Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling

Abstract

Erythropoietin (EPO), originally identified for its critical hormonal role in promoting erythrocyte survival and differentiation, is a member of the large and diverse cytokine superfamily. Recent studies have identified multiple paracrine͞autocrine functions of EPO that coordinate local responses to injury by maintaining vascular autoregulation and attenuating both primary (apoptotic) and secondary (inflammatory) causes of cell death. Experimental evidence also supports a role for EPO in repair and regeneration after brain and spinal cord injury, including the recruitment of stem cells into the region of damage. Tissue expression of the EPO receptor is widespread, especially during development, and includes the heart. However, it is currently unknown as to whether EPO plays a physiological function in adult myocardial tissue. We have assessed the potential protective role of EPO in vitro with adult rat cardiomyocytes, and in vivo in a rat model of myocardial infarction with reperfusion. The results show that EPO markedly prevents the apoptosis of cultured adult rat myocardiocytes subjected to 28 h of hypoxia (Ϸ3% normal oxygen). Additional studies employing a rat model of coronary ischemia-reperfusion showed that the administration of recombinant human EPO (5,000 units͞kg of body weight; i.p. daily for 7 days) reduces cardiomyocyte loss by Ϸ50%, an extent sufficient to normalize hemodynamic function within 1 week after reperfusion. These observations not only suggest a potential therapeutic role for recombinant human EPO in the treatment of myocardial ischemia and infarction by preventing apoptosis and attenuating postinfarct deterioration in hemodynamic function, but also predict that EPO is likely a tissue-protective cytokine in other organs as well.

Erythropoietin as an antiapoptotic, tissue-protective cytokine

“…70 EPO has been shown to be protective of myocardial ischemia either permanent or with reperfusion. 12,71 Further, cardiomyocytes losses were not completely prevented in EPO-treated animals, being reduced by B50%. In spite of tissue loss, maladaptive remodeling did not occur, resulting in a maintained normal cardiac function.…”

“…The protective effects of EPO are not restricted to the CNS as it was recently shown that EPO has also antiapoptotic effects on cardiomyocytes in vitro and in vivo in a rat model of myocardial infarction, where it normalizes hemodynamic functions. 12 All these data stress the importance of EPO as an antiapoptotic and cytoprotective, not only neuroprotective, cytokine.…”

“…In contrast to its antiapoptotic effect, EPO has not shown any activity in preventing necrosis in either the nervous system (Sinor and Greenberg 35 and Mennini et al, unpublished) or the heart. 12 The EPO/EPOR is highly prominent during fetal development, 36 with the very high levels of expression found in many tissues diminishing rapidly after birth to the generally low levels found in the adult. Gene knockout experiments 37 have suggested the importance of this system in development, as the embryos of EPOR À/À animals have abnormal brain development characterized by decreased neuronal progenitor cells as well as grossly decreased neuronal densities associated with massive neuronal apoptosis.…”

Migration of Resident Cardiac Stem Cells in Myocardial Infarction

“…In vitro, EPO markedly prevented the hypoxia-induced apoptosis of cultured adult rat cardiomyocytes. Administering EPO to rats immediately after coronary occlusion (5000 IU/kg/day for 7 days) reduced cardiomyocyte loss by 50% (Calvillo et al, 2003). Recently, Klopsch et al (2009) have demonstrated that intracardiac injection of erythropoietin recruited stem cells, and improved cardiac output and ejection fraction in a rat MI model.…”

Neuroprotection by erythropoietin administration after experimental traumatic brain injury

“…Although peripherally administered recombinant human EPO (rHuEPO) has shown to penetrate the blood-brain barrier (BBB) and reduce brain injury following a variety of insults (Brines et al, 2000;Digicaylioglu and Lipton, 2001;Grasso et al, 2004), its potential neuroprotective efficacy in an in vivo model of experimental TBI has been scarcely investigated (Brines et al, 2000;Lu et al, 2005;Ozturk et al, 2005;Shein et al, 2005;Siren et al, 2006;Verdonck et al, 2007;Yatsiv et al, 2005). Evidence shows widespread efficacy of rHuEPO in injury models of spinal cord (Celik et al, 2002;Gorio et al, 2002;Grasso et al, 2006), subarachnoid hemorrhage (Buemi et al, 2002a,b;Catania et al, 2002;Grasso, 2001;Grasso et al, 2002a,b;Springborg et al, 2002), retina, and the heart damage (Calvillo et al, 2003;Junk et al, 2002).…”