Discovery that the hormone erythropoietin (EPO) and its receptor play
a significant biological role in tissues outside of the hematopoietic system
has fueled significant interest in EPO as a novel cytoprotective agent in
both neuronal and vascular systems. Erythropoietin is now considered to have
applicability in a variety of disorders that include cerebral ischemia, myocardial
infarction, and chronic congestive heart failure. Erythropoietin modulates
a broad array of cellular processes that include progenitor stem cell development,
cellular integrity, and angiogenesis. As a result, cellular protection by
EPO is robust and EPO inhibits the apoptotic mechanisms of injury, including
the preservation of cellular membrane asymmetry to prevent inflammation. As
the investigation into clinical applications for EPO that maximize efficacy
and minimize toxicity progresses, a deeper appreciation for the novel roles
that EPO plays in the brain and heart and throughout the entire body should
Erythropoietin (EPO) and the EPO receptor (EPOR) prevent apoptosis and
cellular inflammation through a series of pathways that originate with the
binding of EPO to the EPOR to activate Janus-tyrosine kinase 2 (Jak2), phosphoinositide
3 kinase (PI 3-K), and protein kinase B (Akt). The signal transducer and activator
or transcription (STAT) proteins are direct substrates of Jak2. Activation
of the specific gene product STAT5 can regulate EPO mediated cell proliferation
and protect against apoptosis. Downstream from activation of Jak2 and Akt,
EPO modulates phosphorylation of the fork head family member FOXO3a, glycogen
synthase kinase-3β (GSK-3β), and nuclear factor-κB (NF-κB).
Hypoxia increases the expression of hypoxia-inducible factor-1 (HIF-1) resulting
in the direct enhancement of EPO expression and a hypoxic-driven increase
in EPOR expression. Erythropoietin maintains cellular integrity and prevents
apoptosis through a number of pathways, such as those involving Bcl-xL (for the maintenance of mitochondrial membrane potential), the modulation
of apoptosis protease activating factor (Apaf)-1, the release of cytochrome
C, and the activation of caspases 1, 3, and 9. Erythropoietin also modulates
cellular inflammation by inhibiting cellular phosphatidylserine membrane exposure
and the subsequent targeting of cells for phagocytosis.
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