Increased myocardial dysfunction after ischemia-reperfusion in mice lacking glucose-6-phosphate dehydrogenase.

Abstract

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
• Journal: Circulation (Circulation) Vol. 109 Issue 7 Pg. 898-903 (Feb 24 2004) ISSN: 1524-4539 [Electronic] United States
• PMID: 14757696 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antioxidants
• Metalloporphyrins
• NADP
• Ribose
• tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex
• Glucosephosphate Dehydrogenase
• Glutathione

Topics

• 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)