Copyright © 2004, European Society of Cardiology
Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion via induction of AP-1
aVascular Cell Biology Laboratory, Lawson Health Research Institute, University of Western Ontario, 800 Commissioners Road, VRL 6th Floor, London, ON, Canada N6A 4G5
bDepartments of Medicine, Physiology and Pharmacology, University of Western Ontario, London, ON, Canada N6A 4G5
cDepartment of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
dDivision of Endocrinology, Metabolism and Diabetes, and Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
eDivision of Hematology, Department of Medicine, University of Western Ontario, London, ON, Canada N6A 4G5
* Corresponding author. Tel.: +1 519 685 8500x55073; fax: +1 519 685 8341. Email address: pkvietys{at}uwo.ca
Objective: Erythropoietin (EPO) prevents the myocardial dysfunction induced by ischemia/reperfusion (I/R). Since I/R-induced myocardial dysfunction is associated with an acute inflammatory response, we assessed the anti-inflammatory properties of EPO using in vitro and in vivo models of I/R.
Methods: Isolated cardiac myocytes were exposed to anoxia/reoxygenation (A/R; the in vitro counterpart to I/R). Hearts were challenged with I/R in situ.
Results: In vitro, A/R increased myocyte oxidant stress and converted the myocytes to a proinflammatory phenotype (these myocytes induced PMN transendothelial migration). Pretreatment of the myocytes with EPO prevented the A/R-induced proinflammatory effects. EPO increased myocyte (1) nuclear translocation of AP-1 (c-fos/c-jun), (2) eNOS, but not iNOS, protein expression, and (3) NO production. An AP-1 "decoy" oligonucleotide prevented the induction of eNOS by EPO and reversed the beneficial effect of EPO. An inhibitor of phosphatidylinostol 3 (PI3)-kinase prevented the nuclear translocation of AP-1 induced by EPO. In vivo, in wild type mice, I/R induced an increase in myocardial MPO activity (indicative of PMN infiltration); an effect prevented by pretreatment of the mice with EPO. This anti-inflammatory effect of EPO was not observed in cardiac specific c-fos–/– mice.
Conclusions: Collectively, these findings indicate that EPO can ameliorate the myocardial inflammatory response in both in vitro and in vivo models of I/R. This beneficial effect of EPO is mediated by eNOS-derived NO via a PI3-kinase-dependent activation of AP-1.
KEYWORDS Myocardial; ischemia/reperfusion; AP-1; eNOS
Abbreviations: AP-1, Activation protein-1 • I/R, ischemia/reperfusion • A/R, anoxia/reoxygenation • EPO, erythropoietin • EPO-R, erythropoietin receptor • NOS, nitric oxide synthase • PMN, polymorphonuclear leukocytes • DHR, dihydrorhodamine • DAF-FM, 4-amino-5-methylamino-2'-7'-difluorofluorescein • NF
B, nuclear factor-kappa B • MPO, myeloperoxidase • PI3-kinase, phosphatidylinositol 3 kinase
Time for primary review 22 days
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