Erythropoietin protects against doxorubicin-induced heart failure

Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2413-21. doi: 10.1152/ajpheart.01096.2010. Epub 2011 Oct 7.


The hormone erythropoietin (EPO) has been demonstrated to have cardioprotective properties. The present study investigates the role of EPO to prevent heart failure following cancer treatment with doxorubicin [adriamycin (AD)]. Male Wistar rats (150 ± 10 g) were treated with saline (vehicle control group); with EPO, subcutaneously at 1,000 IU/kg body wt, three times per week for 4 wk (EPO group); with adriamycin, intraperitoneally at 2.5 mg/kg body wt, three times per week for 2 wk (AD group); and with adriamycin and EPO (EPO-AD group). Echocardiographic measurements showed that EPO-AD treatment prevented the AD-induced decline in cardiac function. Each of the hearts was then exposed to ischemia and reperfusion during Langendorff perfusion. The percentage of recovery after ischemia-reperfusion was significantly greater in EPO-AD than the AD-treated group for left ventricular developed pressure, maximal increase in pressure, and rate pressure product. The level of oxidative stress was significantly higher in AD (5 μM for 24 h)-exposed isolated cardiomyocytes; EPO (5 U/ml for 48 h) treatment prevented this. EPO treatment also decreased AD-induced cardiomyocyte apoptosis, which was associated with the decrease in the Bax-to-Bcl2 ratio and caspase-3 activation. Immunostaining of myocardial tissue for CD31 showed a significant decrease in the number of capillaries in AD-treated animals. EPO-AD treatment restored the number of capillaries. In conclusion, EPO treatment effectively prevented AD-induced heart failure. The protective effect of EPO was associated with a decreased level of oxidative stress and apoptosis in cardiomyocytes as well as improved myocardial angiogenesis.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Capillaries / drug effects
  • Capillaries / physiopathology
  • Cardiotonic Agents / pharmacology*
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Doxorubicin*
  • Enzyme Activation
  • Erythropoietin / pharmacology*
  • Heart Failure / chemically induced
  • Heart Failure / diagnostic imaging
  • Heart Failure / metabolism
  • Heart Failure / physiopathology
  • Heart Failure / prevention & control*
  • Immunohistochemistry
  • Male
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / prevention & control
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control
  • Myocardium / metabolism
  • Myocardium / pathology
  • Neovascularization, Physiologic / drug effects
  • Oxidative Stress / drug effects
  • Perfusion
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Rats, Wistar
  • Recovery of Function
  • Time Factors
  • Ultrasonography
  • Ventricular Function, Left / drug effects
  • Ventricular Pressure / drug effects
  • bcl-2-Associated X Protein / metabolism


  • Bax protein, rat
  • Cardiotonic Agents
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • Erythropoietin
  • Doxorubicin
  • Casp3 protein, rat
  • Caspase 3