Protective effect of γ-glutamylcysteinylethyl ester on dysfunction of the selenium-deficient rat heart

Abstract

We investigated the protective effect of intracellular GSH against cardiac dysfunction in selenium (Se)-deficient neonatal rats and cultured fetal rat myocytes. A Se-deficient diet with or without daily subcutaneous injections of γ-glutamylcysteinylethyl ester (γ-GCE) (a membrane-permeating GSH precursor) was given to rats from gestation day 4 via the dam to postnatal day 14. Se deficiency induced a 62% incidence of electrocardiographic abnormalities such as sinus arrhythmias or extrasystole, a 63% reduction in dP/dt in the left ventricle, and an increase in thiobarbituric acid reacting substances (TBARS), but no ultrastructural cardiac lesions were observed. Administration of γ-GCE increased the intracellular GSH concentration ([GSH] i) of both neonatal rat hearts and cultured fetal rat cardiac myocytes. γ-GCE-like sodium selenite prevented the cardiac dysfunction and the TBARS increment. γ-GCE also prevented H 2O 2 toxicity in the cultured myocytes. The V max, but not the K m, for GSH of Se-dependent GSH peroxidase (Se-Gpx) activity in Se-deficient rat heart homogenates was one-third that of normal rat heart homogenates. Although γ-GCE did not affect the Se-Gpx V max and K m for GSH, it did induce a substantial and significant increase in [GSH] i, which was postulated to increase the velocity of H 2O 2 decomposition by Se-Gpx activity 1.6-fold. These data suggest that the increase in [GSH] i may have played a role in preventing the TBARS increase and cardiac dysfunction in Se-deficient rats.