Basic Research in Cardiology

, Volume 106, Issue 3, pp 343–354

Acute erythropoietin cardioprotection is mediated by endothelial response

  • Ruifeng Teng
  • John W. Calvert
  • Nathawut Sibmooh
  • Barbora Piknova
  • Norio Suzuki
  • Junhui Sun
  • Kevin Martinez
  • Masayuki Yamamoto
  • Alan N. Schechter
  • David J. Lefer
  • Constance Tom Noguchi
Original Contribution

Abstract

Increasing evidence indicates that high levels of serum erythropoietin (Epo) can lessen ischemia–reperfusion injury in the heart and multiple cardiac cell types have been suggested to play a role in this Epo effect. To clarify the mechanisms underlying this cardioprotection, we explored Epo treatment of coronary artery endothelial cells and Epo cardioprotection in a Mus musculus model with Epo receptor expression restricted to hematopoietic and endothelial cells (ΔEpoR). Epo stimulation of coronary artery endothelial cells upregulated endothelial nitric oxide synthase (eNOS) activity in vitro and in vivo, and enhanced nitric oxide (NO) production that was determined directly by real-time measurements of gaseous NO release. Epo stimulated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated kinase (ERK) signaling pathways, and inhibition of PI3K, but not MEK activity, blocked Epo-induced NO production. To verify the potential of this Epo effect in cardioprotection in vivo, ΔEpoR-mice with Epo response in heart restricted to endothelium were treated with Epo. These mice exhibited a similar increase in eNOS phosphorylation in coronary artery endothelium as that found in wild type (WT) mice. In addition, in both WT- and ΔEpoR-mice, exogenous Epo treatment prior to myocardial ischemia provided comparable protection. These data provide the first evidence that endothelial cell response to Epo is sufficient to achieve an acute cardioprotective effect. The immediate response of coronary artery endothelial cells to Epo stimulation by NO production may be a critical mechanism underlying this Epo cardioprotection.

Keywords

Endothelial cells Ischemia Myocardial infarction Nitric oxide Endothelial nitric oxide synthase 

Supplementary material

395_2011_158_MOESM1_ESM.pdf (363 kb)
Supplementary material 1 (PDF 364 kb)

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Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • Ruifeng Teng
    • 1
  • John W. Calvert
    • 2
  • Nathawut Sibmooh
    • 3
  • Barbora Piknova
    • 1
  • Norio Suzuki
    • 4
  • Junhui Sun
    • 5
  • Kevin Martinez
    • 1
  • Masayuki Yamamoto
    • 4
  • Alan N. Schechter
    • 1
  • David J. Lefer
    • 2
  • Constance Tom Noguchi
    • 1
  1. 1.Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA
  2. 2.Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart CenterEmory University School of MedicineAtlantaUSA
  3. 3.Department of Pharmacology, Faculty of ScienceMahidol UniversityBangkokThailand
  4. 4.Department of Medical BiochemistryTohoku University Graduate School of MedicineSendaiJapan
  5. 5.Translational Medicine Branch, National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaUSA

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