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

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-glycogen synthase kinase (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 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-3β in the mitochondria were significantly higher in OLETF than in LETO rats. TUDCA normalized levels of GRP78 and GRP94 and mitochondrial GSK-3β in OLETF rats. Administration of erythropoietin (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 rats. The threshold for mPTP opening was significantly lower in mitochondria from EPO-treated OLETF rats than in those from EPOtreated LETO rats. TUDCA restored responses of GSK-3β, 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-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. © 2009 by the American Diabetes Association.