Abstract

Objective: Alteration in endoplasmic reticulum (ER) stress in diabetic hearts and its effect on cytoprotective signaling are unclear. Here we examine the hypothesis that ER stress in diabetic hearts impairs phospho-GSK-3β-mediated suppression of mitochondrial permeability transition pore (mPTP) opening, compromising myocardial response to cytoprotective signaling.

Research Design and Methods: A rat model of type 2 diabetes (OLETF) and its control (LETO) were treated with TUDCA (100 mg/kg/day for 7 days), an ER stress modulator. Infarction was induced by 20-min coronary occlusion and 2-h reperfusion.

Results: Levels of ER chaperones (GRP78 and GRP94) in the myocardium and level of non-phoshopho-GSK-3β in the mitochondria were significantly higher in OLETF than in LETO. TUDCA normalized levels of GRP78 and GRP94 and mitochondrial GSK-3β in OLETF. Administration of EPO induced phosphorylation of Akt and GSK-3β and reduced infarct size (% risk area) from 47.4±5.2% to 23.9±3.5% in LETO hearts. However, neither phosphorylation of Akt and GSK-3β nor infarct size limitation was induced by EPO in OLETF. The threshold for mPTP opening was significantly lower in mitochondria from EPO-treated OLETF than in those from EPO-treated LETO. TUDCA restored responses of GSK-3β, mPTP opening threshold and infarct size to EPO receptor activation in OLETF. There was a significant correlation between mPTP opening threshold and phospho-GSK-3β-to-total-GSK-3β ratio in the mitochondrial fraction.

Conclusions: Disruption of protective signals leading to GSK-3β phosphorylation and increase in mitochondrial GSK-3β are dual mechanisms by which increased ER stress inhibits EPO-induced suppression of mPTP opening and cardioprotection in diabetic hearts.