Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia
- 14 November 2006
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 103 (46), 17531-17536
- https://doi.org/10.1073/pnas.0608814103
Abstract
Ischemia and chronic hypoxia (CH) trigger a variety of adverse effects arising from metabolic stress that injures cells. In response to reduced O2, hypoxia-inducible factor 1alpha (HIF-1alpha) activates erythropoietin (Epo) as well as many other target genes that counteract the effects of O2 deficiency. Epo produced by the kidney stimulates erythrocyte production, leading to decreased HIF-1alpha production by improved tissue O2 delivery. However, Epo is produced by many other tissues, and it is currently unclear to what extent, if any, locally produced Epo modulates HIF-1alpha expression. Derivatives of Epo that possess tissue-protective activities but do not stimulate erythropoiesis [e.g., carbamylated Epo (CEpo)] are useful tools with which to determine whether exogenous Epo modulates HIF-1alpha in the absence of changes in hemoglobin concentration. We compared the effects of CH (6.5% O2 for 10 days) with or without CEpo administered by daily s.c. injection (10 microg/kg of body weight). CEpo administration did not alter the survival rate, weight loss, or increased hemoglobin concentration associated with CH. Therefore, CEpo does not directly suppress HIF-mediated erythropoiesis. CEpo does, however, prevent CH-induced neuronal increases of HIF-1alpha and Epo receptor-associated immunoreactivity (a measure of stress) while reducing the apoptotic index. In contrast, the myocardium did not exhibit increased HIF-1alpha expression during CH, although CEpo did reduce the apoptotic index. These observations therefore demonstrate that CEpo administration reduces the metabolic stress caused by severe CH, resulting in improved cellular survival independent of erythrocyte production.Keywords
This publication has 49 references indexed in Scilit:
- Discovering erythropoietin's extra-hematopoietic functions: Biology and clinical promiseKidney International, 2006
- Chronic in vivo hypoxia in various organs: Hypoxia-inducible factor-1α and apoptosisBiochemical and Biophysical Research Communications, 2006
- Erythropoietin disrupts hypoxia-inducible factor signaling in ovarian cancer cellsGynecologic Oncology, 2006
- Erythropoietin, Modified to Not Stimulate Red Blood Cell Production, Retains Its Cardioprotective PropertiesJournal of Pharmacology and Experimental Therapeutics, 2005
- Erythropoietin as an antiapoptotic, tissue-protective cytokineCell Death & Differentiation, 2004
- Hypoxia: Unique myocardial morphology?The Journal of Thoracic and Cardiovascular Surgery, 2004
- Protein kinase activation and myocardial ischemia/reperfusion injuryCardiovascular Research, 2004
- Hypoxia-Induced Stroke Tolerance in the Mouse Is Mediated by ErythropoietinStroke, 2003
- Hearts From Rodents Exposed to Intermittent Hypoxia or Erythropoietin Are Protected Against Ischemia-Reperfusion InjuryCirculation, 2003
- In situ detection of fragmented dna (tunel assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: A cautionary noteHepatology, 1995