Acute erythropoietin cardioprotection is mediated by endothelial response

• Type of Material: Article
• Authors: Ruifeng Teng, National Institute of Diabetes and Digestive and Kidney Diseases; John W Calvert, Emory University; Nathawut Sibmooh, Mahidol University; Barbora Piknova, National Institute of Diabetes and Digestive and Kidney Diseases; Norio Suzuki, Tohoku University; Junhui Sun, NHLBI; Kevin Martinez, National Institute of Diabetes and Digestive and Kidney Diseases; Masayuki Yamamoto, Tohoku University; Alan N. Schechter, National Institute of Diabetes and Digestive and Kidney Diseases; David J. Lefer, Emory University; Constance Tom Noguchi, National Institute of Diabetes and Digestive and Kidney Diseases
• Language: English
• Date: 2011-05-01
• Publisher: Springer (part of Springer Nature): Springer Open Choice Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Springer-Verlag (outside the USA).
• Final Published Version (URL): http://dx.doi.org/10.1007/s00395-011-0158-z
• Title of Journal or Parent Work: Basic Research in Cardiology
• ISSN: 0300-8428
• Volume: 106
• Issue: 3
• Start Page: 343
• End Page: 354
• Grant/Funding Information: 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.
• Keywords: IN-VITRO; RECEPTOR; Endothelial cells; ISCHEMIA-REPERFUSION INJURY; Cardiovascular System & Cardiology; Ischemia; ACTIVATION; Science & Technology; Cardiac & Cardiovascular Systems; MYOCARDIAL ISCHEMIA/REPERFUSION INJURY; Life Sciences & Biomedicine; EXPRESSION; PROTEIN-KINASES; Myocardial infarction; Nitric oxide; Endothelial nitric oxide synthase; CELLS; HEART; NITRIC-OXIDE SYNTHASE
• Research Categories: Biology, Molecular; Health Sciences, Medicine and Surgery; Chemistry, Biochemistry

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.