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Acute erythropoietin cardioprotection is mediated by endothelial response

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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.

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Acknowledgments

This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, and grant support from NIH 2R01 HL-060849 to D.J.L. and NIH F32DK077380 to J.W.C.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9N319, 10 CENTER DR MSC-1822, Bethesda, MD, 20892-1822, USA

    Ruifeng Teng, Barbora Piknova, Kevin Martinez, Alan N. Schechter & Constance Tom Noguchi

  2. Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA, USA

    John W. Calvert & David J. Lefer

  3. Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand

    Nathawut Sibmooh

  4. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan

    Norio Suzuki & Masayuki Yamamoto

  5. Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Junhui Sun

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  1. Ruifeng Teng
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Teng, R., Calvert, J.W., Sibmooh, N. et al. Acute erythropoietin cardioprotection is mediated by endothelial response. Basic Res Cardiol 106, 343–354 (2011). https://doi.org/10.1007/s00395-011-0158-z

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