Cardiovascular Drugs and Therapy

, Volume 27, Issue 4, pp 315–331 | Cite as

What is the Role of Erythropoietin in Acute Myocardial Infarct? Bridging the Gap Between Experimental Models and Clinical Trials

  • François Roubille
  • Fabrice Prunier
  • Stéphanie Barrère-Lemaire
  • Florence Leclercq
  • Christophe Piot
  • Ekaterini A. Kritikou
  • Eric Rhéaume
  • David Busseuil
  • Jean-Claude Tardif


Erythropoietin (EPO) is the main hormone that regulates erythropoiesis. Beyond its well-known hematopoietic action, EPO has diverse cellular effects in non-hematopoietic tissues. It has been shown to inhibit apoptosis by activating pro-survival pathways in the myocardium, to mobilize endothelial progenitor cells and to inhibit migration of inflammatory cells. EPO has also been shown to have potent pro-angiogenic properties. Numerous experimental data support the cardioprotective effects of EPO in animal models of acute myocardial infarct (AMI). However, these findings are not supported by recent clinical trials designed to investigate the safety and efficacy of EPO in patients with AMI. In this article, we begin by providing a comprehensive review of the cardioprotective effects of EPO in experimental animal models and the molecular mechanisms underlying these effects. We then discuss the EPO data obtained through clinical trials. We compare similarities and differences between the animal and human studies as well as between the different clinical studies in terms of sample size and study design including the dose, the route and the timing of administration as well as confounding factors such as comorbidities and concomitant treatments. Finally, we question the gap between the experimental and the translational clinical data and propose further developments to address these discrepancies and clearly evaluate the role of EPO in the clinical setting of MI.


Erythropoietin Cardioprotection Reperfusion injury Acute myocardial infarction Experimental models Clinical trials 



Area at risk


Angiotensin-converting-enzyme inhibitor


Acute myocardial infarction


Angiotensin II receptor blockers


Coronary artery bypass graft


Coronary artery disease


European Society of Cardiology




EPO receptor


Extracellular signal-regulated kinases


Fibroblast growth factor


Granulocyte colony-stimulating factor




Hepatocyte growth factor


Heme oxygenase




Insulin growth factor








Infarct size




Left ventricular


Left ventricular ejection fraction


Magnetic resonance imaging


National Heart, Lung, and Blood Institute


Phosphatidylinositol 3-kinase


Primary percutaneous coronary intervention






ST-elevation myocardial infarction


Thrombolysis in myocardial infarction


Tumour necrosis factor-α


Vascular endothelial growth factor



This work was supported by grants from the Fédération Française de Cardiologie (FR). The authors apologize to the authors whose works couldn’t be quoted because of space limitations.

Conflicts of Interest

Dr Roubille has no conflict of interest related to this study. Dr Prunier has received a grant form Amgen for a previous work (Prunier Am J Physiol 2007). Dr Tardif’s laboratory has received research grants from Roche.

Supplementary material

10557_2013_6461_MOESM1_ESM.doc (54 kb)
Supplementary Table 1 (DOC 54 kb)


  1. 1.
    Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation. 2004;110:e82–292.PubMedCrossRefGoogle Scholar
  2. 2.
    WHO. WHO fact sheet N°310, updated June 2011; 2011.Google Scholar
  3. 3.
    Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357:1121–35.PubMedCrossRefGoogle Scholar
  4. 4.
    Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 2008;359:473–81.PubMedCrossRefGoogle Scholar
  5. 5.
    Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation. 2005;112:2143–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Thibault H, Piot C, Staat P, et al. Long-term benefit of postconditioning. Circulation. 2008;117:1037–44.PubMedCrossRefGoogle Scholar
  7. 7.
    Thuny F, Lairez O, Roubille F, et al. Post-conditioning reduces infarct size and edema in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2012;59:2175–81.PubMedCrossRefGoogle Scholar
  8. 8.
    Jelkmann W. Biology of erythropoietin. Clin Invest. 1994;72(6 Suppl):S3–10.Google Scholar
  9. 9.
    Wu XM, Qian ZM, Zhu L, et al. Neuroprotective effect of ligustilide against ischaemia-reperfusion injury via up-regulation of erythropoietin and down-regulation of RTP801. Brit J Pharmacol. 2011;164:332–43.CrossRefGoogle Scholar
  10. 10.
    Siren AL, Fratelli M, Brines M, et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A. 2001;98:4044–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Ruscher K, Freyer D, Karsch M, et al. Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci. 2002;22:10291–301.PubMedGoogle Scholar
  12. 12.
    Chong ZZ, Kang JQ, Maiese K. Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways. Brit J Pharmacol. 2003;138:1107–18.CrossRefGoogle Scholar
  13. 13.
    Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A. 2004;101:14907–12.PubMedCrossRefGoogle Scholar
  14. 14.
    Grimm C, Wenzel A, Groszer M, et al. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med. 2002;8:718–24.PubMedCrossRefGoogle Scholar
  15. 15.
    Junk AK, Mammis A, Savitz SI, et al. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2002;99:10659–64.PubMedCrossRefGoogle Scholar
  16. 16.
    Chong ZZ, Kang JQ, Maiese K. Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation. 2002;106:2973–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Hamano Y, Aoki T, Shirai R, et al. Low-dose darbepoetin alpha attenuates progression of a mouse model of aristolochic acid nephropathy through early tubular protection. Nephron Exp Nephrol. 2010;114:e69–81.PubMedCrossRefGoogle Scholar
  18. 18.
    Patel NS, Sharples EJ, Cuzzocrea S, et al. Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo. Kidney Int. 2004;66:983–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Knudtzon S, Mortensen BT. Growth stimulation of human bone marrow cells in agar culture by vascular cells. Blood. 1975;46:937–43.PubMedGoogle Scholar
  20. 21.
    Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A. 1990;87:5978–82.PubMedCrossRefGoogle Scholar
  21. 21.
    Heeschen C, Aicher A, Lehmann R, et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood. 2003;102:1340–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Westenbrink BD, Lipsic E, van der Meer P, et al. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J. 2007;28:2018–27.PubMedCrossRefGoogle Scholar
  23. 23.
    Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A. 2008;105:10925–30.PubMedCrossRefGoogle Scholar
  24. 24.
    Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML. Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development. 1999;126:3597–605.PubMedGoogle Scholar
  25. 25.
    Calvillo L, Latini R, Kajstura J, et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci U S A. 2003;100:4802–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Parsa CJ, Matsumoto A, Kim J, et al. A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest. 2003;112:999–1007.PubMedGoogle Scholar
  27. 27.
    Wright GL, Hanlon P, Amin K, Steenbergen C, Murphy E, Arcasoy MO. Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury. FASEB. 2004;18:1031–3.Google Scholar
  28. 28.
    Gao E, Boucher M, Chuprun JK, Zhou RH, Eckhart AD, Koch WJ. Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart. Am J Physiol Heart Circ Physiol. 2007;293:H60–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Toma C, Letts DP, Tanabe M, Gorcsan 3rd J, Counihan PJ. Positive effect of darbepoetin on peri-infarction remodeling in a porcine model of myocardial ischemia-reperfusion. J Mol Cell Cardiol. 2007;43:130–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Namiuchi S, Kagaya Y, Ohta J, et al. High serum erythropoietin level is associated with smaller infarct size in patients with acute myocardial infarction who undergo successful primary percutaneous coronary intervention. J Am Coll Cardiol. 2005;45:1406–12.PubMedCrossRefGoogle Scholar
  31. 31.
    Ueda K, Takano H, Niitsuma Y, et al. Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice. J Clin Invest. 2010;120:2016–29.PubMedCrossRefGoogle Scholar
  32. 32.
    Zhang D, Zhang F, Zhang Y, et al. Erythropoietin enhances the angiogenic potency of autologous bone marrow stromal cells in a rat model of myocardial infarction. Cardiology. 2007;108:228–36.PubMedCrossRefGoogle Scholar
  33. 33.
    Kawachi K, Iso Y, Sato T, et al. Effects of erythropoietin on angiogenesis after myocardial infarction in porcine. Hear Vessel. 2012;27:79–88.CrossRefGoogle Scholar
  34. 34.
    Rathod DB, Salahudeen AK. Nonerythropoietic properties of erythropoietin: implication for tissue protection. J Investig Med. 2011;59:1083–5.PubMedGoogle Scholar
  35. 35.
    Chateauvieux S, Grigorakaki C, Morceau F, Dicato M, Diederich M. Erythropoietin, erythropoiesis and beyond. Biochem Pharmacol. 2011;82:1291–303.PubMedCrossRefGoogle Scholar
  36. 36.
    Hand CC, Brines M. Promises and pitfalls in erythopoietin-mediated tissue protection: are nonerythropoietic derivatives a way forward? J Investig Med. 2011;59:1073–82.PubMedGoogle Scholar
  37. 37.
    Brines M, Cerami A. Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J Int Med. 2008;264:405–32.CrossRefGoogle Scholar
  38. 38.
    Joyeux-Faure M. Cellular protection by erythropoietin: new therapeutic implications? J Pharmacol Exp Ther. 2007;323:759–62.PubMedCrossRefGoogle Scholar
  39. 39.
    Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA. 2005;293:90–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Kagaya Y, Asaumi Y, Wang W, et al. Current perspectives on protective roles of erythropoietin in cardiovascular system: erythropoietin receptor as a novel therapeutic target. Tohoku J Exp Med. 2012;227:83–91.PubMedCrossRefGoogle Scholar
  41. 41.
    Cai Z, Manalo DJ, Wei G, et al. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation. 2003;108:79–85.PubMedCrossRefGoogle Scholar
  42. 42.
    Moon C, Krawczyk M, Ahn D, et al. Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc Natl Acad Sci U S A. 2003;100:11612–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Tramontano AF, Muniyappa R, Black AD, et al. Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun. 2003;308:990–4.PubMedCrossRefGoogle Scholar
  44. 44.
    Cai Z, Semenza GL. Phosphatidylinositol-3-kinase signaling is required for erythropoietin-mediated acute protection against myocardial ischemia/reperfusion injury. Circulation. 2004;109:2050–3.PubMedCrossRefGoogle Scholar
  45. 45.
    Schlecht-Bauer D, Antier D, Machet MC, Hyvelin JM. Short- and long-term cardioprotective effect of darbepoetin-alpha: role of Bcl-2 family proteins. J Cardiovasc Pharmacol. 2009;54:223–31.PubMedCrossRefGoogle Scholar
  46. 46.
    Xu B, Dong GH, Liu H, Wang YQ, Wu HW, Jing H. Recombinant human erythropoietin pretreatment attenuates myocardial infarct size: a possible mechanism involves heat shock Protein 70 and attenuation of nuclear factor-kappaB. Ann Clin Lab Sci. 2005;35:161–8.PubMedGoogle Scholar
  47. 47.
    Joyeux-Faure M, Ramond A, Beguin PC, Belaidi E, Godin-Ribuot D, Ribuot C. Early pharmacological preconditioning by erythropoietin mediated by inducible NOS and mitochondrial ATP-dependent potassium channels in the rat heart. Fundam Clin Pharmacol. 2006;20:51–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Burger D, Lei M, Geoghegan-Morphet N, Lu X, Xenocostas A, Feng Q. Erythropoietin protects cardiomyocytes from apoptosis via up-regulation of endothelial nitric oxide synthase. Cardiovasc Res. 2006;72:51–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Burger D, Xiang F, Hammoud L, Lu X, Feng Q. Role of heme oxygenase-1 in the cardioprotective effects of erythropoietin during myocardial ischemia and reperfusion. Am J Physiol Heart Circ Physiol. 2009;296:H84–93.PubMedCrossRefGoogle Scholar
  50. 50.
    Mihov D, Bogdanov N, Grenacher B, Gassmann M, Zund G, Bogdanova A, et al. Erythropoietin protects from reperfusion-induced myocardial injury by enhancing coronary endothelial nitric oxide production. Eur J Cardiothorac Surg. 2009;35:839–46.PubMedCrossRefGoogle Scholar
  51. 51.
    Roubille C, Martel-Pelletier J, Haraoui B, Tardif J-C, Pelletier J-P. Biologics and cardiovascular system: a double edged sword. Antiinflamm Antiallergy Agents Med Chem. 2013;12:68–82.PubMedGoogle Scholar
  52. 52.
    Brines M. The therapeutic potential of erythropoiesis-stimulating agents for tissue protection: a tale of two receptors. Blood Purif. 2010;29:86–92.PubMedCrossRefGoogle Scholar
  53. 53.
    Fiordaliso F, Chimenti S, Staszewsky L, et al. A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2005;102:2046–51.PubMedCrossRefGoogle Scholar
  54. 54.
    Rui T, Feng Q, Lei M, et al. Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion via induction of AP-1. Cardiovasc Res. 2005;65:719–27.PubMedCrossRefGoogle Scholar
  55. 55.
    Tada H, Kagaya Y, Takeda M, et al. Endogenous erythropoietin system in non-hematopoietic lineage cells plays a protective role in myocardial ischemia/reperfusion. Cardiovasc Res. 2006;71:466–77.PubMedCrossRefGoogle Scholar
  56. 56.
    Asaumi Y, Kagaya Y, Takeda M, et al. Protective role of endogenous erythropoietin system in nonhematopoietic cells against pressure overload-induced left ventricular dysfunction in mice. Circulation. 2007;115:2022–32.PubMedCrossRefGoogle Scholar
  57. 57.
    Burger DE, Xiang FL, Hammoud L, Jones DL, Feng Q. Erythropoietin protects the heart from ventricular arrhythmia during ischemia and reperfusion via neuronal nitric-oxide synthase. J Pharmacol Exp Ther. 2009;329:900–7.PubMedCrossRefGoogle Scholar
  58. 58.
    van der Meer P, Lipsic E, Henning RH, et al. Erythropoietin improves left ventricular function and coronary flow in an experimental model of ischemia-reperfusion injury. Eur J Heart Fail. 2004;6:853–9.PubMedGoogle Scholar
  59. 59.
    Bullard AJ, Govewalla P, Yellon DM. Erythropoietin protects the myocardium against reperfusion injury in vitro and in vivo. Basic Res Cardiol. 2005;100:397–403.PubMedCrossRefGoogle Scholar
  60. 60.
    Diwan V, Kant R, Jaggi AS, Singh N, Singh D. Signal mechanism activated by erythropoietin preconditioning and remote renal preconditioning-induced cardioprotection. Mol Cell Biochem. 2008;315:195–201.PubMedCrossRefGoogle Scholar
  61. 61.
    Parsa CJ, Kim J, Riel RU, et al. Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac fibroblasts. J Biol Chem. 2004;279:20655–62.PubMedCrossRefGoogle Scholar
  62. 62.
    Rafiee P, Shi Y, Su J, Pritchard Jr KA, Tweddell JS, Baker JE. Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways. Basic Res Cardiol. 2005;100:187–97.PubMedCrossRefGoogle Scholar
  63. 63.
    Kobayashi H, Miura T, Ishida H, et al. Limitation of infarct size by erythropoietin is associated with translocation of Akt to the mitochondria after reperfusion. Clin Exp Pharmacol Physiol. 2008;35:812–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Olea FD, Vera Janavel G, De Lorenzi A, et al. High-dose erythropoietin has no long-term protective effects in sheep with reperfused myocardial infarction. J Cardiovasc Pharmacol. 2006;47:736–41.PubMedCrossRefGoogle Scholar
  65. 65.
    Kristensen J, Maeng M, Rehling M, et al. Lack of acute cardioprotective effect from preischaemic erythropoietin administration in a porcine coronary occlusion model. Clin Physiol Funct Imaging. 2005;25:305–10.PubMedCrossRefGoogle Scholar
  66. 66.
    Vilarinho KA, de Oliveira PP, Saad MJ, et al. Erythropoietin protects the systolic function of neonatal hearts against ischaemia/reperfusion injury. Eur J Cardiothorac Surg. 2013;43:156–62.PubMedCrossRefGoogle Scholar
  67. 67.
    Voors AA, Belonje AM, Zijlstra F, et al. A single dose of erythropoietin in ST-elevation myocardial infarction. Eur Heart J. 2010;31:2593–600.PubMedCrossRefGoogle Scholar
  68. 68.
    Najjar SS, Rao SV, Melloni C, et al. Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial. JAMA. 2011;305:1863–72.PubMedCrossRefGoogle Scholar
  69. 69.
    Taniguchi N, Nakamura T, Sawada T, et al. Erythropoietin prevention trial of coronary restenosis and cardiac remodeling after ST-elevated acute myocardial infarction (EPOC-AMI): a pilot, randomized, placebo-controlled study. Circ J. 2010;74:2365–71.PubMedCrossRefGoogle Scholar
  70. 70.
    Ozawa T, Toba K, Suzuki H, et al. Single-dose intravenous administration of recombinant human erythropoietin is a promising treatment for patients with acute myocardial infarction - randomized controlled pilot trial of EPO/AMI-1 study. Circ J. 2010;74:1415–23.PubMedCrossRefGoogle Scholar
  71. 71.
    Ferrario M, Arbustini E, Massa M, et al. High-dose erythropoietin in patients with acute myocardial infarction: a pilot, randomised, placebo-controlled study. Int J Cardiol. 2011;147:124–31.PubMedCrossRefGoogle Scholar
  72. 72.
    Ludman AJ, Yellon DM, Hasleton J, et al. Effect of erythropoietin as an adjunct to primary percutaneous coronary intervention: a randomised controlled clinical trial. Heart. 2011;97:1560–5.PubMedCrossRefGoogle Scholar
  73. 73.
    Prunier F, Biere L, Gilard M, et al. Single high-dose erythropoietin administration immediately after reperfusion in patients with ST-segment elevation myocardial infarction: results of the erythropoietin in myocardial infarction trial. Am Heart J. 2012;163:200–7.PubMedCrossRefGoogle Scholar
  74. 74.
    Thibault H, Piot C, Ovize M. Postconditioning in man. Heart Fail Rev. 2007;12:245–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Morel O, Perret T, Delarche N, et al. Pharmacological approaches to reperfusion therapy. Cardiovasc Res. 2012;94:246–52.PubMedCrossRefGoogle Scholar
  76. 76.
    Sack MN, Murphy E. The role of comorbidities in cardioprotection. J Cardiovasc Pharmacol Ther. 2011;16:267–72.PubMedCrossRefGoogle Scholar
  77. 77.
    Penna C, Tullio F, Moro F, Folino A, Merlino A, Pagliaro P. Effects of a protocol of ischemic postconditioning and/or captopril in hearts of normotensive and hypertensive rats. Basic Res Cardiol. 2010;105:181–92.PubMedCrossRefGoogle Scholar
  78. 78.
    Przyklenk K. Efficacy of cardioprotective ‘conditioning’ strategies in aging and diabetic cohorts: the co-morbidity conundrum. Drug Aging. 2011;28:331–43.CrossRefGoogle Scholar
  79. 79.
    Chen Z, Li T, Zhang B. Morphine postconditioning protects against reperfusion injury in the isolated rat hearts. J Surg Res. 2008;145:287–94.PubMedCrossRefGoogle Scholar
  80. 80.
    Xu YC, Xue FS, Liao X, et al. Combined morphine and limb remote ischaemia postconditioning may produce an enhanced cardioprotection. Med Hypotheses. 2009;73:302–5.PubMedCrossRefGoogle Scholar
  81. 81.
    Iliodromitis EK, Andreadou I, Prokovas E, Zoga A, Farmakis D, Fotopoulou T, et al. Simvastatin in contrast to postconditioning reduces infarct size in hyperlipidemic rabbits: possible role of oxidative/nitrosative stress attenuation. Basic Res Cardiol. 2010;105:193–203.PubMedCrossRefGoogle Scholar
  82. 82.
    Kocsis GF, Pipis J, Fekete V, et al. Lovastatin interferes with the infarct size-limiting effect of ischemic preconditioning and postconditioning in rat hearts. Am J Physiol Heart Circ Physiol. 2008;294:H2406–9.PubMedCrossRefGoogle Scholar
  83. 84.
    Messadi-Laribi E, Griol-Charhbili V, Gaies E, et al. Cardioprotection and kallikrein-kinin system in acute myocardial ischaemia in mice. Clin Exp Pharmacol Physiol. 2008;35:489–93.PubMedCrossRefGoogle Scholar
  84. 84.
    Ye Y, Perez-Polo JR, Aguilar D, Birnbaum Y. The potential effects of anti-diabetic medications on myocardial ischemia-reperfusion injury. Basic Res Cardiol. 2011;106:925–52.PubMedCrossRefGoogle Scholar
  85. 85.
    Roubille F, Lairez O, Mewton N, et al. Cardioprotection by clopidogrel in acute ST-elevated myocardial infarction patients: a retrospective analysis. Basic Res Cardiol. 2012;107:275.PubMedCrossRefGoogle Scholar
  86. 86.
    Roubille F, Tardif JC. Cardioprotection - time to take into account clinical complexity: the case of antiplatelet agents. Cardiovasc Drugs Ther. 2013;27:105–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Baker JE, Kozik D, Hsu AK, Fu X, Tweddell JS, Gross GJ. Darbepoetin alfa protects the rat heart against infarction: dose–response, phase of action, and mechanisms. J Cardiovasc Pharmacol. 2007;49:337–45.PubMedCrossRefGoogle Scholar
  88. 88.
    Suh JW, Chung WY, Kim YS, et al. The effect of intravenous administration of erythropoietin on the infarct size in primary percutaneous coronary intervention. Int J Cardiol. 2011;149:216–20.PubMedCrossRefGoogle Scholar
  89. 89.
    Kin H, Zhao ZQ, Sun HY, et al. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res. 2004;62:74–85.PubMedCrossRefGoogle Scholar
  90. 90.
    Gomez L, Thibault H, Gharib A, et al. Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice. Am J Physiol Heart Circ Physiol. 2007;293:H1654–61.PubMedCrossRefGoogle Scholar
  91. 91.
    Gomez L, Paillard M, Thibault H, Derumeaux G, Ovize M. Inhibition of GSK3beta by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion. Circulation. 2008;117:2761–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Talan MI, Ahmet I, Lakatta EG. Did clinical trials in which erythropoietin failed to reduce acute myocardial infarct size miss a narrow therapeutic window? PLoS One. 2012;7:e34819.PubMedCrossRefGoogle Scholar
  93. 93.
    Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M. Postconditioning inhibits mitochondrial permeability transition. Circulation. 2005;111:194–7.PubMedCrossRefGoogle Scholar
  94. 94.
    Fujita M, Asanuma H, Hirata A, et al. Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning. Am J Physiol Heart Circ Physiol. 2007;292:H2004–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Roubille F, Franck-Miclo A, Covinhes A, et al. Delayed postconditioning in the mouse heart in vivo. Circulation. 2011;124:1330–6.PubMedCrossRefGoogle Scholar
  96. 96.
    Adams JA, Bassuk JA, Arias J, et al. Acute effects of “delayed postconditioning” with periodic acceleration after asphyxia induced shock in pigs. Pediatr Res. 2008;64:533–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Ren C, Gao X, Niu G, Yan Z, Chen X, Zhao H. Delayed postconditioning protects against focal ischemic brain injury in rats. PLoS One. 2008;3:e3851.PubMedCrossRefGoogle Scholar
  98. 98.
    Leconte C, Tixier E, Freret T, et al. Delayed hypoxic postconditioning protects against cerebral ischemia in the mouse. Stroke. 2009;40:3349–55.PubMedCrossRefGoogle Scholar
  99. 99.
    Lipsic E, van der Meer P, Henning RH, et al. Timing of erythropoietin treatment for cardioprotection in ischemia/reperfusion. J Cardiovasc Pharmacol. 2004;44:473–9.PubMedCrossRefGoogle Scholar
  100. 100.
    Moon C, Krawczyk M, Paik D, Lakatta EG, Talan MI. Cardioprotection by recombinant human erythropoietin following acute experimental myocardial infarction: dose response and therapeutic window. Cardiovasc Drugs Ther. 2005;19:243–50.PubMedCrossRefGoogle Scholar
  101. 101.
    Basalay M, Barsukevich V, Mastitskaya S, et al. Remote ischaemic pre- and delayed postconditioning - similar degree of cardioprotection but distinct mechanisms. Exp Physiol. 2012;97:908–17.PubMedCrossRefGoogle Scholar
  102. 102.
    Lipsic E, van der Meer P, Voors AA, et al. A single bolus of a long-acting erythropoietin analogue darbepoetin alfa in patients with acute myocardial infarction: a randomized feasibility and safety study. Cardiovasc Drugs Ther. 2006;20:135–41.PubMedCrossRefGoogle Scholar
  103. 103.
    Ott I, Schulz S, Mehilli J, et al. Erythropoietin in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomized, double-blind trial. Circ Cardiovasc Interv. 2010;3:408–13.PubMedCrossRefGoogle Scholar
  104. 104.
    Roubille F, Micheau A, Combes S, Piot C. Intracoronary administration of darbepoetin-alpha at onset of reperfusion in acute myocardial infarction: results of the randomized Intra-Co-EpoMI Trial. Arch Cardiovasc Dis. 2013;106:135–45.PubMedCrossRefGoogle Scholar
  105. 105.
    Kanellakis P, Pomilio G, Agrotis A, Gao X, Du XJ, Curtis D, et al. Darbepoetin-mediated cardioprotection after myocardial infarction involves multiple mechanisms independent of erythropoietin receptor-common beta-chain heteroreceptor. Brit J Pharmacol. 2010;160:2085–96.CrossRefGoogle Scholar
  106. 106.
    Mueller C, Wodack K, Twelker K, Werner N, Custodis F, Nickenig G. Darbepoetin improves endothelial function and increases circulating endothelial progenitor cell number in patients with coronary artery disease. Heart. 2011;97:1474–8.PubMedCrossRefGoogle Scholar
  107. 107.
    Tilling L, Hunt J, Donald A, Clapp B, Chowienczyk P. Darbepoetin enhances endothelium-dependent vasomotor function in patients with stable coronary artery disease only after preceding ischaemia/reperfusion. Clin Sci. 2012;122:329–36.PubMedCrossRefGoogle Scholar
  108. 108.
    Krapf R, Hulter HN. Arterial hypertension induced by erythropoietin and erythropoiesis-stimulating agents (ESA). Clin J Am Soc Nephrol. 2009;4:470–80.PubMedCrossRefGoogle Scholar
  109. 109.
    Vaziri ND. Thrombocytosis in EPO-treated dialysis patients may be mediated by EPO rather than iron deficiency. Am J Kidney Dis. 2009;53:733–6.PubMedCrossRefGoogle Scholar
  110. 110.
    Peterson TE, Katusic ZS. EPO tecting the endothelium. Brit J Pharmacol. 2007;150:823–5.CrossRefGoogle Scholar
  111. 111.
    Tilling L, Clapp B. Erythropoietin: a future therapy for failing hearts? Heart Fail Rev. 2012;17:475–83.PubMedCrossRefGoogle Scholar
  112. 112.
    Elmahdy H, El-Mashad AR, El-Bahrawy H, El-Gohary T, El-Barbary A, Aly H. Human recombinant erythropoietin in asphyxia neonatorum: pilot trial. Pediatrics. 2010;125:e1135–42.PubMedCrossRefGoogle Scholar
  113. 113.
    Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002;8:495–505.PubMedGoogle Scholar
  114. 114.
    Wustenberg T, Begemann M, Bartels C, et al. Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia. Mol Psychiatry. 2011;16:26–36.PubMedCrossRefGoogle Scholar
  115. 115.
    Talving P, Lustenberger T, Kobayashi L, et al. Erythropoiesis stimulating agent administration improves survival after severe traumatic brain injury: a matched case control study. Ann Surg. 2010;251:1–4.PubMedCrossRefGoogle Scholar
  116. 116.
    Fujiwara N, Nakamura T, Sato E, et al. Renovascular protective effects of erythropoietin in patients with chronic kidney disease. Intern Med. 2011;50:1929–34.PubMedCrossRefGoogle Scholar
  117. 117.
    Sorg H, Harder Y, Krueger C, Reimers K, Vogt PM. The nonhematopoietic effects of erythropoietin in skin regeneration and repair: from basic research to clinical use. Med Res Rev. 2013;33:637–64.PubMedCrossRefGoogle Scholar
  118. 118.
    Ehrenreich H, Weissenborn K, Prange H, et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009;40:e647–56.PubMedCrossRefGoogle Scholar
  119. 119.
    Robertson CS, Cherian L, Shah M, et al. Neuroprotection with an erythropoietin mimetic peptide (pHBSP) in a model of mild traumatic brain injury complicated by hemorrhagic shock. J Neurotrauma. 2012;29:1156–66.PubMedCrossRefGoogle Scholar
  120. 120.
    Pankratova S, Kiryushko D, Sonn K, et al. Neuroprotective properties of a novel, non-haematopoietic agonist of the erythropoietin receptor. Brain. 2010;133:2281–94.PubMedCrossRefGoogle Scholar
  121. 121.
    Dumont F, Bischoff P. Non-erythropoietic tissue-protective peptides derived from erythropoietin: WO2009094172. Expert Opin Ther Pat. 2010;20:715–23.PubMedCrossRefGoogle Scholar
  122. 122.
    Li J, Xu H, Gao Q, Wen Y. Effect of erythropoiesis-stimulating agents in acute ST-segment elevation myocardial infarction: a systematic review. Eur J Clin Pharmacol. 2012;68:469–77.PubMedCrossRefGoogle Scholar
  123. 123.
    Badalzadeh R, Mohammadi M, Najafi M, Ahmadiasl N, Farajnia S, Ebrahimi H. The additive effects of ischemic postconditioning and cyclosporine-A on nitric oxide activity and functions of diabetic myocardium injured by ischemia/reperfusion. J Cardiovasc Pharmacol Ther. 2012;17:181–9.PubMedCrossRefGoogle Scholar
  124. 124.
    Boucher M, Pesant S, Lei YH, et al. Simultaneous administration of insulin-like growth factor-1 and darbepoetin alfa protects the rat myocardium against myocardial infarction and enhances angiogenesis. Clin Transl Sci. 2008;1:13–20.PubMedCrossRefGoogle Scholar
  125. 125.
    Hausenloy DJ, Baxter G, Bell R, et al. Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations. Basic Res Cardiol. 2010;105:677–86.PubMedCrossRefGoogle Scholar
  126. 126.
    Jaquet K, Krause K, Tawakol-Khodai M, Geidel S, Kuck KH. Erythropoietin and VEGF exhibit equal angiogenic potential. Microvasc Res. 2002;64:326–33.PubMedCrossRefGoogle Scholar
  127. 127.
    Schneider MD. EPO and super-EPO: erythropoietins direct neoangiogenesis by cardiac progenitor cells. Cell Stem Cell. 2011;9:95–6.PubMedCrossRefGoogle Scholar
  128. 128.
    Treguer F, Donal E, Tamareille S, et al. Speckle tracking imaging improves in vivo assessment of EPO-induced myocardial salvage early after ischemia-reperfusion in rats. Am J Physiol Heart Circ Physiol. 2010;298:H1679–86.PubMedCrossRefGoogle Scholar
  129. 129.
    Heinisch BB, Vcelar B, Kapiotis S, et al. The effect of erythropoietin on platelet and endothelial activation markers: a prospective trial in healthy volunteers. Platelets. 2012;23:352–8.PubMedCrossRefGoogle Scholar
  130. 130.
    Fuste B, Serradell M, Escolar G, et al. Erythropoietin triggers a signaling pathway in endothelial cells and increases the thrombogenicity of their extracellular matrices in vitro. Thromb Haemost. 2002;88:678–85.PubMedGoogle Scholar
  131. 131.
    Stohlawetz PJ, Dzirlo L, Hergovich N, et al. Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood. 2000;95:2983–9.PubMedGoogle Scholar
  132. 132.
    Luft FC. Erythropoietin and arterial hypertension. Clin Nephrol. 2000;53 Suppl 1:S61–4.PubMedGoogle Scholar
  133. 133.
    Vaziri ND. Mechanism of erythropoietin-induced hypertension. Am J Kidney Dis. 1999;33:821–8.PubMedCrossRefGoogle Scholar
  134. 134.
    Teng R, Calvert JW, Sibmooh N, et al. Acute erythropoietin cardioprotection is mediated by endothelial response. Basic Res Cardiol. 2011;106:343–54.PubMedCrossRefGoogle Scholar
  135. 135.
    Liu X, Xie W, Liu P, Duan M, Jia Z, Li W, et al. Mechanism of the cardioprotection of rhEPO pretreatment on suppressing the inflammatory response in ischemia-reperfusion. Life Sci. 2006;78:2255–64.PubMedCrossRefGoogle Scholar
  136. 136.
    Hotta H, Miura T, Miki T, et al. Angiotensin II type 1 receptor-mediated upregulation of calcineurin activity underlies impairment of cardioprotective signaling in diabetic hearts. Circ Res. 2010;106:129–32.PubMedCrossRefGoogle Scholar
  137. 137.
    Tamareille S, Ghaboura N, Treguer F, et al. Myocardial reperfusion injury management: erythropoietin compared with postconditioning. Am J Physiol Heart Circ Physiol. 2009;297:H2035–43.PubMedCrossRefGoogle Scholar
  138. 138.
    Shen Y, Wang Y, Li D, et al. Recombinant human erythropoietin pretreatment attenuates heart ischemia-reperfusion injury in rats by suppressing the systemic inflammatory response. Transplant Proc. 2010;42:1595–7.PubMedCrossRefGoogle Scholar
  139. 139.
    Hirata A, Minamino T, Asanuma H, et al. Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts. Cardiovasc Drugs Ther. 2005;19:33–40.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • François Roubille
    • 1
    • 2
    • 3
  • Fabrice Prunier
    • 4
    • 5
  • Stéphanie Barrère-Lemaire
    • 3
  • Florence Leclercq
    • 2
  • Christophe Piot
    • 2
    • 3
  • Ekaterini A. Kritikou
    • 6
  • Eric Rhéaume
    • 6
    • 7
  • David Busseuil
    • 6
  • Jean-Claude Tardif
    • 6
    • 7
  1. 1.Montreal Heart InstituteUniversité de MontréalMontrealCanada
  2. 2.Cardiology DepartmentUniversity Hospital of MontpellierMontpellierFrance
  3. 3.Inserm, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, INSERM, U661Universités de Montpellier 1 and 2MontpellierFrance
  4. 4.Laboratoire Cardioprotection, Remodelage et ThromboseUniversité d’AngersAngersFrance
  5. 5.Service de CardiologieCentre Hospitalier Universitaire AngersAngersFrance
  6. 6.Montreal Heart InstituteMontrealCanada
  7. 7.Department of MedicineUniversité de MontréalMontrealCanada

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