Diabetes abolishes morphine-induced cardioprotection via multiple pathways upstream of glycogen synthase kinase-3beta.

Abstract

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-)GSK3beta was reduced 5 min after reperfusion in DBRs compared with NDBRs (0.83 +/- 0.29 and 1.94 +/- 0.12 [P < 0.05] pg/microg tissue, respectively). The GSK3beta 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-GSK3beta, 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 GSK3beta.

• Authors: Eric R Gross, Anna K Hsu, Garrett J Gross
• Journal: Diabetes (Diabetes) Vol. 56 Issue 1 Pg. 127-36 (Jan 2007) ISSN: 0012-1797 [Print] United States
• PMID: 17192474 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• STAT1 Transcription Factor
• STAT3 Transcription Factor
• Stat1 protein, rat
• Stat3 protein, rat
• Phosphothreonine
• Morphine
• Jak2 protein, rat
• Janus Kinase 2
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Glycogen Synthase Kinase 3

Topics

• Animals
• Blood Pressure (drug effects)
• Cardiotonic Agents (pharmacology)
• Diabetes Mellitus, Experimental (physiopathology)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Heart Rate (drug effects)
• Hyperglycemia (physiopathology)
• Janus Kinase 2 (metabolism)
• Male
• Morphine (pharmacology)
• Phosphothreonine (metabolism)
• Rats
• Rats, Sprague-Dawley
• STAT1 Transcription Factor (metabolism)
• STAT3 Transcription Factor (metabolism)