title: Acute erythropoietin cardioprotection is mediated by endothelial response.
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.
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1822, USA.
authors.forename: Ruifeng
authors.initials: R
authors.lastname: Teng
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.forename: Nathawut
authors.initials: N
authors.lastname: Sibmooh
authors.forename: Barbora
authors.initials: B
authors.lastname: Piknova
authors.forename: Norio
authors.initials: N
authors.lastname: Suzuki
authors.forename: Junhui
authors.initials: J
authors.lastname: Sun
authors.forename: Kevin
authors.initials: K
authors.lastname: Martinez
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Alan N
authors.initials: AN
authors.lastname: Schechter
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.forename: Constance Tom
authors.initials: CT
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D004921:Erythropoietin / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III