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Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction

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Abstract

Dickkopf-3 (DKK3) is a secreted glycoprotein of the Dickkopf family (DKK1–4) that modulates Wnt signalling. DKK3 has been reported to regulate cell development, proliferation, apoptosis, and immune response. However, the functional role of DKK3 in cardiac remodelling after myocardial infarction (MI) has not yet been elucidated. This study aimed to explore the functional significance of DKK3 in the regulation of post-MI remodelling and its underlying mechanisms. MI was induced by surgical left anterior descending coronary artery ligation in transgenic mice expressing cardiac-specific DKK3 and DKK3 knockout (KO) mice as well as their non-transgenic and DKK3+/+ littermates. Our results demonstrated that after MI, mice with DKK3 deficiency had increased mortality, greater infarct size, and exacerbated left ventricular (LV) dysfunction. Significantly, at 1 week post-MI, the hearts of DKK3-KO mice exhibited increased apoptosis, inflammation, and LV remodelling compared with the hearts of their DKK3+/+ littermates. Conversely, DKK3 overexpression led to the opposite phenotype after infarction. Similar results were observed in cultured neonatal rat cardiomyocytes exposed to hypoxia in vitro. Mechanistically, DKK3 promotes cardioprotection by interrupting the ASK1–JNK/p38 signalling cascades. In conclusion, our results indicate that DKK3 protects against the development of MI-induced cardiac remodelling via negative regulation of the ASK1–JNK/p38 signalling pathway. Thus, our study suggests that DKK3 may represent a potential therapeutic target for the treatment of heart failure after MI.

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Acknowledgments

We thank Takahisa Furukawa (Osaka Bioscience Institute, Japan) for generously providing DKK3-KO mice (129S6/SvEvTac-Dkk3<tm1Tfur>, 129 background). This work was supported by Grants from the National Science Fund for Distinguished Young Scholars (No. 81425005), the National Natural Science Foundation of China (No. 81170086), National Science and Technology Support Project (No. 2011BAI15B02, No. 2012BAI39B05, No. 2013YQ030923-05, 2014BAI02B01, and 2015BAI08B01), the Key Project of the National Natural Science Foundation (No. 81330005), the National Basic Research Program China (No. 2011CB503902), and Natural Science Foundation of Hubei Province (2013CFB259).

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No conflicts of interest were declared.

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Authors and Affiliations

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

    Ming-Wei Bao, Zhongxiang Cai, Xiaoxiong Liu, Nian Wan, Gangying Hu, Hao Xia & Hongliang Li

  2. Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan, 430060, People’s Republic of China

    Ming-Wei Bao, Zhongxiang Cai, Xiaoxiong Liu, Nian Wan, Gangying Hu, Rui Zhang, Xueyong Zhu, Hao Xia & Hongliang Li

  3. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China

    Xiao-Jing Zhang

  4. Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, 210006, China

    Liangpeng Li

  5. Department of Emergency, The Second Artillery General Hospital of Chinese People’s Liberation Army Qinghe Clinic, Beijing, China

    Fengwei Wan

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  1. Ming-Wei Bao
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Correspondence to Hongliang Li.

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M.-W. Bao, Z. Cai, and X.-J. Zhang are co-first authors.

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Bao, MW., Cai, Z., Zhang, XJ. et al. Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction. Basic Res Cardiol 110, 25 (2015). https://doi.org/10.1007/s00395-015-0481-x

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