Document Detail

Cardioprotection by GSK-3 inhibition: role of enhanced glycogen synthesis and attenuation of calcium overload.
MedLine Citation:
PMID:  20053658     Owner:  NLM     Status:  MEDLINE    
AIMS: Glycogen synthase kinase-3 (GSK-3) is a multi-functional kinase that regulates signalling pathways affecting glycogen metabolism, protein synthesis, mitosis, and apoptosis. GSK-3 inhibition limits cardiac ischaemia-reperfusion (IR) injury, but mechanisms are not clearly defined. This study tested the hypothesis that acute GSK-3 inhibition stimulates glycogen synthesis, repartitions glucose away from glycolysis, reduces proton (H+) production from glucose metabolism, and attenuates intracellular Ca2+ (Ca2+(i)) overload. METHODS AND RESULTS: In isolated perfused working rat hearts subjected to global ischaemia and reperfusion, the selective GSK-3 inhibitor, SB-216763 (SB, 3 micromol/L), when added either prior to ischaemia or at the onset of reperfusion, improved recovery of left-ventricular (LV) work. SB increased glycogen synthesis during reperfusion while glycolysis and H+ production were reduced. Rates of glucose and palmitate oxidation were improved by SB. Measurement of Ca2+(i) concentration by rapid acquisition indo-1 fluorescence imaging showed that SB, when added either prior to ischaemia or at the onset of reperfusion, reduced diastolic Ca2+(i) overload during reperfusion. In aerobic hearts depleted of glycogen by substrate-free perfusion to a level similar to that measured at the onset of reperfusion, SB accelerated glycogen synthesis and reduced glycolysis and H+ production independent of changes in LV work. CONCLUSION: Our study indicates that reduction in H+ production by GSK-3 inhibition is an early and upstream event that lessens Ca2+(i) overload during ischaemia and early reperfusion independent of LV work which enhances the recovery of post-ischaemic LV function and that may ultimately contribute to previously observed reductions in cell death and infarction.
Mohamed A Omar; Lianguo Wang; Alexander S Clanachan
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-01-06
Journal Detail:
Title:  Cardiovascular research     Volume:  86     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-13     Completed Date:  2010-06-03     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  478-86     Citation Subset:  IM    
Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 9-70 Medical Sciences Building, Edmonton, Alberta T6G2H7, Canada.
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MeSH Terms
Calcium / metabolism*
Cardiotonic Agents / pharmacology*
Disease Models, Animal
Glucose / metabolism
Glycogen / biosynthesis*
Glycogen Synthase Kinase 3 / antagonists & inhibitors*,  metabolism
Glycolysis / drug effects
Hydrogen-Ion Concentration
Indoles / pharmacology*
Maleimides / pharmacology*
Myocardial Reperfusion Injury / enzymology,  physiopathology,  prevention & control*
Myocardium / enzymology*
Palmitic Acid / metabolism
Protein Kinase Inhibitors / pharmacology*
Rats, Sprague-Dawley
Recovery of Function
Sodium-Calcium Exchanger / metabolism
Sodium-Hydrogen Antiporter / metabolism
Time Factors
Ventricular Function, Left / drug effects
Grant Support
//Canadian Institutes of Health Research
Reg. No./Substance:
0/Cardiotonic Agents; 0/Indoles; 0/Maleimides; 0/Protein Kinase Inhibitors; 0/SB 216763; 0/Sodium-Calcium Exchanger; 0/Sodium-Hydrogen Antiporter; 50-99-7/Glucose; 57-10-3/Palmitic Acid; 7440-70-2/Calcium; 9005-79-2/Glycogen; EC Synthase Kinase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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