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

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.

• Authors: Michael Brines, Nimesh S A Patel, Pia Villa, Courtenay Brines, Tiziana Mennini, Massimiliano De Paola, Zubeyde Erbayraktar, Serhat Erbayraktar, Bruno Sepodes, Christoph Thiemermann, Pietro Ghezzi, Michael Yamin, Carla C Hand, Qiao-wen Xie, Thomas Coleman, Anthony Cerami
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 31 Pg. 10925-30 (Aug 05 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18676614 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokine Receptor Common beta Subunit
• Peptides
• Erythropoietin

Topics

• Animals
• Cytokine Receptor Common beta Subunit (metabolism)
• Erythropoietin (genetics, therapeutic use)
• Kidney (injuries)
• Male
• Mice
• Mice, Inbred C57BL
• Papilledema (drug therapy)
• Pattern Recognition, Visual (physiology)
• Peptides (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (drug therapy)
• Wound Healing (genetics)