby I/R injury represses SIRT1 transcription in the myocardium. There was accumulation of trimethylated histone H3K9 on the proximal SIRT1 promoter in the myocardium in mice following I/R injury and in cultured cardiomyocytes exposed to hypoxia–reoxygenation (H/R). In accordance, the H3K9 trimethyltransferase SUV39H1 bound to the SIRT1 promoter and repressed SIRT1 transcription. SUV39H1 expression was up-regulated in the myocardium in mice following I/R insults and in H/R-treated cardiomyocytes paralleling SIRT1 down-regulation. Silencing SUV39H1 expression or suppression of SUV39H1 activity erased H3K9Me3 from the SIRT1 promoter and normalized SIRT1 levels in cardiomyocytes. Meanwhile, SUV39H1 deficiency or inhibition attenuated I/R-induced infarction and improved heart function in mice likely through influencing ROS levels in a SIRT1-dependent manner. Therefore, our data uncover a novel mechanism for SIRT1 trans-repression during cardiac I/R injury and present SUV39H1 as a druggable target for the development of therapeutic strategies against ischemic heart disease.

Keywords

Epigenetics Ischemia–reperfusion injury SIRT1 SUV39H1 Transcriptional regulation 

Notes

Acknowledgements

This work was supported, in part, by grants from the Natural Science Foundation of China (91439106, 81670223, 81470418, 81270194, and 81270292), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). HLH was supported by an intramural grant (CX135040) from Jiangsu Agriculture Science and Technology Innovation Fund. YX and YHL are Fellows at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine.

Compliance with ethical standards

Conflict of interest

None.

Supplementary material

395_2017_608_MOESM1_ESM.doc (13.7 mb)
Supplementary material 1 (DOC 14078 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Guang Yang
    • 1
  • Xinjian Zhang
    • 1
  • Xinyu Weng
    • 2
  • Peng Liang
    • 1
  • Xin Dai
    • 1
  • Sheng Zeng
    • 1
  • Huihui Xu
    • 1
  • Hailin Huan
    • 3
  • Mingming Fang
    • 1
  • Yuehua Li
    • 1
  • Dachun Xu
    • 1
    • 4
    Email author
  • Yong Xu
    • 1
    Email author
  1. 1.Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of PathophysiologyNanjing Medical UniversityNanjingChina
  2. 2.Shanghai Institute of Cardiovascular Disease, Zhongshan HospitalFudan UniversityShanghaiChina
  3. 3.Institute of Animal ScienceJiangsu Academy of Agricultural SciencesNanjingChina
  4. 4.Department of Cardiology, Shanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina

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