New avenues of exploration for erythropoietin

Abstract

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 be acquired.

Figure. Potential Mechanism of Erythropoietin Cytoprotection

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-x_L (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.