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 1a (HIF-1a) activates erythropoietin (Epo) as well as many other target genes that counteract the effects of O2 deficiency. Epo produced by the kidney stimulates erythrocyte prodn., leading to decreased HIF-1a prodn. 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-1a expression. Derivs. of Epo that possess tissue-protective activities but do not stimulate erythropoiesis [e.g., carbamylated Epo(CEpo)] are useful tools with which to det. whether exogenous Epo modulates HIF-1a in the absence of changes in Hb concn. We compared the effects of CH (6.5% O2 for 10 days) with or without CEpo administered by daily s.c. injection (10 mg/kg of body wt.). CEpo administration did not alter the survival rate, wt. loss, or increased Hb concn. assocd. with CH. Therefore, CEpo does not directly suppress HIF-mediated erythropoiesis. CEpo does, however, prevent CH-induced neuronal increases of HIF-1a and Epo receptor-assocd. immunoreactivity (a measure of stress) while reducing the apoptotic index. In contrast, the myocardium did not exhibit increased HIF-1a 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 prodn.

Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia / M. Fantacci, P. Bianciardi, A. Caretti, T.R. Coleman, A. Cerami, M. Brines, M. Samaja. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 103:46(2006), pp. 17531-17536.

Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia

M. Fantacci
Primo
;
P. Bianciardi
Secondo
;
A. Caretti;M. Samaja
Ultimo
2006

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 1a (HIF-1a) activates erythropoietin (Epo) as well as many other target genes that counteract the effects of O2 deficiency. Epo produced by the kidney stimulates erythrocyte prodn., leading to decreased HIF-1a prodn. 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-1a expression. Derivs. of Epo that possess tissue-protective activities but do not stimulate erythropoiesis [e.g., carbamylated Epo(CEpo)] are useful tools with which to det. whether exogenous Epo modulates HIF-1a in the absence of changes in Hb concn. We compared the effects of CH (6.5% O2 for 10 days) with or without CEpo administered by daily s.c. injection (10 mg/kg of body wt.). CEpo administration did not alter the survival rate, wt. loss, or increased Hb concn. assocd. with CH. Therefore, CEpo does not directly suppress HIF-mediated erythropoiesis. CEpo does, however, prevent CH-induced neuronal increases of HIF-1a and Epo receptor-assocd. immunoreactivity (a measure of stress) while reducing the apoptotic index. In contrast, the myocardium did not exhibit increased HIF-1a 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 prodn.
Apoptosis; Brain; Epo receptor; Heart; Hypoxia-inducible factor 1α
Settore BIO/10 - Biochimica
2006
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/23392
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