| Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3β signaling. | |
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MedLine Citation:
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PMID: 20981553 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Recent studies reported cardioprotective effects of erythropoietin (EPO) against ischemia-reperfusion (I/R) injury through activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been reported to be impaired in diabetes and insulin resistance syndrome, we examined whether EPO-induced cardioprotection was maintained in rat models of type 1 diabetes and insulin resistance syndrome. Isolated hearts were obtained from three rat cohorts: healthy controls, streptozotocin (STZ)-induced diabetes, and high-fat diet (HFD)-induced insulin resistance syndrome. All hearts underwent 25 min ischemia and 30 min or 120 min reperfusion. They were assigned to receive either no intervention or a single dose of EPO at the onset of reperfusion. In hearts from healthy controls, EPO decreased infarct size (14.36 ± 0.60 and 36.22 ± 4.20% of left ventricle in EPO-treated and untreated hearts, respectively, p < 0.05) and increased phosphorylated forms of Akt, ERK1/2, and their downstream target GSK-3β. In hearts from STZ-induced diabetic rats, EPO did not decrease infarct size (32.05 ± 2.38 and 31.88 ± 1.87% in EPO-treated and untreated diabetic rat hearts, respectively, NS) nor did it increase phosphorylation of Akt, ERK1/2, and GSK-3β. In contrast, in hearts from HFD-induced insulin resistance rats, EPO decreased infarct size (18.66 ± 1.99 and 34.62 ± 3.41% in EPO-treated and untreated HFD rat hearts, respectively, p < 0.05) and increased phosphorylation of Akt, ERK1/2, and GSK-3β. Administration of GSK-3β inhibitor SB216763 was cardioprotective in healthy and diabetic hearts. STZ-induced diabetes abolished EPO-induced cardioprotection against I/R injury through a disruption of upstream signaling of GSK-3β. In conclusion, direct inhibition of GSK-3β may provide an alternative strategy to protect diabetic hearts against I/R injury. |
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Authors:
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Nehmat Ghaboura; Sophie Tamareille; Pierre-Henri Ducluzeau; Linda Grimaud; Laurent Loufrani; Anne Croué; Yves Tourmen; Daniel Henrion; Alain Furber; Fabrice Prunier |
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Publication Detail:
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Type: In Vitro; Journal Article Date: 2010-10-28 |
Journal Detail:
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Title: Basic research in cardiology Volume: 106 ISSN: 1435-1803 ISO Abbreviation: Basic Res. Cardiol. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-30 Completed Date: 2011-04-18 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 0360342 Medline TA: Basic Res Cardiol Country: Germany |
Other Details:
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Languages: eng Pagination: 147-62 Citation Subset: IM |
Affiliation:
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Protection et Remodelage du Myocarde, UPRES EA 3860, Faculté de Médecine, Université d'Angers, Rue Haute de Reculée, 49045 Angers Cedex 1, France. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects Cardiotonic Agents / administration & dosage Diabetes Mellitus, Experimental / complications*, metabolism Dietary Fats Erythropoietin / pharmacology, therapeutic use* Glucose / toxicity Glycogen Synthase Kinase 3 / metabolism* Hemodynamics Insulin Resistance* MAP Kinase Signaling System Myocardial Infarction / etiology, pathology, prevention & control Myocardial Reperfusion Injury / complications, metabolism, pathology, prevention & control* Myocardium / pathology Phosphatidylinositol 3-Kinases / metabolism Phosphorylation Proto-Oncogene Proteins c-akt / metabolism Rats Rats, Wistar Receptors, Erythropoietin / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Cardiotonic Agents; 0/Dietary Fats; 0/Receptors, Erythropoietin; 11096-26-7/Erythropoietin; 50-99-7/Glucose; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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