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01-05-2015 | Original Contribution

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

Authors: Ming-Wei Bao, Zhongxiang Cai, Xiao-Jing Zhang, Liangpeng Li, Xiaoxiong Liu, Nian Wan, Gangying Hu, Fengwei Wan, Rui Zhang, Xueyong Zhu, Hao Xia, Hongliang Li

Published in: Basic Research in Cardiology | Issue 3/2015

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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Title: Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction
Authors: Ming-Wei Bao
Zhongxiang Cai
Xiao-Jing Zhang
Liangpeng Li
Xiaoxiong Liu
Nian Wan
Gangying Hu
Fengwei Wan
Rui Zhang
Xueyong Zhu
Hao Xia
Hongliang Li
Publication date: 01-05-2015
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 3/2015
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-015-0481-x

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