title: Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3β signaling.
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.
authors.affiliation: Protection et Remodelage du Myocarde, UPRES EA 3860, Faculté de Médecine, Université d'Angers, Rue Haute de Reculée, 49045 Angers Cedex 1, France.
authors.forename: Nehmat
authors.initials: N
authors.lastname: Ghaboura
authors.forename: Sophie
authors.initials: S
authors.lastname: Tamareille
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Ducluzeau
authors.forename: Linda
authors.initials: L
authors.lastname: Grimaud
authors.forename: Laurent
authors.initials: L
authors.lastname: Loufrani
authors.forename: Anne
authors.initials: A
authors.lastname: Croué
authors.forename: Yves
authors.initials: Y
authors.lastname: Tourmen
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.forename: Alain
authors.initials: A
authors.lastname: Furber
authors.forename: Fabrice
authors.initials: F
authors.lastname: Prunier
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D004041:Dietary Fats; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use*; D005947:Glucose / Q000633:toxicity; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006439:Hemodynamics; D066298:In Vitro Techniques; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017467:Receptors, Erythropoietin / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D004041:Dietary Fats; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D005947:Glucose