Skip to main content

Advertisement

SpringerLink
Log in

Effects of erythropoietin on angiogenesis after myocardial infarction in porcine

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Erythropoietin (EPO) has recently been shown to confer cardioprotective effects via angiogenesis and antiapoptosis. The administration of EPO after myocardial infarction (MI) reduces infarct size and improves cardiac function in small animals. The purpose of this study is to investigate the protective effects of EPO in porcine MI. Each animal in the EPO group received four injections of recombinant human EPO (rhEPO; 6000 U per injection) at 2-day intervals, starting after coronary occlusion. Animals in the control group received saline. Left ventriculography was performed just after coronary occlusion and at 28 days. Time-course changes in serum levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and fibroblast growth factor (FGF) were measured. The number of vessels was calculated, and the mRNA expressions of VEGF and insulin-like growth factor (IGF) were examined. Left ventricular function was similar between the groups. The numbers of cells positive for anti-α-smooth muscle actin, von Willebrand factor, and c-kit were significantly higher in the EPO group than in the controls (P < 0.05). The EPO group exhibited significantly higher HGF and FGF concentrations (P < 0.05) and higher expression of VEGF and IGF mRNA (P < 0.05) compared with the controls. In conclusion, EPO accelerates angiogenesis via the upregulation of systemic levels such as HGF and FGF, and the local expression of VEGF and IGF, in porcine MI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Krantz SB (1991) Erythropoietin. Blood 77:419–434

    PubMed  CAS  Google Scholar 

  2. Cotter DJ, Thamer M, Kimmel PL, Sadler JH (1998) Secular trends in recombinant erythropoietin therapy among the US hemodialysis population: 1990–1996. Kidney Int 54:2129–2139

    Article  PubMed  CAS  Google Scholar 

  3. Jelkmann W (1994) Biology of erythropoietin. Clin Invest 72:S3–S10

    CAS  Google Scholar 

  4. Moritz KM, Lim GB, Wintour EM (1997) Developmental regulation of erythropoietin and erythropoiesis. Am J Physiol 273R:1829–1881

    Google Scholar 

  5. Smith KJ, Bleyer AJ, Little WC, Sane DC (2003) The cardiovascular effects of erythropoietin. Cardiovasc Res 59:538–548

    Article  PubMed  CAS  Google Scholar 

  6. Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA 98:4044–4049

    Google Scholar 

  7. Ogilvie M, Yu X, Nicolas-Metral V, Pulido SM, Liu C, Ruegg UT, Noguchi CT (2000) Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts. J Biol Chem 275:39754–39761

    Article  PubMed  CAS  Google Scholar 

  8. Calvillo L, Latini R, Kajstura J, Leri A, Anversa P, Ghezzi P, Salio M, Cerami A, Brines M (2003) Recombinant human erythropoietin protects the myocardium from ischemia–reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci USA 100:4802–4806

    Google Scholar 

  9. Nakamura R, Takahashi A, Yamada T, Miyai N, Irie H, Kinoshita N, Sawada T, Azuma A, Matsubara H (2009) Erythropoietin in patients with acute coronary syndrome and its cardioprotective action after percutaneous coronary intervention. Circ J 73:1920–1192

    Google Scholar 

  10. Moon C, Krawczyk M, Ahn D, Ahmet I, Paik D, Lakatta EG, Talan MI (2003) Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc Natl Acad Sci USA 100:11612–11617

    Google Scholar 

  11. Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, Walton GB, Thompson RB, Petrofski JA, Annex BH, Stamler JS, Koch WJ (2003) A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 112:999–1007

    PubMed  CAS  Google Scholar 

  12. van der Meer P, Lipsic E, Henning RH, Boddeus K, van der Velden J, Voors AA, van Veldhuisen DJ, van Gilst WH, Schoemaker RG (2005) Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol 46:125–133

    Article  PubMed  Google Scholar 

  13. Tramontano AF, Muniyappa R, Black AD, Blendea MC, Cohen I, Deng L, Sowers JR, Cutaia MV, El-Sherif N (2003) Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun 308:990–994

    Article  PubMed  CAS  Google Scholar 

  14. Parsa CJ, Kim J, Riel RU, Thompson RB, Petrofski JA, Matsumoto A, Stamler JS, Koch WJ (2004) Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac fibroblasts. J Biol Chem 279:20655–20662

    Article  PubMed  CAS  Google Scholar 

  15. Lipsic E, van der Meer P, Henning RH, Suurmeijer AJ, Boddeus KM, van Veldhuisen DJ, van Gilst WH, Schoemaker RG (2004) Timing of erythropoietin treatment for cardioprotection in ischemia/reperfusion. J Cardiovasc Pharmacol 44:473–479

    Article  PubMed  CAS  Google Scholar 

  16. Hirata A, Minamino T, Asanuma H, Fujita M, Wakeno M, Myoishi M, Tsukamoto O, Okada K, Koyama H, Komamura K, Takashima S, Shinozaki Y, Mori H, Shiraga M, Kitakaze M, Hori M (2006) Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs. J Am Coll Cardiol 48:176–184

    Article  PubMed  CAS  Google Scholar 

  17. Lin X, Fujita M, Kanemitsu N, Kimura Y, Tambara K, Premaratne GU, Nagasawa A, Ikeda T, Tabata Y, Komeda M (2007) Sustained-release erythropoietin ameliorates cardiac function in infarcted rat-heart without inducing polycythemia. Circ J 71:132–137

    Article  PubMed  CAS  Google Scholar 

  18. Nishiya D, Omura T, Shimada K, Matsumoto R, Kusuyama T, Enomoto S, Iwao H, Takeuchi K, Yoshikawa J, Yoshiyama M (2006) Effects of erythropoietin on cardiac remodeling after myocardial infarction. J Pharmacol Sci 101:31–39

    Article  PubMed  CAS  Google Scholar 

  19. Hirata A, Minamino T, Asanuma H, Sanada S, Fujita M, Tsukamoto O, Wakeno M, Myoishi M, Okada K, Koyama H, Komamura K, Takashima S, Shinozaki Y, Mori H, Tomoike H, Hori M, Kitakaze M (2005) Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphaticylinositol-3 kinase-dependent pathway in canine hearts. Cardiovasc Drugs Ther 19:33–40

    Article  PubMed  CAS  Google Scholar 

  20. Westenbrink BD, Lipsic E, van der Meer P, van der Harst P, Oeseburg H, Du Marchie Sarvaas GJ, Koster J, Voors AA, van Veldhuisen DJ, van Gilst WH, Schoemaker RG (2007) Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J 28:2018–2027

    Article  PubMed  CAS  Google Scholar 

  21. Nakano M, Satoh K, Fukumoto Y, Ito Y, Kagaya Y, Ishii N, Sugamura K, Shimokawa H (2007) Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res 100:662–669

    Article  PubMed  CAS  Google Scholar 

  22. Bahlmann FH, De Groot K, Spandau JM, Landry AL, Hertel B, Duckert T, Boehm SM, Menne J, Haller H, Fliser D (2004) Erythropoietin regulates endothelial progenitor cells. Blood 103:921–926

    Article  PubMed  CAS  Google Scholar 

  23. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967

    Article  PubMed  CAS  Google Scholar 

  24. Chen MC, Chen CJ, Yang CH, Liu WH, Fang CY, Hsieh YK, Chang HW (2010) Relationship of the percentage of circulating endothelial progenitor cell to the severity of coronary artery disease. Heart Vessels 23:47–52

    Article  Google Scholar 

  25. Brunner S, Winogradow J, Huber BC, Zaruba MM, Fischer R, David R, Assmann G, Herbach N, Wanke R, Mueller-Hoecker J, Franz WM (2009) Erythropoietin administration after myocardial infarction in mice attenuates ischemic cardiomyopathy associated with enhanced homing of bone marrow-derived progenitor cells via the CXCR-4/SDF-1 axis. FASEB J 23:351–361

    Article  PubMed  CAS  Google Scholar 

  26. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 98:10344–10349

    Article  PubMed  CAS  Google Scholar 

  27. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410:701–705

    Article  PubMed  CAS  Google Scholar 

  28. Shao Z, Kawasuji M, Takaji K, Katayama Y, Matsukawa M (2008) Therapeutic angiogenesis with autologous hepatic tissue implantation and omental wrapping. Circ J 72:1894–1899

    Article  PubMed  CAS  Google Scholar 

  29. Hosoda T, Kajstura Y, Leri A, Anversa P (2010) Mechanisms of myocardial regeneration. Circ J 74:13–17

    Article  PubMed  CAS  Google Scholar 

  30. De Haro J, Acin F, Lopez-Quintana A, Florez A, Martinez-Aguilar E, Varela C (2009) Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease. Heart Vessels 24:321–328

    Article  PubMed  Google Scholar 

  31. Takahashi M, Li T, Suzuki R, Kobayashi T, Ito H, Ikeda Y, Matsuzaki M, Hamano K (2006) Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury. Am J Physiol Heart Circ Physiol 291:H886–H893

    Article  PubMed  CAS  Google Scholar 

  32. Ben-Dor I, Hardy B, Fuchs S, Kaganovsky E, Kadmon E, Sagie A, Coleman R, Mansur M, Politi B, Fraser A, Harell D, Okon E, Battler A, Haim M (2007) Repeated low-dose of erythropoietin is associated with improved left ventricular function in rat acute myocardial infarction model. Cardiovasc Drugs Ther 21:339–346

    Article  PubMed  CAS  Google Scholar 

  33. Ozawa T, Toba K, Suzuki H, Kato K, Iso Y, Akutsu Y, Kobayashi Y, Takeyama Y, Kobayashi N, Yoshimura N, Akazawa K, Aizawa Y, EPO/AMI-I Pilot Study Researchers (2010) Single-dose intravenous-administration of 12,000 IU recombinant human erythropoietin is a promising treatment for patients with acute myocardial infarction: a randomized controlled pilot trial of EPO/AMI-I study. Circ J 74:1415–1423

    Google Scholar 

  34. Minamino T, Kitakaze M (2006) New therapeutic application of erythropoietin against ischemic heart diseases. J Pharmacol Sci 101:179–181

    Article  PubMed  CAS  Google Scholar 

  35. Abramowicz M (2001) Darbepoetin (Aranesp)—a long-acting erythropoietin. Med Lett Drugs Ther 43:109–110

    Google Scholar 

  36. Begg TB, Hearns JB (1966) Components in blood viscosity. The relative contribution of haematocrit, plasma fibrinogen and other proteins. Clin Sci 31:87–93

    PubMed  CAS  Google Scholar 

  37. Turitto VT, Weiss HJ (1980) Red blood cells: their dual role in thrombus formation. Science 207:541–543

    Article  PubMed  CAS  Google Scholar 

  38. Imai N, Higuchi M, Kawamura A, Tomonoh K, Oh-Eda M, Fujiwara M, Shimonaka Y, Ochi N (1990) Physicochemical and biological characterization of asialoerythropoietin. Eur J Biochem 194:457–462

    Article  PubMed  CAS  Google Scholar 

  39. Wang X, Zhu C, Wang X, Gerwien JG, Schrattenholz A, Sandberg M, Leist M, Blomgren K (2004) The nonerythropoietic asialoerythropoietin protects against neonatal hypoxia-ischemia as potently as erythropoietin. J Neurochem 91:900–910

    Article  PubMed  CAS  Google Scholar 

  40. Fiordaliso F, Chimenti S, Staszewsky L, Bai A, Carlo E, Cuccovillo I, Doni M, Mengozzi M, Tonelli R, Ghezzi P, Coleman T, Brines M, Cerami A, Latini R (2005) A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury. Proc Natl Acad Sci USA 97:2046–2051

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiology, Department of Internal Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa, 227-8501, Japan

    Keisuke Kawachi, Yoshitaka Iso, Kohei Wakabayashi, Youichi Takeyama & Hiroshi Suzuki

  2. Division of Cardiology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan

    Takatoshi Sato & Youichi Kobayashi

Authors
  1. Keisuke Kawachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshitaka Iso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takatoshi Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kohei Wakabayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Youichi Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Youichi Takeyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroshi Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroshi Suzuki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kawachi, K., Iso, Y., Sato, T. et al. Effects of erythropoietin on angiogenesis after myocardial infarction in porcine. Heart Vessels 27, 79–88 (2012). https://doi.org/10.1007/s00380-011-0197-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-011-0197-2

Keywords

Search

Navigation