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Knockdown of dishevelled-1 attenuates cyclosporine A-induced apoptosis in H9c2 cardiomyoblast cells

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Abstract

Cyclosporine (CsA) has become a mainstay for immune suppression of organ transplants. It is known that patients receiving CsA manifest increased growth of aggressive cardiotoxicity. We have demonstrated that CsA induces myocardium cell apoptosis in vivo and vitro. Recently, dishevelled-1 (Dvl-1) protein, which is a cytoplasmic mediator of Wnt/β-catenin signaling, was explored in cardiac diseases. However, whether Dvl-1 is involved in CsA-induced apoptosis remains to be determined. The aim of this study was to explore the role of Dvl-1 in CsA-induced apoptosis in H9c2 cardiomyoblast cells and to investigate the role of the Wnt/β-catenin signaling cascade in this progress. H9c2 cells were treated with CsA in dose and time-dependent manners. We found that the appropriate concentrations and time-points of CsA-induced the expression of Dvl-1 and subsequent up-regulation of β-catenin and c-Myc, which is consistent with previously demonstrated concentrations and time-points when H9c2 cells apoptosis occurred. Then, cells were transfected with small interfering RNA (siRNA) against Dvl-1 and stimulated with previously demonstrated concentration of CsA. Dvl-1 down-regulation decreased the apoptotic rate, caspase-3 activity, and the Bax/Bcl-2 ratio in H9c2 cells treated with CsA. Furthermore, knocking down the expression of Dvl-1 partially suppressed the activity of the Wnt/β-catenin pathway. Moreover, we further deleted the downstream member β-catenin by specific siRNA, and found that CsA-induced the Bax/Bcl-2 ratio and the expression of c-Myc, which were attenuated. Our results are the first to unveil this novel aspect of Dvl-1 signaling. In addition, these data provide insight into the pathogenesis and the therapeutic strategies of CsA-induced myocardial injury.

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Acknowledgments

We thank Dr. Hong Ling for the generous gift of the H9c2 cell line. This study was supported by the National Natural Science Foundation of China (30872387) and the Postgraduate Foundation of the National Education Ministry of China (200802260006).

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Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, No. 23, YouZheng Street, NanGang District, Harbin, 150001, Heilongjiang Province, People’s Republic of China

    Yejing Zhu, Jinyu Chi, Yue Liu, Yu Fu, Xiaohui Zhang, Xueliang Ding, Xinhua Yin & Dechao Zhao

  2. Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Baojian Road, Harbin, 150081, Heilongjiang Province, People’s Republic of China

    Yihua Sun

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  1. Yejing Zhu
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  2. Jinyu Chi
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  3. Yue Liu
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Correspondence to Xinhua Yin or Dechao Zhao.

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Zhu, Y., Chi, J., Liu, Y. et al. Knockdown of dishevelled-1 attenuates cyclosporine A-induced apoptosis in H9c2 cardiomyoblast cells. Mol Cell Biochem 374, 113–123 (2013). https://doi.org/10.1007/s11010-012-1510-9

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  • DOI: https://doi.org/10.1007/s11010-012-1510-9

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