Disease relevance of Epo

• Identification of novel cytoprotective pathways used by EPO may serve as therapeutic targets for cerebral vascular disease [1].
• Exogenous erythropoietin (EPO) is a potent neurotrophic factor in vivo, protective against neuronal death in animal models of brain ischemia and human stroke [2].
• Erythropoietin (EPO) has been suggested to have a cardioprotective effect against ischemia [3].
• Effects of erythropoietin on cardiac remodeling after myocardial infarction [3].
• In addition, EPO significantly attenuated the interstitial fibrosis and remodeling-related gene expression in non-infarcted myocardium [3].

Psychiatry related information on Epo

• Infusion of EPO into the lateral ventricles of gerbils prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from lethal ischemic damage [4].
• Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats [5].
• It is suggested that depression of erythropoiesis during water deprivation in the rat depends on a reduced sensitivity to erythropoietin, possibly associated with decreased production of the hormone [6].
• After 3 mo of EPO treatment, aged rats exhibited significantly impaired maze learning compared to controls [7].
• Systemic injection of erythropoietin (EPO) over several days reduces sleep fragmentation in patients with periodic limb movements in sleep (PLMS) [8].

High impact information on Epo

• Erythropoietin, a kidney cytokine regulating haematopoiesis (the production of blood cells), is also produced in the brain after oxidative or nitrosative stress [9].
• The regenerating liver produces erythropoietin in response to hypoxia [10].
• Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis [11].
• Although EPO is clearly antiapoptotic for neurons after experimental stroke, it is unknown whether EPO also directly modulates EPO receptor (EPO-R)-expressing glia, microglia, and other inflammatory cells [11].
• We reasoned that benefits of EPO might be offset by increases in hematocrit and evaluated the direct effects of EPO in the ischemic heart [12].

Chemical compound and disease context of Epo

• In an in vitro model of cerebral ischemia (oxygen glucose deprivation, OGD) we investigated whether erythropoietin (EPO) plays a critical role in ischemic preconditioning [13].
• In contrast, vitamin E (tested from 0.05 to 500 micrograms/ml) and vitamin C (tested from 2 to 200 micrograms/ml) did not increase Epo production in hepatoma cell cultures [14].
• Neuroprotective effects of erythropoietin on glutamate and nitric oxide toxicity in primary cultured retinal ganglion cells [15].
• Production of the immunoreactive Epo was dependent on O2 tension for cell culture; hypoxia enhanced the production [16].
• Immunohistochemical analysis for EPO, EpoR expression, and pimonidazole adducts was performed on 26 tumor biopsies with contiguous sections from 10 patients with breast cancer [17].

Biological context of Epo

• OBJECTIVE: Erythropoietin (EPO) is a pleiotropic cytokine originally identified for its role in erythropoiesis [18].
• In conclusion, when administered after MI, EPO prevents cardiac remodeling and improves ventricular function with enhanced angiogenesis and reduced apoptosis [3].
• Furthermore, EPO significantly enhanced angiogenesis and reduced apoptotic cell death in peri-infarcted myocardium [3].
• Furthermore, EPO-induced neuroprotection as well as phosphorylation of the proapoptotic Bcl family member Bad was reduced by the phosphoinositide-3 kinase (PI3K) inhibitor LY294002 [13].
• EPO significantly attenuated this ventricular remodeling and systolic and diastolic dysfunction [3].

Anatomical context of Epo

• The authors examined the ability of EPO to modulate a series of death-related cellular pathways during free radical-induced injury in cerebral microvascular endothelial cells (ECs) [1].
• Exogenous EPO maintains both genomic DNA integrity and cellular membrane asymmetry through parallel pathways that prevent the induction of Apaf-1 and preserve mitochondrial membrane potential in conjunction with enhanced Bcl-XL expression [1].
• Erythropoietin (EPO) plays a prominent role in the regulation of the hematopoietic system, but the potential function of this trophic factor as a cytoprotectant in the cerebral vascular system is not known [1].
• Furthermore, we show that EPO mediates the classic neurotrophic effects of proliferation, differentiation and maintenance in a dopaminergic cell line [2].
• After HIF-1 activation the astrocytes express and release EPO [13].

Associations of Epo with chemical compounds

• Thus, while vitamins E and C may have the potential to protect cells from oxidative damage, vitamin A exerts a specific stimulation of Epo production [14].
• Vitamin A induced a dose-dependent increase (half-maximal stimulation at 0.2 microgram/ml) in the production of immunoreactive Epo during 24 hours of incubation (such as 680 +/- 51 U Epo/g cell protein in HepG2 cultures with 3 micrograms/ml retinol acetate compared to 261 +/- 15 U/g in untreated controls; N = 4) [14].
• Because retinal ganglion cell (RGC) death is a common cause of reduced visual function in several ocular diseases, we explored whether Epo might potentially be beneficial in protecting RGCs from glutamate and nitric oxide (NO)-induced cytotoxicity, using isolated RGCs by a two-step panning method [15].
• EPO suppressed Ca(2+)-induced dopamine release from PC12 cells in a concentration- and time-dependent manner [19].
• However, in the presence of PD98,059, an inhibitor of ERK, and salicylic acid, an NF-kappaB inhibitor, the EPO-induced morphological differentiation of astrocytes and expression of FGAP and EPO receptor were reduced [20].

Physical interactions of Epo

• These biological activities were completely inhibited by the anti-Epo antiserum and the extracellular domain of the Epo receptor capable of binding with Epo [16].

Regulatory relationships of Epo

• Consistent with the modulation of Apaf-1 and the release of cytochrome c, EPO also inhibits the activation of caspase-9 and caspase-3-like activities [1].
• Our results suggest a new mechanism for Epo-induced neuroprotection, in which circulating Epo controls and maintains the BBB through an Epo receptor signalling pathway and the re-establishment of cell junctions [21].
• Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats [22].
• Epo (20 U/mL) induced mild oxidative stress as shown by increases in heme oxygenase (HO)-1 mRNA and protein expression that could be suppressed by antioxidant coadministration [23].
• At week 1, spermatids and sperm were more abundant in testes with pCAGGS-Epo than those in the control testes [24].

Other interactions of Epo

• Apaf-1, Bcl-xL, cytochrome c, and caspase-9 form the critical elements for cerebral vascular protection by erythropoietin [1].
• Two weeks after injury, EPO immunoreactivity was scarcely detected in neurons, whereas glial cells and vascular endothelium expressed strong EPO-R immunoreactivity [18].
• Cultured neurons express EpoR, and the Janus kinase-2 (JAK-2) inhibitor AG490 abolished EPO-induced tolerance against OGD [13].
• After 24 h of 10% O(2), Spalax Epo reaches its maximal expression, remarkably 6-fold higher than the maximum in Rattus; (ii) the HIF-1 alpha level in normoxia is 2-fold higher in Spalax than in Rattus [25].
• Through pathways that involve the initial activation of protein kinase B, EPO maintains mitochondrial membrane potential [26].

Analytical, diagnostic and therapeutic context of Epo

• Our results establish EPO as an important paracrine neuroprotective mediator of ischemic preconditioning [13].
• Epo secretion significantly increased to 674 +/- 92 mU/g kidney (N = 7) when vitamins A (0.5 microgram/ml), E (0.5 microgram/ml) and C (10 micrograms/ml) in combination were added to the perfusion medium [14].
• The effects of the single vitamins were studied in Epo-producing hepatoma cell cultures (lines HepG2 and Hep3B) [14].
• CONCLUSIONS: These results demonstrate that liver-targeted pCAGGS-EpoR/IgG(1)Fc transfer by tail-vein injection with hydrodynamics-based transfection is useful for neutralizing Epo delivered by in vivo electroporation [27].
• RT-PCR and Western blot analysis revealed that hypoxia-ischemia only marginally affected EPO expression [28].

References