Role of heme oxygenase-1 in the cardioprotective effects of erythropoietin during myocardial ischemia and reperfusion.
We have recently demonstrated that erythropoietin (EPO) protects cardiomyocytes from apoptosis during myocardial ischemia-reperfusion (I/R). The objective of the present study was to investigate the role of heme oxygenase (HO)-1 in the antiapoptotic effects of EPO. Primary cultures of neonatal mouse cardiomyocytes were subjected to anoxia-reoxygenation (A/R). Pretreatment with EPO significantly reduced apoptosis in A/R-treated cells. This reduction in apoptosis was preceded by an increase in the mRNA and protein expression of HO-1. Selective inhibition of HO-1 using chromium mesoporphyrin (CrMP) significantly diminished the ability of EPO to inhibit apoptosis. Cotreatment of EPO with SB-202190, an inhibitor of p38 activation, blocked the EPO-mediated HO-1 expression and antiapoptotic effects, suggesting a p38-dependent mechanism. The in vivo significance of p38 and HO-1 as mediators of EPO's cardioprotection was investigated in mice subjected to myocardial I/R. Pretreatment with EPO decreased infarct size as well as I/R-induced apoptosis in wild-type mice. However, these effects were significantly diminished in HO-1(-/-) mice. Furthermore, EPO given during ischemia reduced infarct size in mice subjected to I/R, and this effect was blocked by CrMP treatment in wild-type mice. Moreover, inhibition of p38 diminished the cardioprotective effects of EPO. We conclude that upregulation of HO-1 expression via p38 signaling contributes to EPO-mediated cardioprotection during myocardial I/R.
Burger
Dylan
D
Dept. of Physiology and Pharmacology, Univ. of Western Ontario, London, ON, Canada N6A 5C1.
Xiang
Fuli
F
Hammoud
Lamis
L
Lu
Xiangru
X
Feng
Qingping
Q
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002248:Carbon Monoxide / Q000502:physiology; D002316:Cardiotonic Agents; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D053453:Caspase 9 / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D004921:Erythropoietin / Q000494:pharmacology*; D006352:Heart Ventricles; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000502:physiology*; D006454:Hemoglobins / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D002316:Cardiotonic Agents; D006454:Hemoglobins; D011994:Recombinant Proteins; D004921:Erythropoietin; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9