Document Detail

Erythropoietin (EPO) affords more potent cardioprotection by activation of distinct signaling to mitochondrial kinases compared with carbamylated EPO.
MedLine Citation:
PMID:  20953685     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Erythropoietin (EPO) and its non-erythrogenic derivative, carbarmylated EPO (CEPO), have been reported to activate different receptors (homomeric EPO receptor vs. heteromeric receptor consisting of EPO receptor monomer and common β-subunit). The aim of this study was to examine differences between EPO and CEPO in efficacy of cardioprotection against infarction and in activation of pro-survival kinases.
METHODS: In isolated rat hearts, infarction was induced by global ischemia followed by reperfusion. Infarct size was determined 2 h after reperfusion, and ventricular tissues for immunoblotting were sampled at 5 min after reperfusion.
RESULTS: Pretreatment with EPO (10 units/ml) before ischemia reduced infarct size (% of risk area; %IS/AR) from 47.0 ± 2.1% of the control after 20-min ischemia to 24.7 ± 4.3% and from 62.0 ± 3.0% after 25-min ischemia to 45.5 ± 4.1%. Desialylated EPO (asialoEPO, 100 ng/ml) mimicked the protection by EPO. However, CEPO (100 ng/ml) failed to reduce infarct size after 20-min ischemia (%IS/AR = 47.5 ± 5.9%) and that after 25-min ischemia (%IS/AR = 56.1 ± 4.2%). The infarct size-limiting effect of CEPO was not shown either by increasing CEPO dose to 500 ng/ml or by shortening ischemia to 15 min. Both EPO and CEPO enhanced phosphorylation of cytosolic GSK-3β upon reperfusion. In contrast, phosphorylation of GSK-3β, Akt, and PKC-ε in mitochondria upon reperfusion was significantly enhanced by EPO but not by CEPO.
CONCLUSION: EPO affords more potent protection against infarction than does CEPO by distinct activation of signaling leading to phosphorylation of pro-survival protein kinases in mitochondria upon reperfusion.
Takahiro Sato; Masaya Tanno; Takayuki Miki; Toshiyuki Yano; Tatsuya Sato; Kazuaki Shimamoto; Tetsuji Miura
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy     Volume:  24     ISSN:  1573-7241     ISO Abbreviation:  Cardiovasc Drugs Ther     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2011-03-09     Completed Date:  2011-07-07     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  8712220     Medline TA:  Cardiovasc Drugs Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  401-8     Citation Subset:  IM    
Division of Cardiology, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
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MeSH Terms
Cardiotonic Agents / pharmacology*
Erythropoietin / analogs & derivatives*,  pharmacology*
Extracellular Signal-Regulated MAP Kinases
Glycogen Synthase Kinase 3 / metabolism
Mitochondria / drug effects,  enzymology*
Myocardial Infarction / enzymology,  prevention & control*
Myocardial Reperfusion Injury / drug therapy*,  enzymology
Phosphorylation / drug effects
Protein Kinase C-epsilon / metabolism
Protein Kinases / metabolism*
Proto-Oncogene Proteins c-akt / metabolism
Rats, Sprague-Dawley
Receptors, Erythropoietin / metabolism
Signal Transduction / drug effects
Reg. No./Substance:
0/Cardiotonic Agents; 0/Receptors, Erythropoietin; 0/carbamylated erythropoietin; 11096-26-7/Erythropoietin; EC 2.7.-/Protein Kinases; EC Proteins c-akt; EC synthase kinase 3 beta; EC Kinase C-epsilon; EC Signal-Regulated MAP Kinases; EC Synthase Kinase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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