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Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3β signaling

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Abstract

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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Acknowledgments

We would like to thank Pierre Legras and Jerome Roux from the animal facilities for taking care of the animals, and Robert Filmon (Service Commun d’Imageries et d’Analyses Microscopiques) for his technical assistance. S. Tamareille and N. Ghaboura were supported by a fellowship from the Conseil Général du Maine et Loire.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Protection et Remodelage du Myocarde, UPRES EA 3860, Faculté de Médecine, Université d’Angers, Rue Haute de Reculée, 49045, Angers Cedex 1, France

    Nehmat Ghaboura, Sophie Tamareille, Alain Furber & Fabrice Prunier

  2. INSERM U694, Faculté de Médecine, Université d’Angers, Angers, France

    Pierre-Henri Ducluzeau

  3. INSERM U771, CNRS UMR 6214, Faculté de Médecine, Université d’Angers, Angers, France

    Linda Grimaud, Laurent Loufrani & Daniel Henrion

  4. Laboratoire d’Anatomie Pathologique, CHU d’Angers, Angers, France

    Anne Croué

  5. Laboratoire de Biochimie, CHU d’Angers, Angers, France

    Yves Tourmen

  6. Service de Cardiologie, CHU d’Angers, Angers, France

    Alain Furber & Fabrice Prunier

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  1. Nehmat Ghaboura
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Correspondence to Fabrice Prunier.

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Ghaboura, N., Tamareille, S., Ducluzeau, PH. et al. Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3β signaling. Basic Res Cardiol 106, 147–162 (2011). https://doi.org/10.1007/s00395-010-0130-3

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