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Regulatory role of CARD3 in left ventricular remodelling and dysfunction after myocardial infarction

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Abstract

Caspase activation and recruitment domain 3 (CARD3) is a caspase recruitment domain (CARD)-containing serine/threonine kinase and plays a pivotal role in apoptosis, immunity, tissue development and proliferation. To date, the causal relationship between CARD3 and myocardial infarction (MI) remains largely unexplored. This study aimed to identify the functional significance of CARD3 in the regulation of cardiac remodelling after MI and the underlying mechanisms of its effects. The levels of CARD3 expression were up-regulated in failing human and mouse post-infarction hearts. In addition, CARD3-knockout (KO) mice and transgenic mice overexpressing CARD3 in the heart were then generated and subjected to MI. Compared with wild-type (WT) control mice, CARD3-KO mice developed smaller infarct sizes, improved survival rates, and preserved left ventricle (LV) function after MI. Significantly, CARD3-KO hearts had less cardiomyocyte apoptosis and inflammatory cell infiltration in the infarct border zone. Attenuated LV remodelling was also observed in the KO hearts following MI, with reduced cardiac hypertrophy and fibrosis. Conversely, CARD3 overexpression resulted in the opposite MI-induced phenotype. Similar results were observed in ex vivo-cultured neonatal rat cardiomyocytes exposed to hypoxia. Mechanistically, we discovered that the CARD3-mediated detrimental effects of MI were associated with the activation of the NF-κB and p38 signalling cascades. Taken together, these data demonstrate that CARD3 serves as a novel positive modulator of ventricular remodelling after MI via the regulation of the NF-κB and p38 signalling. Thus, CARD3 may be a promising therapeutic target for the treatment of heart failure after MI.

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Acknowledgments

We thank Dr. Richard Flavell (Howard Hughes Medical Institute, Yale University, New Haven, Connecticut) for providing the CARD3-KO mice. We thank Rui Zhang, Xueyong Zhu, Zhangli Li, Ya Deng, Yan Zhang and Xin Zhang for providing experimental technological assistance. Dr. Xin Chen is a fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine. This study was supported by grants from the National Natural Science Foundation of China (No. 81370259), the Natural Science Foundation for Young Scientists of Jiangsu Province (No. BK20150093), and the 333 project in Jiangsu Province (2015).

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Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Changle Road 68, Nanjing, 210006, Jiangsu, People’s Republic of China

    Liangpeng Li, Xiaodi Wang, Wen Chen, Haoyu Qi, Fuhua Huang, Liming Wang & Xin Chen

  2. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China

    Ding-Sheng Jiang, Ling Huang & Hongliang Li

  3. Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, People’s Republic of China

    Ding-Sheng Jiang, Ling Huang & Hongliang Li

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  1. Liangpeng Li
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  2. Xiaodi Wang
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Li, L., Wang, X., Chen, W. et al. Regulatory role of CARD3 in left ventricular remodelling and dysfunction after myocardial infarction. Basic Res Cardiol 110, 56 (2015). https://doi.org/10.1007/s00395-015-0515-4

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