A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury

Fabio Fiordaliso, Stefano Chimenti, Lidia Staszewsky, Antonio Bai, Eleonora Carlo, Ivan Cuccovillo, Mirko Doni, Manuela Mengozzi, Rossella Tonelli, Pietro Ghezzi, Thomas Coleman, Michael Brines, Anthony Cerami, Roberto Latini

Research output: Contribution to journalArticle

Abstract

The cytokine erythropoietin (EPO) protects the heart from ischemic injury, in part by preventing apoptosis. However, EPO administration can also raise the hemoglobin concentration, which, by increasing oxygen delivery, confounds assignment of cause and effect. The availability of EPO analogs that do not bind to the dimeric EPO receptor and lack erythropoietic activity, e.g., carbamylated EPO (CEPO), provides an opportunity to determine whether EPO possesses direct cardioprotective activity. In vivo, cardiomyocyte loss after experimental myocardial infarction (MI) of rats (40 min of occlusion with reperfusion) was reduced from ≈57% in MI-control to ≈45% in animals that were administered CEPO daily for 1 week (50 μg/kg of body weight s.c.) with the first dose administered intravenously 5 min before reperfusion. CEPO did not increase the hematocrit, yet it prevented increases in left ventricular (LV) end-diastolic pressure, reduced LV wall stress in systole and diastole, and improved LV response to dobutamine infusion compared with vehicle-treated animals. In agreement with the cardioprotective effect observed in vivo, staurosporine-induced apoptosis of adult rat or mouse cardiomyocytes in vitro was also significantly attenuated (≈35%) by CEPO, which is comparable with the effect of EPO. These data indicate that prevention of cardiomyocyte apoptosis, in the absence of an increase in hemoglobin concentration, explains EPO's cardioprotection. Non-erythropoietic derivatives such as CEPO, devoid of the undesirable effects of EPO, e.g., thrombogenesis, could represent safer and more effective alternatives for treatment of cardiovascular diseases, such as MI and heart failure. Furthermore, these findings expand the activity spectrum of CEPO to tissues outside the nervous system.

Original languageEnglish
Pages (from-to)2046-2051
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number6
DOIs
Publication statusPublished - Feb 8 2005

Keywords

  • Apoptosis
  • Cardioprotection
  • Cytokine
  • Tissue injury

ASJC Scopus subject areas

  • Genetics
  • General

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