Endoplasmic Reticulum Stress in Diabetic Hearts Abolishes Erythropoietin-Induced Myocardial Protection by Impairment of Phospho-Glycogen Synthase Kinase-3β-Mediated Suppression of Mitochondrial Permeability Transition

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-glycogen synthase kinase (GSK)-3 beta-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 tauroursodeoxycholic acid (TUDCA) (100 mg . kg(-1) . day(-1) 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 nonphoshopho-GSK-3 beta in the mitochondria were significantly higher in OLETF than in LETO rats. TUDCA normalized levels of GRP78 and GRP94 and mitochondrial GSK-3 beta in OLETF rats. Administration of erythropoietin (EPO) induced phosphorylation of Akt and GSK-3 beta 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-3 beta nor infarct size limitation was induced by EPO in OLETF rats. The threshold for mPTP opening was significantly lower in mitochondria from EPO-treated OLETF rats than in those from EPO-treated LETO rats. TUDCA restored responses of GSK-3 beta, mPTP opening threshold, and infarct size to EPO receptor activation in OLETF rats. There was a significant correlation between mPTP opening threshold and phospho-GSK-3 beta-to-total GSK-3 beta ratio in the mitochondrial fraction. CONCLUSIONS-Disruption of protective signals leading to GSK-3 beta phosphorylation and increase in mitochondrial GSK-3 beta are dual mechanisms by which increased ER stress inhibits EPO-induced suppression of mPTP opening and cardioprotection in diabetic hearts. Diabetes 58:2863-2872, 2009