In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 109, No. 3 ( 2004-01-27), p. 406-411
Abstract:
Background— The negative effect of tumor necrosis factor-α (TNF-α) on heart contraction, which is mediated by sphingosine, is a major component in heart failure. Because the cellular level of glutathione may limit sphingosine production via the inhibition of the Mg-dependent neutral sphingomyelinase (N-SMase), we hypothesized that cardiac glutathione status might determine the negative contractile response to TNF-α. Methods and Results— We examined the effects of TNF-α in isolated cardiomyocytes obtained from control rats or rats that were given the glutathione precursor N -acetylcysteine (NAC, 100 mg IP per animal). In cardiomyocytes obtained from control rats, 25 ng/mL TNF-α increased reactive oxygen species generation and N-SMase activity (500% and 34% over basal, respectively) and decreased the amplitude of [Ca 2+ ] i in response to electrical stimulation (22% below basal). NAC treatment increased cardiac glutathione content by 42%. In cardiomyocytes obtained from NAC-treated rats, 25 ng/mL TNF-α had no effect on reactive oxygen species production or N-SMase activity but increased the amplitude of [Ca 2+ ] i transients and contraction in response to electrical stimulation by 40% to 50% over basal after 20 minutes. This was associated with a hastened relaxation (20% reduction in t 1/2 compared with basal) and an increased phosphorylation of both Ser 16 - and Thr 17 -phospholamban residues (260% and 115% of maximal isoproterenol effect, respectively). Conclusions— It is concluded that cardiac glutathione status, by controlling N-SMase activation, determines the severity of the adverse effects of TNF-α on heart contraction. Glutathione supplementation may therefore provide therapeutic benefits for vulnerable hearts.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/01.CIR.0000109499.00587.FF
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2004
detail.hit.zdb_id:
1466401-X
