title: Peptide-binding heat shock protein GRP78 protects cardiomyocytes from hypoxia-induced apoptosis.
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.
authors.affiliation: 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. bhardy@post.tau.ac.il
authors.forename: Britta
authors.initials: B
authors.lastname: Hardy
authors.forename: Annat
authors.initials: A
authors.lastname: Raiter
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D034741:RNA, Small Interfering