Copyright © 1995 by the European Society of Cardiology.
© 1995 The European Society of Cardiology
Protection of myocytes against free radical-induced damage by accelerated turnover of the glutathione redox cycle
Departments of Cardiology Leiden, The Netherlands
*Clinical Oncology, University Hospital Leiden, The Netherlands
revised 28 April 1994; accepted 20 October 1994.
Dr A. Van der Laarse, PhD, Department of Cardiology, University Hospital, Building 1, C5-P24, Rijnsburgerweg 10, 2333 AA Leiden, The Netherlands.
Abstract
The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alkoxyl radicals is the glutathione redox cycle. The purpose of the present study was to increase the turnover rate of this cycle by stimulating the glutathione peroxidase catalysed reaction (2GSH
GSSG), the glutathione reductase catalysed reaction (GSSG2GSH), or both, Neonatal rat heart cell cultures were subjected to a standardized protocol of oxidative stress using 80 µmol. l–1 cumene hydroperoxide (CHPO) for 0–90 min. The consequences of this protocol were described in terms of cellular concentrations of GSH, GSSG, NADPH and ATP, formation of malondialdehyde (MDA), release of GSSG and of ATP catabolites, depression of contraction frequency, cellular calcium overload, and enzyme release.
Trolox-C, an analogue of vitamin E, accelerated the glutathione peroxidase reaction leading to lowering of GSH concentration and the GSH/GSSG ratio, less MDA formation, diminished negative chronotropy, delayed calcium overload, and less enzyme release. Glucose was used to accelerate the glutathione reductase reaction by supplying NADPH, leading to higher GSH concentration and a higher GSH/GSSG ratio, less MDA formation, diminished negative chronotropy, unchanged development of calcium overload, and less enzyme release. As a full turn of the glutathione redox cycle involves both the peroxidase and the reductase reactions, the combination of Trolox-C and glucose was superior to either of the two alone: 90 min following addition of CHPO together with Trolox-C and glucose, the GSH concentration and the GSH/GSSG ratio were almost normal, MDA formation was extremely low, calcium overload was markedly delayed, and enzyme release hardly occurred at all. Cells remained beating in the observation period of 30 min. We conclude that the capacity of the glutathione redox cycle to withstand oxidative stress can be increased by stimulation of either the peroxidase reaction or the reductase reaction, and that optimal redox cycling is achieved by stimulation of both reactions.
Key Words: Free radicals • myocytes • cell damage • lipid peroxidation • malondialdehyde • NADPH • glutathione • glutathione redox cycle • glucose • Trolox-C
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