Molecular basis of cardioprotection by erythropoietin.
Erythropoietin (EPO), a glycoprotein essential for red blood cell production acts on several non-erythropoietic tissues. The EPO receptor (EPOR) is expressed in a variety of cell types including neurons, endothelial cells, and cardiomyocytes. Recently, a number of reports have indicated that EPO preserves heart function in models of cardiac ischemia-reperfusion (I/R) injury. A diverse range of cellular/physiological processes is modulated by EPO and are thought to play a role in the preservation of heart function. In vivo, reductions in infarct size, apoptosis, oxidative stress, and inflammation have been reported. More recently, increases in angiogenesis and reductions in arrhythmias have been implicated in the cardioprotective effects of EPO. In vitro, EPO reduces apoptosis, oxidative stress, and inflammation. These cardioprotective effects appear to be mediated by a receptor interaction that is distinct from that responsible for EPO's erythropoietic effects. Downstream of receptor interactions, the activation of phosphatidylinositol-3 kinase (PI3-kinase) and Akt appear to mediate many of EPO's cardioprotective effects. However, there is emerging evidence for Akt-independent mechanisms of cardioprotection including the inhibition of glycogen synthase kinase 3beta, as well as the activation of potassium channels, protein kinase C, and protein kinases such as ERK1/2. This review focuses on the effects of EPO in the heart and the molecular mechanisms by which EPO achieves its cardioprotective effects.
Burger
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Department of Physiology & Pharmacology, University of Western Ontario, London, Ontario, N6A 5C1 Canada.
Xenocostas
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Feng
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D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004921:Erythropoietin / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017467:Receptors, Erythropoietin / Q000378:metabolism; D015398:Signal Transduction
D002316:Cardiotonic Agents; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3