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First published online August 6, 2004
Journal of Experimental Biology 207, 3233-3242 (2004)
Published by The Company of Biologists 2004
doi: 10.1242/jeb.01049

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Erythropoietin and the hypoxic brain

Hugo H. Marti

Institute of Physiology and Pathophysiology, University of Heidelberg, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany

View larger version (28K): [in a new window]   Fig. 1. Regulation of hypoxia-inducible factor (HIF) activity in response to cellular oxygen level. Two independent hydroxylation pathways regulate HIF activity in response to cellular oxygen level. In normoxia, oxygen availability enables hydroxylation of proline (P) residues of the HIF- oxygen-dependent degradation domain via prolyl hydroxylase domain (PHD) enzymes. This prolyl hydroxylation allows binding of the von Hippel-Lindau (VHL) E3 ligase, leading to ubiquitylation and proteasomal degradation of HIF- subunits. Oxygen availability also enables hydroxylation of asparagine (N) residues of the C-terminal transactivation domain (C-TAD), blocking interaction with the transcriptional co-activator p300/CBP (CREB binding protein). This event is governed by an asparaginyl hydroxylase termed factor-inhibiting HIF (FIH). As a consequence, in the presence of oxygen, active PHDs and FIH result in inactivation of HIF, and thus HIF-mediated gene transcription is blocked. In hypoxia, the PHD and FIH enzymes are inactive and the lack of hydroxylation results in stable HIF- and an active C-TAD, which is able to form a DNA-binding heterodimer with the constitutive present HIF-ß subunit and recruit the co-activator p300/CBP. Lack of oxygen and thus inactive PHD and FIH enzymes result in active HIF, which enables hypoxia-dependent gene expression of, for example, erythropoietin (EPO) and vascular endothelial growth factor (VEGF). Reproduced with permission from Masson and Ratcliffe (2003).

View larger version (24K): [in a new window]   Fig. 2. Hypoxia-induced neuronal protection mechanisms in the central nervous system. Tissue hypoxia and cerebral ischaemia activate hypoxia-inducible factor-1 (HIF-1), which in turn activates gene transcription of a variety of oxygen-regulated factors, among them erythropoietin (EPO) and vascular endothelial growth factor (VEGF). These factors, as well as HIF-1 itself, might also be activated by hypoxia-independent stimuli such as growth factors or cytokines. EPO and VEGF then confer cellular protection. The main target for EPO (indicated by a thicker arrow) is neurones, while VEGF mainly prevents apoptosis and stimulates proliferation of endothelial cells, resulting in new vessel growth (angiogenesis) and ultimately better oxygenation of hypoxic tissues. However, to a lesser extent, EPO also contributes to endothelial cell proliferation, and VEGF is also a direct neuroprotective factor (indicated by thinner arrows). In addition, both EPO and VEGF also have neurotrophic properties. Finally, as receptors for both EPO and VEGF are expressed on microglial cells and astrocytes, glial cells might be a target for both factors, although the effects on these cells are less clear (indicated by broken arrows) and the contribution to neuronal survival remains to be established.