Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin

Brines, Michael, Patel, Nimesh S A, Villa, Pia, Brines, Courtenay, Mennini, Tiziana, De Paola, Massimiliano, Erbayraktar, Zubeyde, Erbayraktar, Serhat, Sepodes, Bruno, Thiemermann, Christoph, Ghezzi, Pietro, Yamin, Michael, Hand, Carla C, Xie, Qiao-wen, Coleman, Thomas and Cerami, Anthony (2008) Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proceedings of the National Academy of Sciences, 105 (31). pp. 10925-10930. ISSN 1091-6490

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Abstract

Erythropoietin (EPO), a member of the type 1 cytokine superfamily, plays a critical hormonal role regulating erythrocyte production as well as a paracrine/autocrine role in which locally produced EPO protects a wide variety of tissues from diverse injuries. Significantly, these functions are mediated by distinct receptors: hematopoiesis via the EPO receptor homodimer and tissue protection via a heterocomplex composed of the EPO receptor and CD131, the beta common receptor. In the present work, we have delimited tissue-protective domains within EPO to short peptide sequences. We demonstrate that helix B (amino acid residues 58-82) of EPO, which faces the aqueous medium when EPO is bound to the receptor homodimer, is both neuroprotective in vitro and tissue protective in vivo in a variety of models, including ischemic stroke, diabetes-induced retinal edema, and peripheral nerve trauma. Remarkably, an 11-aa peptide composed of adjacent amino acids forming the aqueous face of helix B is also tissue protective, as confirmed by its therapeutic benefit in models of ischemic stroke and renal ischemia-reperfusion. Further, this peptide simulating the aqueous surface of helix B also exhibits EPO's trophic effects by accelerating wound healing and augmenting cognitive function in rodents. As anticipated, neither helix B nor the 11-aa peptide is erythropoietic in vitro or in vivo. Thus, the tissue-protective activities of EPO are mimicked by small, nonerythropoietic peptides that simulate a portion of EPO's three-dimensional structure.

Item Type: Article
Keywords: cognition, cytoprotection, excitotoxicity, ischemia–reperfusion, injury, wound healing
Schools and Departments: Brighton and Sussex Medical School > Clinical and Laboratory Investigation
Subjects: Q Science > QR Microbiology
R Medicine
Depositing User: Patricia Butler
Date Deposited: 02 Nov 2012 16:11
Last Modified: 02 Nov 2012 16:11
URI: http://sro.sussex.ac.uk/id/eprint/41982
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