| Erythropoietin (EPO) affords more potent cardioprotection by activation of distinct signaling to mitochondrial kinases compared with carbamylated EPO. | |
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MedLine Citation:
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PMID: 20953685 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Takahiro Sato; Masaya Tanno; Takayuki Miki; Toshiyuki Yano; Tatsuya Sato; Kazuaki Shimamoto; Tetsuji Miura |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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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:
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Created Date: 2011-03-09 Completed Date: 2011-07-07 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 8712220 Medline TA: Cardiovasc Drugs Ther Country: United States |
Other Details:
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Languages: eng Pagination: 401-8 Citation Subset: IM |
Affiliation:
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Division of Cardiology, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cardiotonic Agents / pharmacology* Erythropoietin / analogs & derivatives*, pharmacology* Extracellular Signal-Regulated MAP Kinases Glycogen Synthase Kinase 3 / metabolism Male 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 Rats, Sprague-Dawley Receptors, Erythropoietin / metabolism Signal Transduction / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Cardiotonic Agents; 0/Receptors, Erythropoietin; 0/carbamylated erythropoietin; 11096-26-7/Erythropoietin; EC 2.7.-/Protein Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.13/Protein Kinase C-epsilon; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 2.7.11.26/Glycogen Synthase Kinase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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