Cardiovascular Drugs and Therapy

, Volume 19, Issue 4, pp 243–250 | Cite as

Cardioprotection by Recombinant Human Erythropoietin Following Acute Experimental Myocardial Infarction: Dose Response and Therapeutic Window

  • Chanil Moon
  • Melissa Krawczyk
  • Doojin Paik
  • Edward G. Lakatta
  • Mark I. Talan
Basic Pharmacology


Background: Recombinant human erythropoietin (rhEPO) protects tissue from ischemic damage, but translation of this finding into useful guidelines with respect to human trials for myocardial infarction (MI) requires a determination of the minimum effective rhEPO dose and the therapeutic window following MI.

Method and Results: Serial echocardiography revealed that during four weeks following MI, induced by a permanent coronary ligation in rats, the LV end-diastolic and end-systolic volumes in untreated rats expanded from 0.35 ± 0.01 and 0.14 ± 0.01 ml to 0.84 ± 0.04 and 0.61 ± 0.06 ml, respectively, and ejection fraction (EF) reduced by 50%. A single i.v. injection of rhEPO immediately following MI in a dose of 150 IU/kg was as effective as 3000 IU/kg in causing a 2-fold reduction of the number of apoptotic nuclei in the AAR 24-h later, a 2-fold reduction of the MI size measured 4 weeks later, attenuation of progressive LV dilatation and fall in EF. A 3000 IU/kg dose had similar therapeutic effects when delayed by 4, 8, or 12 h following MI, but was not effective after a 24-h delay. A single dose of 150 IU/kg was effective within 4 h post-MI, but was without effect if administered after an 8-h delay.

Conclusion: Cell death, final MI size, myocardial remodeling and functional decline are significantly reduced in rats by a single injection of rhEPO in a dose as low as 150 IU/kg if administered during the first 4 h after the ischemic event. Higher doses extend the therapeutic window up to 12 h.

Key Words

myocardial infarct left ventricular remodeling apoptosis erythopoietin 



human recombinant erythropoietin


myocardial area at risk


myocardial infarction


left ventricular


end-diastolic volume


end-systolic volume


ejection fraction


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Erslev AJ, Caro J. Erythropoietin: From mountain top to bedside. Adv Exp Med Biol 1989;271:1–7.PubMedGoogle Scholar
  2. 2.
    Youssoufian H, Longmore G, Neumann D, Yoshimura A, Lodish HF. Structure, function, and activation of the erythropoietin receptor. Blood 1993;81:2223–2236 (Review).PubMedGoogle Scholar
  3. 3.
    Masuda S, Nagao M, Sasaki R. Erythropoietic, neurotrophic, and angiogenic functions of erythropoietin and regulation of erythropoietin production. Int J Hematol 1999;70:1–6 (Review).PubMedGoogle Scholar
  4. 4.
    Sadamoto Y, Igase K, Sakanaka M, et al. Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem Biophys Res Commun 1998;253:26–32.PubMedCrossRefGoogle Scholar
  5. 5.
    Bernaudin M, Marti HH, Roussel S, et al. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. Cereb Blood Flow Metab 1999;19:643–651.Google Scholar
  6. 6.
    Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc. Natl Acad Sci USA 2000;97:10526–10531.PubMedCrossRefGoogle Scholar
  7. 7.
    Smith KJ, Bleyer AJ, Little WC, Sane DC. The cardiovascular effects of erythropoietin. Cardiovasc Res 2003;59:538–548 (Review).PubMedCrossRefGoogle Scholar
  8. 8.
    Bogoyevitch MA. An update on the cardiac effects of erythropoietin cardioprotection by erythropoietin and the lessons learnt from studies in neuroprotection. Cardiovasc Res 2004;63:208–216 (Review).PubMedCrossRefGoogle Scholar
  9. 9.
    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
  10. 10.
    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 USA 2003;100:11612–11617.PubMedGoogle Scholar
  11. 11.
    Cheung WK, Goon BL, Guilfoyle MC, Wacholtz MC. Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects. Clin Pharmacol 1998;64:412–423.Google Scholar
  12. 12.
    Stohlawetz PJ, Dzirlo L, Hergovich N, et al. Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood 2000;95:2983–2989.PubMedGoogle Scholar
  13. 13.
    Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000;97:10526–10531.PubMedCrossRefGoogle Scholar
  14. 14.
    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;66:983–989.PubMedCrossRefGoogle Scholar
  15. 15.
    Jaquet K, Krause K, Tawakol–Khodai M, Geidel S, Kuck K. Erythropoietin and VEGF exhibit equal angiogenic potential. Microvasc Res 2002;64:326–333.PubMedCrossRefGoogle Scholar
  16. 16.
    Shingo T, Sorokan ST, Shimazaki T, Weiss S. Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci 2001;21:9733–9743.PubMedGoogle Scholar
  17. 17.
    Heeschen C, Aicher A, Lehmann R, et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood 2003;102:1340–1346.PubMedCrossRefGoogle Scholar
  18. 18.
    Rodriguez M, Schaper J. Apoptosis: measurement and technical issues. J Molec Cell Cardiol 2005;38:15–20.Google Scholar
  19. 19.
    Suzuki K, Kostin S, Person V, Elsasser A, Schaper J. Time course of the apoptotic cascade and effects of caspase inhibitors in adult rat ventricular cardiomyocytes. J Mol Cell Cardiol 2001;33:983–994.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhao W, Lu L, Chen SS, Sun Y. Temporal and spatial characteristics of apoptosis in the infarcted rat heart. Biochem Biophys Res Commun 2004;325:605–611.PubMedGoogle Scholar
  21. 21.
    Feng QZ, Li TD, Wei LX, et al. Tempero–spatial dissociation between the expression of Fas and apoptosis after coronary occlusion. Mol Pathol 2003;56:362–367.PubMedGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Shi Y, Rafiee P, Su J, Pritchard KA Jr, Tweddell JS, Baker JE. Acute cardioprotective effects of erythropoietin in infant rabbits are mediated by activation of protein kinases and potassium channels. Basic Res Cardiol 2004;99:173–182.PubMedCrossRefGoogle Scholar
  24. 24.
    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 USA 2003;100:4802–4816.PubMedCrossRefGoogle Scholar
  25. 25.
    Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci USA 2004;101:14907–14912.PubMedCrossRefGoogle Scholar
  26. 26.
    Juhaszova M, Zorov DB, Kim SH, et al. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 2004;113:1535–1549.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Chanil Moon
    • 1
  • Melissa Krawczyk
    • 1
  • Doojin Paik
    • 2
  • Edward G. Lakatta
    • 1
  • Mark I. Talan
    • 1
  1. 1.Laboratory of Cardiovascular SciencesGerontology Research Center, National Institute on AgingBaltimoreUSA
  2. 2.Department of Anatomy and Cell BiologyHanyang UniversitySeoul 133-791Korea

Personalised recommendations