Abstract 3512: Diabetes Mellitus Abrogates Erythropoietin-Induced Cardioprotection Against Ischemic-Reperfusion Injury by Alteration of the RISK/GSK-3β Signaling
Background: Recent studies using healthy animals have demonstrated cardioprotective effects of erythropoietin (EPO) against ischemic-reperfusion injury by the RISK pathway up-regulation. Here, we sought to examine whether EPO-induced cardioprotection is maintained in presence of type I diabetes mellitus or insulin resistance.
Methods: To address this issue, isolated Langendorff-perfused hearts were obtained from 3 cohorts of Wistar rats: healthy adults; animals injected 4 weeks earlier with streptozotocin (STZ) to induce diabetes and rats fed with a high fat diet (HFD) for 4 weeks to induce insulin resistance. All hearts underwent 25 min ischemia, and within each cohort, were assigned to receive either 2h reperfusion with no intervention or with a single dose of EPO (1000 IU/kg) injected at the onset of reperfusion.
Results: In hearts from healthy rats:
EPO was cardioprotective: infarct size was 14.4±0.6% vs 36.2±4.2% of the left ventricle in EPO-treated vs untreated hearts (p<0.05);
EPO-induced cardioprotection was associated with significant increase in phosphorylated forms of Akt, ERK1/2 and their downstream target GSK-3β, at 30 min reperfusion.
At 4 weeks post-STZ injection, rats displayed:
inhibition of EPO-induced cardioprotection: infarct size was 32.1±2.4% vs 31.9±1.9% in EPO-treated vs untreated diabetic rat hearts (p=ns);
no up-regulation of PI3K/Akt, ERK1/2 and GSK-3β signaling in response to EPO.
In contrast, at 4 weeks post-HFD, rats showed:
cardioprotective effect of EPO: infarct size was 18.7±1.9% vs 34.6±3.4% in EPO-treated vs untreated HFD rat hearts (p<0.05);
up-regulation in PI3K/Akt, ERK1/2 and GSK-3β signaling in response to EPO, at 30 min reperfusion.
Furthermore, administration of the GSK-3β inhibitor SB216367 (3μmol/L) was cardioprotective in both healthy and diabetic rat hearts: infarct size was 18.9±2.3% and 20.3±3.9% vs 36.2±4.2% and 31.9±1.9% in treated vs untreated healthy and diabetic hearts respectively (p<0.05).
Conclusion: Diabetic rat hearts are refractory to EPO-induced cardioprotection because of the disruption of GSK-3β signaling upstream. Thus, direct inhibition of GSK-3β may provide a novel therapeutic strategy to protect diabetic hearts against ischemic-reperfusion injury.