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

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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.

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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.

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    Authors and Affiliations

    1. Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing, 210029, Jiangsu, China

      Guang Yang, Xinjian Zhang, Peng Liang, Xin Dai, Sheng Zeng, Huihui Xu, Mingming Fang, Yuehua Li, Dachun Xu & Yong Xu

    2. Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

      Xinyu Weng

    3. Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, China

      Hailin Huan

    4. Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Yanchang Middle Rd, Shanghai, 200072, China

      Dachun Xu

    Author notes

    1. G. Yang, X. Zhang, and X. Weng contributed equally to this study.

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      Yang, G., Zhang, X., Weng, X. et al. SUV39H1 mediated SIRT1 trans-repression contributes to cardiac ischemia–reperfusion injury. Basic Res Cardiol 112, 22 (2017). https://doi.org/10.1007/s00395-017-0608-3

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