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

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 1; pp. 127 - 136
• Main Authors: GROSS, Eric R, HSU, Anna K, GROSS, Garrett J
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.01.2007
• Subjects: Analgesics; Analysis; Biological and medical sciences; Care and treatment; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genetic aspects; Glycogen; Medical sciences; Morphine; Neuropharmacology; Pharmacology. Drug treatments; Synthesis; Endocrinopathy; Enzyme; Glycogen; Kinase; Transferases; Diabetes mellitus; Opiates; Morphine; Synthase; Narcotic analgesic
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-0907

Diabetes Abolishes Morphine-Induced Cardioprotection via Multiple Pathways Upstream of Glycogen Synthase Kinase-3β Eric R. Gross , Anna K. Hsu and Garrett J. Gross 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 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-)GSK3β 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 GSK3β 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-GSK3β, 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 GSK3β. 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 Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted October 13, 2006. Received July 3, 2006. DIABETES