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Interferon regulatory factor 3 is a negative regulator of pathological cardiac hypertrophy

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Abstract

Interferon regulatory factor (IRF) 3, a member of the highly conserved IRF family transcription factors, plays a pivotal role in innate immune response, apoptosis, and oncogenesis. Recent studies have implicated IRF3 in a wide range of host defense. However, whether IRF3 induces defensive responses to hypertrophic stresses such as biomechanical stress and neurohumoral factors remains unclear. Herein, we employed an IRF3-deficient mouse model, cardiac-specific IRF3-overexpression mouse model and isolated cardiomyocytes to investigate the role of IRF3 in cardiac hypertrophy induced by aortic banding (AB) or isoproterenol (ISO). The extent of cardiac hypertrophy was quantitated by echocardiography as well as by pathological and molecular analysis. Our results demonstrate that IRF3 deficiency profoundly exacerbated cardiac hypertrophy, whereas overexpression of IRF3 in the heart significantly blunted pathological cardiac remodeling induced by pressure overload. Similar results were also observed in cultured cardiomyocytes upon the treatment with ISO. Mechanistically, we discovered that IRF3 interacted with ERK2 and thereby inhibited the ERK1/2 signaling. Furthermore, inactivation of ERK1/2 by U0126 offset the IRF3-deficient-mediated hypertrophic response induced by aortic banding. Altogether, these data demonstrate that IRF3 plays a protective role in AB-induced hypertrophic response by inactivating ERK1/2 in the heart. Therefore, IRF3 could be a new target for the prevention and therapy of cardiac hypertrophy and failure.

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Acknowledgments

We thank Dr. Tadatsugu Taniguchi for providing IRF3-knockout mice and Dr. Kensuke Tsushima for discussion by Email. This study was supported Funds for Distinguished Young Scientists of Hubei (2010CDA092) and by the National Natural Science Foundation of China (Grants 30900524 and 81170086, 3087451 and 30801351), and National Science and Technology Support Project (NO. 2011BAI15B02 and No. 2012BAI39B05), National Basic Research Program of China (No. 2011CB503902).

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The authors have declared that no conflict of interest exists.

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Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital, Cardiovascular Research Institute, Wuhan University, Jiefang Road 238, 430060, Wuhan, People’s Republic of China

    Jing Lu, Zhou-Yan Bian, Yan Zhang, Ling Yan, Shu-Min Zhang, Ding-Sheng Jiang & Hongliang Li

  2. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, People’s Republic of China

    Ran Zhang

  3. Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Chen Liu

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

    Xiang Wei & Xue Hai Zhu

  5. Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada

    Manyin Chen & Peter P. Liu

  6. Laboratory of Molecular Cardiology, NHLBI, National Institutes of Health, Bethesda, MD, 20892-1762, USA

    Ai-Bing Wang

  7. Cardiovascular Division, University of Minnesota, Minneapolis, MN, 55455, USA

    Yingjie Chen

  8. Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, 35294-3360, USA

    Qinglin Yang

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  1. Jing Lu
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J. Lu, Z.-Y. Bian and R. Zhang are co-first authors.

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Lu, J., Bian, ZY., Zhang, R. et al. Interferon regulatory factor 3 is a negative regulator of pathological cardiac hypertrophy. Basic Res Cardiol 108, 326 (2013). https://doi.org/10.1007/s00395-012-0326-9

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