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Calcium-sensing receptor activating phosphorylation of PKCδ translocation on mitochondria to induce cardiomyocyte apoptosis during ischemia/reperfusion

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Abstract

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that activates intracellular effectors; for example, it causes inositol phosphate (IP) and 1,2 diacylglycerol (DAG) accumulation, stimulating the release of intracellular calcium and the activation of the protein kinase Cs (PKCs). The activation of CaSR by ischemia/reperfusion (I/R) induces cardiomyocyte apoptosis through the mitochondrial apoptotic pathway; however, the underlying mechanisms remain unclear. In this study, rat hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion in the presence of a CaSR activator, GdCl3. Our results revealed that, under these conditions, the expression of CaSR was increased, the number of apoptotic cardiomyocytes was significantly increased (as shown by terminal deoxy-nucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay) and the cells with a typical apoptotic morphology were observed using transmission electron microscopy. Our data further showed that mitochondria isolated from hearts that had undergone I/R combined with GdCl3 exhibited a significant increase in the translocation of phosphorylated PKCδ to the mitochondria, an increase in cytochrome c (cyt c) release from the mitochondria and a marked decrease in mitochondrial potential. The administration of rottlerin, an inhibitor of PKCδ, significantly reduced reperfusion-induced apoptosis, phospho-PKCδ translocation to the mitochondria and the release of cyt c from the mitochondria. Thus, the involvement of CaSR in cardiac apoptosis through the mitochondrial pathway during I/R with GdCl3 is related to phospho-PKCδ translocation to the mitochondria.

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Acknowledgments

This study was supported by a Yu Weihan grant for excellent young scientists at Harbin Medical University (for Weihua Zhang), and also supported by the National Natural Science Foundation of China (30700288, 81000059, and 81070123) and Heilongjiang Educational Ministry Fund (No. 11541111).

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Authors and Affiliations

  1. Department of Pathophysiology, Harbin Medical University, Harbin, 150086, China

    Huishuang Zheng, Chong Liu, Fanghao Lu, Yajun Zhao, Xiaoning Leng, Jing Jia, Guangxia Hu, Shiyun Dong, Xin Zhong, Hongzhu Li, Changqing Xu & Weihua Zhang

  2. Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China

    Jun Liu

  3. Department of Pathology, Harbin Medical University, Harbin, 150086, China

    Zhanfeng Jin

  4. Bio-pharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, 150086, China

    Baofeng Yang, Changqing Xu & Weihua Zhang

  5. Department of Immunology, Harbin Medical University, Harbin, 150086, China

    Huan Ren

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  1. Huishuang Zheng
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  2. Jun Liu
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  3. Chong Liu
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  7. Huan Ren
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  8. Xiaoning Leng
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  11. Shiyun Dong
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  13. Hongzhu Li
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  14. Baofeng Yang
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  15. Changqing Xu
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  16. Weihua Zhang
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Corresponding authors

Correspondence to Changqing Xu or Weihua Zhang.

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Huishuang Zheng and Jun Liu contributed equally to this work.

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Zheng, H., Liu, J., Liu, C. et al. Calcium-sensing receptor activating phosphorylation of PKCδ translocation on mitochondria to induce cardiomyocyte apoptosis during ischemia/reperfusion. Mol Cell Biochem 358, 335–343 (2011). https://doi.org/10.1007/s11010-011-0984-1

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  • DOI: https://doi.org/10.1007/s11010-011-0984-1

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