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Cyclosporin A induces apoptosis in H9c2 cardiomyoblast cells through calcium-sensing receptor-mediated activation of the ERK MAPK and p38 MAPK pathways

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Abstract

The cardiotoxicity of cyclosporine A (CsA) limits its clinical application in extensive and long-term therapies. Our group has shown that CsA induces myocardium cell apoptosis in vivo and increases calcium-sensing receptor (CaSR) expression. However, its molecular mechanism remains unknown. The purpose of this study was to determine whether CaSR plays an essential role in CsA-induced apoptosis in H9c2 cells and to investigate the role of the mitogen-activated protein kinase (MAPK) signaling cascade in this process. H9c2 cells were treated with CsA in a dose-dependent manner, and decreased Bcl-2 expression, increased Bax expression, and caspase-3 activation were observed. In a time-dependent manner, CsA increased CaSR expression, activated the extracellularly regulated kinase (ERK) and p38 MAPK pathways, and inactivated the c-Jun N-terminal kinase (JNK) MAPK signaling pathway. When H9c2 cardiomyoblast cells pretreated with gadolinium chloride (GdCl3), a CaSR activator, were treated with CsA, decreased phosphorylation of ERK1/2, increased phosphorylation of p38, decreased Bcl-2 expression, increased Bax expression, and activated caspase-3 were observed. Cells pretreated with the CaSR inhibitor NPS2390 inhibited this process. Furthermore, the MEK1/2 inhibitor U0126 and the p38 MAPK inhibitor SB203580 markedly blocked the effect of CsA on cell apoptosis, apoptotic-related protein expression, and caspase-3 activation. These findings showed that CsA induced apoptosis in H9c2 cells in vitro, and CaSR mediated the degradation of ERK MAPK and the upregulation of the p38 MAPK pathway involved in CsA-induced H9c2 cardiomyoblast cell apoptosis.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (30872387) and the Postgraduate Foudation of the National Education Ministry of China (200802260006).

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Authors and Affiliations

  1. Department of Cardiology, First Affiliated Hospital of Harbin Medical University, No. 199 Dazhi Street, Harbin, 150001, China

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

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  1. Jinyu Chi
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  2. Yejing Zhu
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  3. Yu Fu
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  4. Yue Liu
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  5. Xiaohui Zhang
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  7. Xinhua Yin
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  8. Dechao Zhao
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Correspondence to Xinhua Yin or Dechao Zhao.

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Chi, J., Zhu, Y., Fu, Y. et al. Cyclosporin A induces apoptosis in H9c2 cardiomyoblast cells through calcium-sensing receptor-mediated activation of the ERK MAPK and p38 MAPK pathways. Mol Cell Biochem 367, 227–236 (2012). https://doi.org/10.1007/s11010-012-1336-5

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