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Interferon regulatory factor 9 is an essential mediator of heart dysfunction and cell death following myocardial ischemia/reperfusion injury

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Abstract

This study aimed to investigate whether interferon regulatory factor 9 (IRF9) is involved in the pathogenesis of myocardial ischemia–reperfusion (I/R) injury and to explore the underlying molecular mechanisms of this process. Cell death plays a major role in myocardial I/R injury. We recently determined the importance of IRF9 in coordinating molecular events in response to hypertrophic stress in cardiomyocytes. However, the roles of IRF9 in lethal myocardial injury remain to be elucidated. The involvement of IRF9 was assessed via functional assays in a mouse myocardial I/R injury model by genetic knockout and cardiomyocyte-specific transgenic overexpression of IRF9, and its effects on cardiomyocyte apoptosis and inflammation were further studied in vivo and in vitro. IRF9 was upregulated in human ischemic heart tissue and mouse hearts after I/R injury. Ablation of IRF9 protected the heart against I/R-induced cardiomyocyte death, development of inflammation, and loss of heart function. In contrast, cardiomyocyte-specific transgenic overexpression of IRF9 aggravated myocardial reperfusion injury and inflammation. IRF9 negatively regulated the Sirt1-p53 axis under I/R conditions in vivo and in vitro. Downregulation of Sirt1 expression and its downstream apoptosis-related signaling cascade, which results from I/R, was ameliorated by loss of IRF9 and exacerbated by overexpression of IRF9. Cardiomyocyte-specific deletion of Sirt1 abolished the protective effect of IRF9 knockout against I/R injury, which further indicated that IRF9 mediated myocardial reperfusion injury by modulating the Sirt1-p53 axis. Thus, IRF9 may be a novel therapeutic target for the prevention of I/R injury resulting from revascularization therapy after acute myocardial infarction (MI).

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Acknowledgments

We thank the valuable technological assistance that Rui Zhang, Xue-Yong Zhu, Zhang-Li Li, Miao Yin, Qiang Wang and Xin Zhang provided for this study. This work was supported by grants from the National Natural Science Foundation of China (No.81170086, No. 81100230, No. 81070089, No. 81200071, No. 81270306, No. 81270184, and No. 81370365), National Science and Technology Support Project (No. 2011BAI15B02, No. 2012BAI39B05, No. 2013YQ030923-05, and 2014BAI02B01), the National Basic Research Program of China (No. 2011CB503902), the Key Project of the National Natural Science Foundation (No. 81330005), the Key Project of the Natural Science Foundation of Hubei province (No. 2013CFA077) and the Independent Scientific Research Project of Wuhan University (No. 2042014kf0194).

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Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Yan Zhang, Xiaoxiong Liu, Ding-Sheng Jiang, Nian Wan, Hao Xia & Hongliang Li

  2. Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan, 430060, China

    Yan Zhang, Xiaoxiong Liu, Ding-Sheng Jiang, Nian Wan, Hao Xia & Hongliang Li

  3. Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, San Diego, CA, USA

    Zhi-Gang She

  4. Department of Thoracic and Cardiovascular Surgery Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xue-Hai Zhu & Xiang Wei

  5. College of Life Sciences, Wuhan University, Wuhan, 430072, China

    Xiao-Dong Zhang

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  1. Yan Zhang
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Correspondence to Hongliang Li.

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Y. Zhang, X. Liu, and Z.-G. She are co-first authors.

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Zhang, Y., Liu, X., She, ZG. et al. Interferon regulatory factor 9 is an essential mediator of heart dysfunction and cell death following myocardial ischemia/reperfusion injury. Basic Res Cardiol 109, 434 (2014). https://doi.org/10.1007/s00395-014-0434-9

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  • DOI: https://doi.org/10.1007/s00395-014-0434-9

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