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Peptide-binding heat shock protein GRP78 protects cardiomyocytes from hypoxia-induced apoptosis

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Abstract

Myocardial ischemia is a severe stress condition that causes extensive biochemical changes triggering cardiac cell death. The 78-kDa glucose-regulated protein (GRP78), a heat shock protein present in all cells and a widely used marker of endoplasmic reticulum stress, functions in controlling the structural maturation of nascent glycoproteins. However, GRP78 was also found to be expressed on the cell surface of several cells such as endothelial cells, macrophages, and tumor cells where it functions as a receptor for a variety of ligands in signaling pathways. Recently, we have identified peptides from two different sources that specifically bind GRP78 protein. We have shown that binding of these peptides to endothelial cell surface GRP78 resulted in angiogenesis. In this study, we first established the presence of cell surface GRP78 on cardiac myocytes. Analysis of cardiomyocytes under hypoxia determined the significant increase in cell surface GRP78 in addition to gene expression and total protein. Apoptosis that was significantly increased in cardiomyocytes under hypoxic conditions was inhibited by the presence of the peptide-binding GRP78 during hypoxia. Inhibition of apoptosis was mediated by the binding of the peptide to cardiomyocytes cell surface GRP78 resulting in blocking caspase-3/7 activation. Silencing GRP78 RNA that reduced GRP78 receptor abrogated the peptide activity. Apoptosis of cardiac cells induced by myocardial infarction in a mouse model was also significantly inhibited by the administration of the peptide to mouse hearts. Our findings may make ADoPep1 a useful therapeutic tool for relieving of ischemia.

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Acknowledgments

The authors wish to express their gratitude to Ms. Sara Dominitz for her excellent editorial assistance and to Ms. Moran Kleman for her high expertise in statistical analysis.

Sources of funding

This work was funded by the Tel-Aviv University Research Grant.

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None.

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Authors and Affiliations

  1. The Laboratory of Cellular and Vascular Immunology, Felsenstein Medical Research Center, Tel-Aviv University Sackler School of Medicine, Rabin Medical Center, Beilinson Campus, Petach-Tikva, 49100, Israel

    Britta Hardy & Annat Raiter

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  1. Britta Hardy
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  2. Annat Raiter
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Correspondence to Britta Hardy.

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Hardy, B., Raiter, A. Peptide-binding heat shock protein GRP78 protects cardiomyocytes from hypoxia-induced apoptosis. J Mol Med 88, 1157–1167 (2010). https://doi.org/10.1007/s00109-010-0657-7

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  • DOI: https://doi.org/10.1007/s00109-010-0657-7

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