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Erythropoietin protects the infant heart against ischemia–reperfusion injury by triggering multiple signaling pathways

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Abstract

The immediate protective effect of erythropoietin (EPO) against ischemia in heart suggests a role beyond hematopoiesis and the treatment of anemia. We determined the role of JAK/STAT and Ras/Rac/MAPK in the protective effect of EPO against ischemia–reperfusion injury in infant rabbit heart. EPO (1.0 U/ml) administered 15 minutes prior to 30–minutes global ischemia and 35 minutes reperfusion resulted in increased recovery of postischemic ventricular developed pressure in rabbit hearts. EPO exerted its immediate cardioprotective effect via activation of multiple signaling pathways by: 1) phosphorylation and activation of JAK1/2, STAT3 and STAT5A but not of STAT1α and STAT5B, 2) phosphorylation and activation of PI3 kinase and its downstream kinases Akt and Rac, 3) activation of PKCε, Raf, MEK1/2, p42/44 MAPK and p38 MAPK. Pretreatment with Wortmannin abolished EPO–induced Akt activation and phosphorylation. Pretreatment with Chelerythrine followed by EPO treatment resulted in partial inhibition of Raf activation, and abolished PKCε and p38 MAPK activation without any effect on Akt, MEK1/2 and p42/44 MAPK. PD98059 abolished MEK1/2 and p42/44 MAPK activation with no effect on Akt, Raf and p38 MAPK activation. SB203580 inhibited only p38 MAPK activation by EPO. We can conclude EPO increases immediate cardioprotection through the activation of multiple signal transduction pathways.

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Authors and Affiliations

  1. Pediatric Surgery Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

    J. E. Baker PhD

  2. Medical College of Wisconsin, Division of Pediatric Surgery, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

    P. Rafiee, Y Shi, J. Su, K. A. Pritchard Jr. & J. E. Baker PhD

  3. Division of Cardiothoracic Surgery, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

    J. S. Tweddell

  4. Department of Pharmacology and Toxicology, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

    J. E. Baker PhD

  5. Children’s Hospital of Wisconsin, 9000 W. Wisconsin Avenue, Milwaukee, WI 53226, USA

    J. S. Tweddell

  6. Children’s Research Institute, 9000 W. Wisconsin Avenue, Milwaukee, WI 53226, USA

    P. Rafiee, Y Shi, J. Su, K. A. Pritchard Jr., J. S. Tweddell & J. E. Baker PhD

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  1. P. Rafiee
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Correspondence to J. E. Baker PhD.

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Rafiee, P., Shi, Y., Su, J. et al. Erythropoietin protects the infant heart against ischemia–reperfusion injury by triggering multiple signaling pathways. Basic Res Cardiol 100, 187–197 (2005). https://doi.org/10.1007/s00395-004-0508-1

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  • DOI: https://doi.org/10.1007/s00395-004-0508-1

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