Inhibition of glyceraldehyde-3-phosphate dehydrogenase in post-ischaemic myocardium (original) (raw)

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aaDepartment of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095-6948, USA

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bbDepartment of Cardiology B 2142, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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aaDepartment of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095-6948, USA

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aaDepartment of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095-6948, USA

*Corresponding author. Tel.: (+1-310) 825-2843; fax: (+ 1-310) 825-4517.

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Received:

05 February 1996

Published:

01 December 1996

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Richard J Knight, Klaus F Kofoed, Heinrich R Schelbert, Denis B Buxton, Inhibition of glyceraldehyde-3-phosphate dehydrogenase in post-ischaemic myocardium, Cardiovascular Research, Volume 32, Issue 6, December 1996, Pages 1016–1023, https://doi.org/10.1016/S0008-6363(96)00137-X
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Abstract

Objective:

Myocardial reperfusion following brief periods of ischaemia is associated with prolonged, reversible periods of metabolic dysfunction. As the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is inhibited in vitro by reactive oxygen species, we hypothesized that production of reactive oxygen species during reperfusion would lead to inhibition of GAPDH in post-ischaemic myocardium. Methods: Anaesthetized closed-chest dogs were subjected to 20 min balloon occlusion of the left anterior descending coronary artery. Biopsy samples were taken after 3 and 24 h of reperfusion, to determine the activity of GAPDH and the concentrations of glycolytic intermediates in post-ischaemic and remote, non-ischaemic territories. Results: A significant reduction in GAPDH activity was observed in post-ischaemic relative to remote tissue after 3 h reperfusion (4.8 ± 0.5 vs. 2.9 ± 0.2 μmol/min/mg protein; P < 0.01). Western blotting revealed no reduction in the levels of GAPDH protein. Analysis of enzyme kinetics showed the loss of activity to be associated with decreased _V_max (5.9 ± 0.5 vs. 3.2 ± 0.2 μmol/min/mg protein; P < 0.01) with no significant change in the _K_m for glyceraldehyde-3-phosphate (GAP). Incubation of the inhibited enzyme under both mild and strong reducing conditions failed to reactivate the enzyme. The acute reduction in enzyme activity in post-ischaemic tissue was accompanied by regional differences in glycolytic intermediates, notably a twofold accumulation of GAP (P < 0.05), and a reduction in the glucose metabolic rate (GMR) determined by positron emission tomography and [18F]2-fluorodeoxyglucose. By 24 h reperfusion, no regional differences in GAPDH activity, reaction _V_max or _K_m, GAP concentrations or GMR were detectable. Conclusions: These results suggest that inhibition of GAPDH activity may represent an important point at which glycolysis is limited during reperfusion, and further, that the mechanisms of enzyme inhibition do not involve simple oxidation or _S_-thiolation of critical active site thiol groups.

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Copyright © 1996, European Society of Cardiology

Topic:

• myocardium
• positron-emission tomography
• ischemia
• anterior descending branch of left coronary artery
• western blotting
• oxidation
• reperfusion therapy
• physiologic reperfusion
• biopsy
• glucose
• balloon occlusion
• dog, domestic
• glyceraldehyde 3-phosphate
• glyceraldehyde-3-phosphate dehydrogenases
• glycolysis
• myocardial reperfusion
• reactive oxygen species
• sulfhydryl compounds
• enzymes
• chest
• enzyme kinetics
• metabolic disturbance
• geographic difference
• metabolic rate
• enzyme activity

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