Key result
Erythropoietin reduced infarct size from 47.4% to 23.9% in control rats, but this protection was abolished in diabetic rats unless pretreated with the ER stress modulator TUDCA.
Absolute Event Rate: 23.9% vs 47.4%
In a diabetic rat model, increased ER stress abolishes EPO-induced cardioprotection against ischemia-reperfusion injury, a defect that can be reversed by the ER stress modulator TUDCA.
EPO cardioprotection may be lost in diabetes; leaves open ER stress modulation to restore benefit in future studies.
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)-3beta-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-3beta in the mitochondria were significantly higher in OLETF than in LETO rats. TUDCA normalized levels of GRP78 and GRP94 and mitochondrial GSK-3beta in OLETF rats. Administration of erythropoietin (EPO) induced phosphorylation of Akt and GSK-3beta 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-3beta 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-3beta, 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-3beta-to-total GSK-3beta ratio in the mitochondrial fraction. CONCLUSIONS: Disruption of protective signals leading to GSK-3beta phosphorylation and increase in mitochondrial GSK-3beta are dual mechanisms by which increased ER stress inhibits EPO-induced suppression of mPTP opening and cardioprotection in diabetic hearts.
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Miki et al. (2009) studied Type 2 diabetes and myocardial infarction. Tauroursodeoxycholic acid (TUDCA) and Erythropoietin (EPO) vs. Control (LETO) rats / untreated OLETF rats was evaluated on Infarct size (% risk area). Erythropoietin reduced infarct size from 47.4% to 23.9% in control rats, but this protection was abolished in diabetic rats unless pretreated with the ER stress modulator TUDCA.
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