| Increased myocardial dysfunction after ischemia-reperfusion in mice lacking glucose-6-phosphate dehydrogenase. | |
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MedLine Citation:
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PMID: 14757696 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. Date: 2004-02-02 |
Journal Detail:
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Title: Circulation Volume: 109 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2004 Feb |
Date Detail:
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Created Date: 2004-02-24 Completed Date: 2004-06-01 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 898-903 Citation Subset: AIM; IM |
Affiliation:
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Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, Mass 02118, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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:
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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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