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J. Biol. Chem., Vol. 277, Issue 27, 24411-24419, July 5, 2002
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From the Exact adjustment of the
Embden-Meyerhof pathway (EMP) is an important issue in ischemic
preconditioning (IP) because an attenuated ischemic lactate
accumulation contributes to myocardial protection. However, precise
mechanisms of glycolytic flux and its regulation in IP remain to be
elucidated. In open chest pigs, IP was achieved by two cycles of 10-min
coronary artery occlusion and 30-min reperfusion prior to a 45-min
index ischemia and 120-min reperfusion. Myocardial contents in
glycolytic intermediates were assessed by high performance liquid
chromatographic analysis of serial myocardial biopsies under control
conditions and IP. Detailed time courses of metabolite contents allow
an in-depth description of EMP regulation during index ischemia using
metabolic control analysis. IP reduced myocardial infarct size
(control, 90.0 ± 3.1 versus 5.05 ± 2.1%;
p < 0.001) and attenuated myocardial lactate
accumulation (end-ischemic contents, 31.9 ± 4.47 versus 10.3 ± 1.26 µmol/wet weight,
p < 0.0001), whereby a decrease in anaerobic
glycolytic flux by at least 70% could constantly be observed
throughout index ischemia. By calculation of flux:metabolite
co-responses, the mechanisms of glycolytic regulation were
investigated. The continuous deceleration of EMP flux in control
myocadium could neither be explained on the basis of substrate
availability nor be attributed to regulatory "key enzymes," as
multisite regulation was employed for flux adjustment. In myocardium
subjected to IP, an even pronounced deceleration of EMP flux during
index ischemia was observed. Again, the adjustment of EMP flux was
because of multisite modulation without any evidence for flux
limitation by substrate availability or a key enzyme. However,
IP changed the regulatory properties of most EMP enzymes, and some of
these patterns could not be explained on the basis of substrate
kinetics. Instead, other regulatory mechanisms, which have previously
not yet been described for EMP enzymes, must be considered. These
altered biochemical properties of the EMP enzymes have not yet been described.
Regulation of Glycolytic Flux in Ischemic Preconditioning
A STUDY EMPLOYING METABOLIC CONTROL ANALYSIS*
§,,,,
, and
Medizinische Universitätsklinik
(Ludolf-Krehl-Klinik), Abteilung Innere Medizin III (Schwerpunkt
Kardiologie, Angiologie und Pulmologie), Bergheimer Straße 58, D-69115
Heidelberg, Germany and the ¶ School of Molecular and Biological
Sciences, Oxford Brookes University, Headington,
Oxford OX3 0BP, United Kingdom
*
This work was supported in part by a grant from the Deutsche
Forschungsgemeinschaft, Bonn, Germany, within the
Sonderforschungsbereich 320, "Herzfunktion und ihre Regulation,"
and the University of Heidelberg (Teilprojekt C14), Germany (to A. V.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by Wellcome Trust, UK, Showcase awards 048728 and 056275.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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