N-Acetylcysteine Prevents the Deleterious Effect of Tumor Necrosis Factor-α on Calcium Transients and Contraction in Adult Rat Cardiomyocytes
- 27 January 2004
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 109 (3), 406-411
- https://doi.org/10.1161/01.cir.0000109499.00587.ff
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 [Ca2+]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 [Ca2+]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 t1/2 compared with basal) and an increased phosphorylation of both Ser16- and Thr17-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.Keywords
This publication has 20 references indexed in Scilit:
- Dual Site Phospholamban Phosphorylation and Its Physiological Relevance in the HeartTrends in Cardiovascular Medicine, 2002
- TNFα‐induced glutathione depletion lies downstream of cPLA2 in L929 cellsFEBS Letters, 2001
- Genetically Engineered Models with Alterations in Cardiac Membrane Calcium-Handling ProteinsAnnual Review of Physiology, 2000
- Tumor Necrosis Factor-α Decreases the Phosphorylation Levels of Phospholamban and Troponin I in Spontaneously Beating Rat Neonatal Cardiac MyocytesJournal of Molecular and Cellular Cardiology, 1999
- Glutathione Regulation of Neutral Sphingomyelinase in Tumor Necrosis Factor-α-induced Cell DeathPublished by Elsevier BV ,1998
- Sphingosine Mediates the Immediate Negative Inotropic Effects of Tumor Necrosis Factor-α in the Adult Mammalian Cardiac MyocytePublished by Elsevier BV ,1997
- Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart.JCI Insight, 1993
- Elevated Circulating Levels of Tumor Necrosis Factor in Severe Chronic Heart FailureNew England Journal of Medicine, 1990
- Synthesis of stress proteins in rat cardiac myocytes 2-4 days after imposition of hemodynamic overload.JCI Insight, 1988
- Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridineAnalytical Biochemistry, 1980