Raves and risks for erythropoietin - PubMed (original) (raw)

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Raves and risks for erythropoietin

Kenneth Maiese et al. Cytokine Growth Factor Rev. 2008 Apr.

Abstract

Global use of erythropoietin (EPO) continues to increase as a proven agent for the treatment of anemia. Yet, EPO is no longer believed to have exclusive biological activity in the hematopoietic system and is now considered applicable for a variety of disorders such as diabetes, Alzheimer's disease, and cardiovascular disease. Treatment with EPO is considered to be robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. On the converse side, observations that EPO administration is not without risk have fueled controversy. Here we present recent advances that have elucidated a number of novel cellular pathways governed by EPO to open new therapeutic avenues for this agent and avert its potential deleterious effects.

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Figures

Figure 1

Figure 1. Cytoprotection by erythropoietin (EPO) requires multiple signal transduction pathways

EPO and the EPO receptor (EPOR) can increase cell survival, promote progenitor cell development, and control inflammatory cell activation through pathways that involve the Janus-tyrosine kinase 2 (Jak2) protein, protein kinase B (Akt), and signal transducer and activator of transcription (STAT) proteins. Subsequent downstream signaling governs extracellular signal-related kinases (ERKs), the forkhead family member FOXO3a, glycogen synthase kinase-3β (GSK-3β), and nuclear factor-κB (NF-κB). Intimately linked to the ability of EPO to maintain cellular integrity and prevent inflammatory activation that ultimately can lead to cellular apoptosis are the maintenance of mitochondrial membrane potential (ΔΨm), the release of cytochrome c, (Cyto-c), and the prevention of caspase activation.

Figure 2

Figure 2. Erythropoietin (EPO) sequesters FOXO3a in the cytoplasm during oxygen-glucose deprivation (OGD)

Administration of EPO (10 ng/ml) with an 8 hour period of OGD, OGD alone, or untreated cells (Control) was followed at 6 hours with immunofluorescent staining for FOXO3a (Texas-red) in endothelial cells (ECs). Nuclei of ECs were counterstained with DAPI. In merged images, cells with combined EPO and OGD show EC nuclei with minimal FOXO3a staining (blue/white) and show EC cytoplasm with significant FOXO3a staining (red) in contrast to cells with OGD alone with significant FOXO3a staining in both the cytoplasm and the nuclei of ECs, demonstrating the ability of EPO to sequester FOXO3a in the cytoplasm.

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