Copyright © 2006, European Society of Cardiology
Erythropoietin protects cardiomyocytes from apoptosis via up-regulation of endothelial nitric oxide synthase
aCardiology Research Laboratory, Centre for Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada
bDepartment of Medicine, University of Western Ontario, London, Ontario, Canada
cDepartment of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
dDepartment of Medicine, Division of Hematology, University of Western Ontario, London, Ontario, Canada
* Corresponding author. Cardiology Research Laboratory, Lawson Health Research Institute, VRL 6th Floor, A6-134, 800 Commissioners Road, London, Ontario, Canada N6A 4G5. Tel.: +1 519 685 8300x55443; fax: +1 519 685 8341. Email address: qfeng{at}uwo.ca
Objective: Erythropoietin (EPO), a cytokine best known for its ability to increase red blood cell mass, has recently been shown to protect cardiomyocytes from apoptotic cell death. The objective of the present study was to investigate the role of endothelial nitric oxide synthase (eNOS) in the anti-apoptotic effects of EPO in cardiomyocytes.
Methods and results: Neonatal mouse ventricular cardiomyocytes were isolated and cultured from wild-type and eNOS–/– mice. Treatment with EPO significantly reduced apoptosis induced by norepinephrine (NE) in the wild-type cardiomyocytes. The reduction of apoptosis was associated with significant increases in eNOS expression, phosphorylation and NO production. However, the anti-apoptotic effects of EPO were significantly decreased in wild-type cardiomyocytes treated with L-NAME, which inhibits nitric oxide synthase activity. The results were further confirmed using eNOS–/– cardiomyocytes. To investigate the in vivo significance of eNOS in mediating the anti-apoptotic effects of EPO, wild-type and eNOS–/– mice were subjected to myocardial ischemia and reperfusion. EPO decreased myocardial apoptosis and infarct size in wild-type mice. However, the protective effects of EPO were significantly diminished in eNOS–/– mice.
Conclusions: EPO increases eNOS expression and NO production in cardiomyocytes. The anti-apoptotic effects of EPO in cardiomyocytes are mediated by eNOS-derived NO production.
KEYWORDS Apoptosis; Myocytes; Ischemia; Nitric oxide; Nitric oxide synthase; Signal transduction; Erythropoietin
Time for primary review 27 days
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