Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion via induction of AP-1

Cardiovasc Res. 2005 Feb 15;65(3):719-27. doi: 10.1016/j.cardiores.2004.11.019.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Cells, Cultured
  • Erythropoietin / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Nitric Oxide / physiology
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Oxidative Stress
  • Transcription Factor AP-1 / physiology*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Transcription Factor AP-1
  • Erythropoietin
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse