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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.

Background: We recently found that myocardial response to protective effects of erythropoietin (EPO) against ischemic/ reperfusion (I/R) injury is mediated by the up-regulation of survival kinases (PI3K/Akt and ERK1/2) during the early minute of reperfusion. However the question of whether EPO-induced cardioprotection is maintained in diabetes mellitus and insulin resistance is unknown. Our current aim was to establish the effect of EPO in an experimental model of diabetes mellitus and insulin resistance. Methods: To address this issue, isolated Langendorff-perfused hearts were obtained from 3 cohorts of Wistar rats: healthy adults; animals injected 4 wks earlier with streptozotocin (STZ) to induce diabetes and rats fed 4 wks earlier with a high fat diet (HF diet) to induce insulin resistance. All hearts underwent 25 min global ischemia, and within each cohort, were assigned to receive either complete reperfusion with no intervention (controls) or with a single dose of EPO (1000 IU/ kg) injected at the onset of reperfusion. Results: In hearts from healthy rats; i) EPO was cardioprotective (Left ventricular developed pressure (LVDP) was 73.18±10.23 mmHg in EPO hearts vs 18.57±4.67 mmHg in Ctrl hearts at 30 min of reperfusion; ρ<0.05); ii) EPO-induced cardioprotection was associated with significant increases in phosphorylated forms of Akt, ERK1/2 and their downstream target GSK-3β. At 4 wks post-STZ injection, rats displayed; i) low plasma insulin levels and hyperglycemia; ii) inhibition of EPO-induced cardioprotection; iii) no up-regulation of PI3K/Akt, ERK1/2 and GSK-3β signalling in response to EPO. In contrast, at 4 wks post-HF diet, rats showed; i) high plasma insulin levels and normoglycemia; ii) cardioprotective effect of EPO (LVDP was 63.63±3.75 mmHg in EPO hearts vs 49.83±7.11 mmHg in Ctrl hearts at 30 min of reperfusion; ρ<0.05); iii) up-regulation in PI3K/ Akt, ERK1/2 and GSK-3β signalling. Conclusion: EPO improves post-ischemic cardiac function recovery in insulin resistance but not in diabetic rat hearts. Survival signalling pathways seem to be impaired in presence of diabetes. [Copyright &y& Elsevier]