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Diabetes Abolishes Morphine-Induced Cardioprotection via Multiple Pathways Upstream of Glycogen Synthase Kinase-3ß

From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin

Address correspondence and reprint requests to Garrett J. Gross, PhD, Medical College of Wisconsin, Department of Pharmacology and Toxicology, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: ggross{at}mcw.edu

Abbreviations: AAR, area at risk; DMEM, Dulbecco’s modified Eagle’s medium; GSK, glycogen synthase kinase; IPC, ischemic preconditioning; JAK, janus-activated kinase; MAPK, mitogen-activated protein kinase; P-, phospho-; PI3k, phosphatidylinositol-3 kinase; STAT, signal transducer and activator of transcription

The cardioprotective effect of opioids or glycogen synthase kinase (GSK) inhibitors given at reperfusion has not been investigated in diabetes models. Therefore, nondiabetic (NDBR) or streptozotocin-induced diabetic (DBR) rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. Groups of NDBR or DBR were administered either vehicle, morphine (0.3 mg/kg), or the GSK inhibitor SB216763 (0.6 mg/kg) 5 min before reperfusion. SB216763 (but not morphine) reduced infarct size in DBRs (44 ± 1* and 55 ± 2%, respectively), while both agents reduced infarct size in NDBRs versus untreated NDBRs or DBRs (44 ± 3*, 42 ± 3*, 60 ± 2, and 56 ± 2%, respectively, *P < 0.001). Morphine-induced phospho- (P-)GSK3ß was reduced 5 min after reperfusion in DBRs compared with NDBRs (0.83 ± 0.29 and 1.94 ± 0.12 [P < 0.05] pg/µg tissue, respectively). The GSK3ß mediators, P-Akt, P–extracellular signal–related kinase (ERK)1, and P–signal transducer and activator of transcription (STAT)3, were also significantly reduced in untreated DBR compared with NDBR rats. Morphine-induced elevations of P-Akt, P-ERK1, P-p70s6, P–janus-activated kinase-2, and P-STAT3 in NDBRs were also blunted in DBRs. H9C2 cells raised in 25 mmol/l compared with 5.56 mmol/l glucose media also demonstrated reduced morphine-induced P-GSK3ß, P-Akt, P-STAT3, and P-ERK1 after 15 min. Hence, acute GSK inhibition may provide a novel therapeutic strategy for diabetic patients during an acute myocardial infarction, whereas morphine is less effective due to signaling events that adversely affect GSK3ß.

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