Diabetes Abolishes Morphine-Induced Cardioprotection via Multiple Pathways Upstream of Glycogen Synthase Kinase-3β
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 reprin...
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Published in | Diabetes (New York, N.Y.) Vol. 56; no. 1; pp. 127 - 136 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
Alexandria, VA
American Diabetes Association
01.01.2007
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Subjects | |
Online Access | Get full text |
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Summary: | 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 |
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ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/db06-0907 |