Regulation of glutathione in cardiac myocytes

Shumin Li, Xun Li, George J. Rozanski

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Reduced glutathione (GSH) is an essential, multifunctional tripepetide that controls redox-sensitive cellular processes, but its regulation in the heart is poorly understood. The present study used a pharmocological model of GSH depletion to examine cellular mechanisms controlling cardiac GSH. Inhibition of GSH metabolism was elicited in normal rats by daily injections of buthionine sulfoximine (BSO), a blocker of γ-glutamylcysteine synthetase, plus 1, 3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. After 3 d of BSO/BCNU treatment, intracellular [GSH] was measured in isolated-ventricular myocytes by fluorescence microscopy using the probe monochlorobimane. Basal [GSH] in left-ventricular myocytes from BSO/ BCNU-treated rats (2.0 ± 0.05 amol/μm3, n = 146) was 50% less than control (4.0 ± 0.13 amol/μm3, n = 116; P < 0.05). Incubation of myocytes from BSO/BCNU rats with 0.1 μM insulin normalized [GSH] after a delay of 3-4 h (3.6 ± 0.29 amol/μm 3, n = 66). This effect of insulin was blocked by pre-treating myocytes with cycloheximide. A protein tyrosine phosphatase inhibitor, bis-peroxovanadium-1, 10-phenanthroline (bpV(phen), 1 μM), elicited a similar effect as insulin, while neither agent altered [GSH] in myocytes from control rats. Moreover, the effect of insulin and bpV(phen) to up-regulate GSH was blocked by inhibitors of PI 3-kinase (wortmannin, LY294002), MEK (PD98059) and p38 MAP kinases (SB203580). These data suggest that the insulin-signaling cascade regulates [GSH] in ventricular myocytes by a coordinated activation of PI 3-kinase and MAP kinase pathways. These signaling mechanisms may play essential roles in controlling intracellular redox state and normal function of cardiac myocytes.

Original languageEnglish (US)
Pages (from-to)1145-1152
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume35
Issue number9
DOIs
StatePublished - Sep 1 2003

Keywords

  • Glutathione
  • Insulin
  • MAP kinase
  • Myocyte
  • PI 3-kinase
  • Redox

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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