Role of heme oxygenase-1 in the cardioprotective effects of erythropoietin during myocardial ischemia and reperfusion

Am J Physiol Heart Circ Physiol. 2009 Jan;296(1):H84-93. doi: 10.1152/ajpheart.00372.2008. Epub 2008 Nov 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Carbon Monoxide / physiology
  • Cardiotonic Agents*
  • Caspase 3 / biosynthesis
  • Caspase 3 / genetics
  • Caspase 9 / biosynthesis
  • Caspase 9 / genetics
  • Cells, Cultured
  • Erythropoietin / pharmacology*
  • Heart Ventricles
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / physiology*
  • Hemoglobins / metabolism
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Knockout
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / enzymology*
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Recombinant Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation / physiology
  • p38 Mitogen-Activated Protein Kinases / physiology

Substances

  • Cardiotonic Agents
  • Hemoglobins
  • Recombinant Proteins
  • Erythropoietin
  • Carbon Monoxide
  • Heme Oxygenase-1
  • p38 Mitogen-Activated Protein Kinases
  • Caspase 3
  • Caspase 9