Timing of Erythropoietin Treatment for Cardioprotection in Ischemia/Reperfusion

Erythropoietin (EPO) is a hormone known to stimulate hematopoiesis. However, recent research suggests additional properties of EPO, such as protection against ischemia/reperfusion (I/R) injury in various tissues. We studied the effect of timing of EPO administration on cardioprotection during I/R in the heart. Male Sprague–Dawley rats were subjected to 45 minutes of coronary occlusion, followed by 24 hours of reperfusion. Animals were randomized to receive saline or single dose of EPO (5000 IU/kg) either 2 hours before I/R, at the start of ischemia, or after the onset of reperfusion. The ratio of infarct area/area at risk (planimetry), left ventricular (LV) function (pressure development), and apoptosis (number of active caspase-3 positive cells) were determined after 24-hour reperfusion. Administration of EPO during different time points resulted in a 19 to 23% (P < 0.05) reduction in the infarct area/area at risk, which was accompanied by a trend toward better LV hemodynamic parameters. Apoptosis was significantly attenuated in groups treated with EPO at the start of ischemia (29% reduction) and after the onset of reperfusion (38%), and to a lesser extent (16%) in the group pre-treated with EPO. Thus, in vivo administration of EPO at different time points protects the myocardial structure and preserves cardiac function during I/R. Cardioprotective effect of EPO is associated with inhibition of apoptosis.

[1]  R. Henning,et al.  Erythropoietin improves left ventricular function and coronary flow in an experimental model of ischemia‐reperfusion injury , 2004, European journal of heart failure.

[2]  E. Ozer,et al.  Selective Inhibition of Nitric Oxide in Hypoxic-Ischemic Brain Model in Newborn Rats: Is It an Explanation for the Protective Role of Erythropoietin? , 2004, Neonatology.

[3]  D. Yellon,et al.  New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. , 2004, Cardiovascular research.

[4]  David W. Johnson,et al.  Erythropoietin protects against ischaemic acute renal injury. , 2004, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[5]  A. Voors,et al.  Erythropoietin in cardiovascular diseases. , 2004, European heart journal.

[6]  R. Guyton,et al.  Progressively developed myocardial apoptotic cell death during late phase of reperfusion , 2001, Apoptosis.

[7]  K. Pritchard,et al.  Acute cardioprotective effects of erythropoietin in infant rabbits are mediated by activation of protein kinases and potassium channels , 2004, Basic Research in Cardiology.

[8]  Lily Yang,et al.  Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. , 2003, Cancer research.

[9]  B. Walker,et al.  Erythropoietin Administration In Vivo Increases Vascular Nitric Oxide Synthase Expression , 2003, Journal of cardiovascular pharmacology.

[10]  Richard B. Thompson,et al.  A novel protective effect of erythropoietin in the infarcted heart. , 2003, The Journal of clinical investigation.

[11]  E. Lakatta,et al.  Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  A. D. Black,et al.  Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. , 2003, Biochemical and biophysical research communications.

[13]  C. Heeschen,et al.  Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. , 2003, Blood.

[14]  G. Semenza,et al.  Hearts From Rodents Exposed to Intermittent Hypoxia or Erythropoietin Are Protected Against Ischemia‐Reperfusion Injury , 2003, Circulation.

[15]  Z. Erbayraktar,et al.  Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Ç. Ulukuş,et al.  Neuroprotective Effect of Erythropoietin on Hypoxic-Ischemic Brain Injury in Neonatal Rats , 2003, Neonatology.

[17]  Pietro Ghezzi,et al.  Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  R. Henning,et al.  Erythropoietin protects against ischaemic damage in isolated rat heart , 2003 .

[19]  Kenneth Maiese,et al.  Erythropoietin Is a Novel Vascular Protectant Through Activation of Akt1 and Mitochondrial Modulation of Cysteine Proteases , 2002, Circulation.

[20]  K. Huber,et al.  Clinical and experimental evidence of prostaglandin E1-induced angiogenesis in the myocardium of patients with ischemic heart disease. , 2002, Cardiovascular research.

[21]  M. Díaz-Ricart,et al.  Erythropoietin Triggers a Signaling Pathway in Endothelial Cells and Increases the Thrombogenicity of their Extracellular Matrices In Vitro , 2002, Thrombosis and Haemostasis.

[22]  K. Kuck,et al.  Erythropoietin and VEGF exhibit equal angiogenic potential. , 2002, Microvascular research.

[23]  P. Lewczuk,et al.  Erythropoietin Therapy for Acute Stroke Is Both Safe and Beneficial , 2002, Molecular medicine.

[24]  C. Grimm,et al.  HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration , 2002, Nature Medicine.

[25]  E. Kaptanoğlu,et al.  Erythropoietin prevents ischemia-reperfusion from inducing oxidative damage in fetal rat brain , 2002, Child's Nervous System.

[26]  Federica Limana,et al.  Mobilized bone marrow cells repair the infarcted heart, improving function and survival , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Stuart A. Lipton,et al.  Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-κB signalling cascades , 2001, Nature.

[28]  A. Stephanou,et al.  Apoptosis of Endothelial Cells Precedes Myocyte Cell Apoptosis in Ischemia/Reperfusion Injury , 2001, Circulation.

[29]  P. Kelly,et al.  Low doses of EPO activate MAP kinases but not JAK2-STAT5 in rat vascular smooth muscle cells. , 2001, Biochemical and biophysical research communications.

[30]  P. Lewczuk,et al.  Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. Gabrilove.  Overview: erythropoiesis, anemia, and the impact of erythropoietin. , 2000, Seminars in hematology.

[32]  P Ghezzi,et al.  Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[33]  T. Kishimoto,et al.  Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction. , 2000, Cardiovascular research.

[34]  F. Eberli,et al.  Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. , 2000, American journal of physiology. Heart and circulatory physiology.

[35]  R. Jaster,et al.  Activation of STAT5 during EPO-directed suppression of apoptosis. , 2000, Cellular signalling.

[36]  R. Konrad,et al.  New automated chemiluminescent assay for erythropoietin , 2000, Journal of clinical laboratory analysis.

[37]  D. Duncker,et al.  Hypothermia extends the cardioprotection by ischaemic preconditioning to coronary artery occlusions of longer duration. , 1998, Cardiovascular research.

[38]  K. Aoki,et al.  Characterization and biological effects of recombinant human erythropoietin. , 1986, Immunobiology.