Tumor necrosis factor-alpha-mediated decrease in glutathione increases the sensitivity of pulmonary vascular endothelial cells to H2O2.

Ishii, Yoshiki; Partridge, Catherine A.; Vecchio, P. J. Del; Malik, Asrar B.

doi:10.1172/jci115658

Cited by 103 publications

(51 citation statements)

References 45 publications

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“…Furthermore, diminished tissue concentrations of the necessary cofactor glutathione, seen in patients with CHF, under the influence of elevated local levels of TNF-␣ could further aggravate the impaired GPX activity, leading to ROS-mediated cell damage. 11,20,21 This notion is strongly supported by the inverse correlation between TNF-␣ protein levels in SM and GPX activity in the present study. One might argue that the increase in local TNF-␣ and IL-1␤ protein levels in CHF is the result of enhanced binding of circulating cytokines on tissue-specific receptor.…”

Section: Expression Of Radical Scavenger Enzymes In Sm Of Patients Wisupporting

confidence: 87%

“…3,4,18,19 Most intriguing was the training-induced reduction of the local expression of tumor necrosis factor (TNF)-␣ that is known to diminish intracellular levels of reduced glutathione (ie, glutathione containing an SH group [GSH]), which is an essential cofactor of GPX and hence, decrease GPX activity 11,20,21 ; however, it is currently unknown whether the trainingmediated downregulation of SM inflammation is associated with restoration of the local enzymatic radical scavenger system. Therefore, we aimed to investigate whether aerobic exercise training in stable CHF reconstitutes the activity of SOD, Cat, and GPX, thereby reducing oxidative stress and apoptosis of myocytes in SM.…”

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confidence: 99%

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Antioxidative Effects of Exercise Training in Patients With Chronic Heart Failure

et al. 2005

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Background-In chronic heart failure (CHF), cross-talk between inflammatory activation and oxidative stress has been anticipated in skeletal muscle (SM). The role of the radical scavenger enzymes superoxide dismutase (SOD), catalase (Cat), and glutathione peroxidase (GPX), which remove oxygen radicals, has never been assessed in the SM in this context. Moreover, it remains unknown whether exercise training augments the activity of these enzymes in CHF. Methods and Results-Twenty-three patients with CHF were randomized to either 6 months of exercise training (T) or a sedentary lifestyle (C); 12 age-matched healthy subjects (HS) were studied in parallel. Activity of Cat, SOD, and GPX was assessed in SM biopsies before and after 6 months (6 months). Oxidative stress was determined by measuring nitrotyrosine formation. SOD, Cat, and GPX activity was reduced by 31%, 57%, and 51%, respectively, whereas nitrotyrosine formation was increased by 107% in SM in CHF (PϽ0.05 versus HS). In CHF, exercise training augmented GPX and Cat activity in SM by 41% (PϽ0.05 versus before and group C) and 42% (PϽ0.05 versus before and group C), respectively, and decreased nitrotyrosine production by 35% (from 3.8Ϯ0.4% tissue area before to 2.5Ϯ0.3% after 6 months; PϽ0.05 versus before). Conclusions-The reduced activity of major antioxidative enzymes in the SM of CHF patients is associated with increased local oxidative stress. Exercise training exerts antioxidative effects in the SM in CHF, in particular, due to an augmentation in activity of radical scavenger enzymes.

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Section: Expression Of Radical Scavenger Enzymes In Sm Of Patients Wisupporting

confidence: 87%

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confidence: 99%

Antioxidative Effects of Exercise Training in Patients With Chronic Heart Failure

et al. 2005

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“…Then the cells were washed and scraped from the plate, extracted, and Western blot performed using anti-PARP monoclonal antibody. The band shown in the ®gure was at 116 kDa, which was degraded into 85 kDa fragment limiting enzyme in the synthesis of GSH, and several reports indicate that treatment of cells with TNF reduces intracellular GSH levels (Ishii et al, 1992;Shoji et al, 1995;Goossens et al, 1995;Phelps et al, 1995;Liu et al, 1998;Kinscherf et al, 1998) and treatments that enhance intracellular GSH levels (Ishii et al, 1992;Goossens et al, 1995;Mehlen et al, 1996;Obrador et al, 1997;Fernandez-Checa et al, 1997;Kinscherf et al, 1998) protect cells from TNFmediated cytotoxicity. Thus one possible mechanism by which g-GCS protects cells from TNF-induced cytotoxicity is through generation of GSH.…”

Section: Discussionmentioning

confidence: 97%

Overexpression of γ-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1

1999

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Tumor necrosis factor (TNF) is a highly pleiotropic cytokine whose activity is at least partially regulated by the redox status of the cell. The cellular redox status is controlled primarily by glutathione, a major cellular antioxidant, whose synthesis is regulated by the ratelimiting enzyme g-glutamylcysteine synthetase (g-GCS).In the present report we investigated the e ect of g-GCS overexpression on the TNF-induced activation of nuclear transcription factors NF-kB and AP-1, stress-activated protein kinase/c-Jun amino-terminal kinase (JNK) and apoptosis. Transfection of cells with g-GCS cDNA blocked TNF-induced NF-kB activation, cytoplasmic IkBa degradation, nuclear translocation of p65, and NF-kB-dependent gene transcription. g-GCS overexpression also completely suppressed NF-kB activation induced by phorbol ester and okadaic acid, whereas that induced by H 2 O 2 , ceramide, and lipopolysaccharide was minimally a ected. g-GCS also abolished the activation of AP-1 induced by TNF and inhibited TNF-induced activation of JNK and mitogen-activated protein kinase kinase. TNF-mediated cytotoxicity and activation of caspase-3 were both abrogated in g-GCS-overexpressing cells. Overall, our results indicate that most of the pleiotropic actions of TNF are regulated by the glutathione-controlled redox status of the cell.

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“…However, any effect of decreased GSH concentration will certainly be amplified in situations of increased oxidative burden. Due to the primary and secondary infections, HIVϩ individuals tend to have activated respiratory burst of the immune cells, elevated level of pro-oxidative cytokine (24,25), and increased intake of pharmaceutical compounds that either cause oxidative damage (e.g. zidovudine (27)) or require GSH for detoxification (13).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Decreased Glutathione Content in Human Immunodeficiency Virus Type 1 Tat-transgenic Mice

Choi¹,

Liu²,

Kundu³

et al. 2000

Journal of Biological Chemistry

153

105

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Human immunodeficiency virus (HIV) progressively depletes GSH content in humans.Although the accumulated evidence suggests a role of decreased GSH in the pathogenesis of HIV, significant controversy remains concerning the mechanism of GSH depletion, especially in regard to envisioning appropriate therapeutic strategies to help compensate for such decreased antioxidant capacity. Tat, a transactivator encoded by HIV, is sufficient to cause GSH depletion in vitro and is implicated in AIDS-associated Kaposi's sarcoma and B cell lymphoma. In this study, we report a decrease in GSH biosynthesis with Tat, using HIV-1 Tat transgenic (Tat؉) mice. A significant decline in the total intracellular GSH content in liver and erythrocytes of Tat؉ mice was accompanied by decreased ␥-glutamylcysteine synthetase regulatory subunit mRNA and protein content, which resulted in an increased sensitivity of ␥-glutamylcysteine synthetase to feedback inhibition by GSH. Further study revealed a significant reduction in the activity of GSH synthetase in liver of Tat؉ mice, which was linearly associated with their GSH content. Therefore, Tat appears to decrease GSH in vivo, at least partially, through modulation of GSH biosynthetic enzymes. Human immunodeficiency virus (HIV)1 infection is associated with a systemic decrease in the GSH content in humans (1, 2). Such biochemical alteration appears to be a direct consequence of retroviral infection rather than a late and indirect consequence of advanced disease state, is progressive in nature, and often occurs in the absence of any symptoms associated with AIDS (2-5). The importance of this decreased GSH is suggested by the fact that decreased GSH can enhance HIV expression via activation of NF-B (4, 6, 7) and contribute to diverse immune dysfunctions found in AIDS, including the loss of CD4ϩ T lymphocytes via apoptosis (8 -11). In fact, such decline in the GSH content may play a role in the increased drug toxicity and oxidative damage, often found in HIV-infected individuals (12-15). Furthermore, increased GSH or other sulfhydryl compounds can inhibit viral replication (7, 16), HIV-1 reverse transcriptase activity (16,17), and the late stage of viral expression (18). GSH content may even predict the survival of HIV-seropositive (HIVϩ) individuals (19,20). Therefore, it is perhaps crucial to determine whether this decrease in GSH occurs through an accelerated loss of GSH or specific modulation of its synthesis, especially as it relates to potential therapeutic strategies to compensate for such decreased antioxidant capacity. However, despite over a decade of intensive research on this subject, the exact mechanism(s) causing decreased GSH content with HIV remains unclear.Cells maintain their high GSH content in part by reducing GSSG back to GSH, preventing the loss of GSH as GSSG (12). Also, GSH is synthesized from its amino acid constituents via two consecutive reactions catalyzed by ␥-glutamylcysteine synthetase (GCS; glutamate-cysteine ligase, EC 6.3.2.2) and GSH synthetase (GS; EC6.3.2.3). I...

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Tumor necrosis factor-alpha-mediated decrease in glutathione increases the sensitivity of pulmonary vascular endothelial cells to H2O2.

Cited by 103 publications

References 45 publications

Antioxidative Effects of Exercise Training in Patients With Chronic Heart Failure

Antioxidative Effects of Exercise Training in Patients With Chronic Heart Failure

Overexpression of γ-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1

Molecular Mechanism of Decreased Glutathione Content in Human Immunodeficiency Virus Type 1 Tat-transgenic Mice

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