Journal
DIABETES
Volume 56, Issue 1, Pages 127-136Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db06-0907
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R37HL074314] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL074314, HL08311] Funding Source: Medline
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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 +/- 3:1, 60 +/- 2, and 56 +/- 2%, respectively, *P < 0.001). Morphine-induced phospho-(P-)GSK30 was reduced 5 min after reperfusion in DBRs compared with NDBRs (0.83 +/- 0.29 and 1.94 +/- 0.12 [P < 0.05] pg/mu g tissue, respectively). The GSK3 beta 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-p70sA, P-janus-activated kinase-2, and P-STAT3 in ND-BRs 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-GSK3 beta, 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 GSK3 beta.
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