Document Detail


Increased myocardial dysfunction after ischemia-reperfusion in mice lacking glucose-6-phosphate dehydrogenase.
MedLine Citation:
PMID:  14757696     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Free radical injury contributes to cardiac dysfunction during ischemia-reperfusion. Detoxification of free radicals requires maintenance of reduced glutathione (GSH) by NADPH. The principal mechanism responsible for generating NADPH and maintaining GSH during periods of myocardial ischemia-reperfusion remains unknown. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, generates NADPH in a reaction linked to the de novo production of ribose. We therefore hypothesized that G6PD is essential for maintaining GSH levels and protecting the heart during ischemia-reperfusion injury. METHODS AND RESULTS: Susceptibility to myocardial ischemia-reperfusion injury was determined in Langendorff-perfused hearts isolated from wild-type mice (WT) and mice lacking G6PD (G6PD(def)) (20% of WT myocardial G6PD activity). During global zero-flow ischemia, cardiac function was similar between WT and G6PD(def) hearts. On reperfusion, however, cardiac relaxation and contractile performance were greatly impaired in G6PD(def) myocardium, as demonstrated by elevated end-diastolic pressures and decreased percent recovery of developed pressure relative to WT hearts. Contractile dysfunction in G6PD(def) hearts was associated with depletion of total glutathione stores and impaired generation of GSH from its oxidized form. Increased ischemia-reperfusion injury in G6PD(def) hearts was reversed by treatment with the antioxidant MnTMPyP but unaffected by supplementation of ribose stores. CONCLUSIONS: These results demonstrate that G6PD is an essential myocardial antioxidant enzyme, required for maintaining cellular glutathione levels and protecting against oxidative stress-induced cardiac dysfunction during ischemia-reperfusion.
Authors:
Mohit Jain; Lei Cui; Daniel A Brenner; Bo Wang; Diane E Handy; Jane A Leopold; Joseph Loscalzo; Carl S Apstein; Ronglih Liao
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2004-02-02
Journal Detail:
Title:  Circulation     Volume:  109     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2004 Feb 
Date Detail:
Created Date:  2004-02-24     Completed Date:  2004-06-01     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  898-903     Citation Subset:  AIM; IM    
Affiliation:
Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, Mass 02118, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antioxidants / pharmacology,  therapeutic use
Female
Genotype
Glucosephosphate Dehydrogenase / genetics,  physiology*
Glucosephosphate Dehydrogenase Deficiency / complications*
Glutathione / metabolism
Male
Metalloporphyrins / pharmacology,  therapeutic use
Mice
Mice, Knockout
Myocardial Contraction / drug effects,  physiology*
Myocardial Ischemia / enzymology,  genetics*,  physiopathology
Myocardial Reperfusion Injury / enzymology,  genetics*,  physiopathology
NADP / physiology
Oxidation-Reduction
Ribose / deficiency,  pharmacology
Grant Support
ID/Acronym/Agency:
HL-004399/HL/NHLBI NIH HHS; HL-007224/HL/NHLBI NIH HHS; HL-055993/HL/NHLBI NIH HHS; HL-058976/HL/NHLBI NIH HHS; HL-061795/HL/NHLBI NIH HHS; HL-067297/HL/NHLBI NIH HHS; HL-073756/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Metalloporphyrins; 50-69-1/Ribose; 53-59-8/NADP; 70-18-8/Glutathione; 70649-54-6/tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; EC 1.1.1.49/Glucosephosphate Dehydrogenase

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


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