1
40
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Text
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URL Address
<a href="http://doi.org/10.1038/nature09599" target="_blank" rel="noreferrer noopener">http://doi.org/10.1038/nature09599</a>
Pages
1115–1118
Issue
7327
Volume
468
Dublin Core
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Title
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S-glutathionylation uncouples eNOS and regulates its cellular and vascular function.
Publisher
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Nature
Date
A point or period of time associated with an event in the lifecycle of the resource
2010
2010-12-23
Subject
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ENDOTHELIUM; GLUTATHIONE; INORGANIC compounds; NITRIC oxide; SUPEROXIDES; TETRAHYDROBIOPTERIN; VASCULAR grafts
Creator
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Chun-An Chen; Tse-Yao Wang; Varadharaj Saradhadevi; Reyes Levy A; Hemann Craig; Talukder M A Hassan; Chen Yeong-Renn; Druhan Lawrence J; Zweier Jay L
Description
An account of the resource
Endothelial nitric oxide synthase (eNOS) is critical in the regulation of vascular function, and can generate both nitric oxide (NO) and superoxide (O2•−), which are key mediators of cellular signalling. In the presence of Ca2+/calmodulin, eNOS produces NO, endothelial-derived relaxing factor, from l-arginine (l-Arg) by means of electron transfer from NADPH through a flavin containing reductase domain to oxygen bound at the haem of an oxygenase domain, which also contains binding sites for tetrahydrobiopterin (BH4) and l-Arg. In the absence of BH4, NO synthesis is abrogated and instead O2•− is generated. While NOS dysfunction occurs in diseases with redox stress, BH4 repletion only partly restores NOS activity and NOS-dependent vasodilation. This suggests that there is an as yet unidentified redox-regulated mechanism controlling NOS function. Protein thiols can undergo S-glutathionylation, a reversible protein modification involved in cellular signalling and adaptation. Under oxidative stress, S-glutathionylation occurs through thiol-disulphide exchange with oxidized glutathione or reaction of oxidant-induced protein thiyl radicals with reduced glutathione. Cysteine residues are critical for the maintenance of eNOS function; we therefore speculated that oxidative stress could alter eNOS activity through S-glutathionylation. Here we show that S-glutathionylation of eNOS reversibly decreases NOS activity with an increase in O2•− generation primarily from the reductase, in which two highly conserved cysteine residues are identified as sites of S-glutathionylation and found to be critical for redox-regulation of eNOS function. We show that eNOS S-glutathionylation in endothelial cells, with loss of NO and gain of O2•− generation, is associated with impaired endothelium-dependent vasodilation. In hypertensive vessels, eNOS S-glutathionylation is increased with impaired endothelium-dependent vasodilation that is restored by thiol-specific reducing agents, which reverse this S-glutathionylation. Thus, S-glutathionylation of eNOS is a pivotal switch providing redox regulation of cellular signalling, endothelial function and vascular tone. [ABSTRACT FROM AUTHOR]
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<a href="http://doi.org/10.1038/nature09599" target="_blank" rel="noreferrer noopener">10.1038/nature09599</a>
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
2010
Chen Yeong-Renn
Chun-An Chen
Department of Integrative Medical Sciences
Druhan Lawrence J
Endothelium
Glutathione
Hemann Craig
INORGANIC compounds
Nature
NEOMED College of Medicine
NITRIC oxide
Reyes Levy A
SUPEROXIDES
Talukder M A Hassan
TETRAHYDROBIOPTERIN
Tse-Yao Wang
Varadharaj Saradhadevi
VASCULAR grafts
Zweier Jay L
-
Text
A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text.
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n/a
Rights
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Pages
1738-1746
Issue
11
Volume
22
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<p>Users with a NEOMED Library login can search for full-text journal articles at the following url: <a href="https://libraryguides.neomed.edu/home">https://libraryguides.neomed.edu/home</a></p>
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The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.
Title
A name given to the resource
INFLUENCE OF N-ACETYLCYSTEINE ON INDIRECT INDICATORS OF TISSUE OXYGENATION IN SEPTIC SHOCK PATIENTS - RESULTS FROM A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND-STUDY
Publisher
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Critical Care Medicine
Date
A point or period of time associated with an event in the lifecycle of the resource
1994
1994-11
Subject
The topic of the resource
blood gas analysis; critical illness; critically-ill patients; endotoxin; gastric mucosa; General & Internal Medicine; glutathione; intramural ph; l-arginine; multiple organ failure; n-acetylcysteine; nitric-oxide synthesis; organ failure; oxygen consumption; ph; relaxing factor; sepsis; septic; shock; skeletal-muscle; tissue oxygenation
Creator
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Spies C D; Reinhart K; Witt I; Meierhellmann A; Hannemann L; Bredle D L; Schaffartzik W
Description
An account of the resource
Objectives: Deactivation of endothelium-derived relaxing factor due to an increased oxygen radical load during sepsis may contribute to an impairment in microcirculatory blood flow. We investigated whether treatment with the sulfhydryl donor and oxygen radical scavenger, N-acetylcysteine, would improve whole-body oxygen consumption (Vo(2)), gastric intramucosal pH, and veno-arterial CO2 gradient (veno-arterial PCO2) during septic shock. Design: Prospective, randomized, double-blind study conducted over 2 yrs. Setting: Septic shock patients admitted to the intensive care unit. Patients: Fifty-eight patients requiring hemodynamic monitoring (radial and pulmonary artery catheters) due to septic shock, were included in this study. All patients were examined within 72 hrs after the onset of sepsis. They were optimally resuscitated by conventional means with volume and inotropic agents, and exhibited stable clinical conditions (hemodynamic values, body temperature, hemoglobin, FIO2). Interventions: A gastric tonometer was inserted to measure the gastric intramucosal pH. Subjects randomly received either 150 mg/kg of intravenous N-acetylcysteine or placebo over a 15-min period, then a continuous infusion of 12.5 mg/hr of N-acetylcysteine or placebo over similar to 90 mins. Measurements: Infusion measurements were begun 60 mins after the beginning of infusion and lasted similar to 30 mins. The infusion was then discontinued and 2 hrs later the final measurements were taken. Main Results: Basic patient characteristics (age, sex, Acute Physiology and Chronic Health Evaluation [APACHE] II scores, Multiple Organ Failure scores) did not differ significantly, nor did pre- and 2-hr postinfusion measurements differ between any of the groups. Thirteen (45%) patients responded (i.e., showed an increase in Vo(2) >10%, reaching a mean of 19%) to the N-acetylcysteine infusion. The N-acetylcysteine responders also showed an increase in gastric intramucosal pH, a decrease in veno-arterial PCO2, an increase in oxygen delivery, cardiac index, stroke index, and left ventricular stroke work index, as well as a significant decrease in systemic vascular resistance in comparison to baseline. The N-acetylcysteine nonresponders, as well as the patients in the placebo group, did not show any significant changes in any of these variables. The N-acetylcysteine responders had a higher survival rate (69%) than the nonresponders (19%) and were studied earlier after onset of sepsis (37 hrs) than the nonresponders (61 hrs). The only significant difference between the entire N-acetylcysteine group (which included responders plus nonresponders) and the placebo group was an increased 30, in the entire N-acetylcysteine group during infusion measurements. Conclusions: N-acetylcysteine provided a transient improvement in tissue oxygenation in about half of the septic shock patients, as indicated by an increase in Vo(2) and gastric intramucosal pH and a decrease in veno-arterial PCO2. The higher survival rate in the N-acetylcysteine responders and the fact that half of the patients receiving N-acetylcysteine did not respond, suggests that, in some patients, sepsis irreversibly damages the microvasculature to the extent that N-acetylcysteine has no effect. If analyzed by intention to treat, the N-acetylcysteine did not produce effects that were significantly different from the placebo. Whether the N-acetylcysteine challenge was merely diagnostic or whether N-acetylcysteine can be effective in the treatment of sepsis deserves further investigation.
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n/a
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Journal Article
1994
Blood Gas Analysis
Bredle D L
Critical care medicine
Critical Illness
critically-ill patients
endotoxin
gastric mucosa
General & Internal Medicine
Glutathione
Hannemann L
intramural ph
Journal Article
l-arginine
Meierhellmann A
multiple organ failure
n-acetylcysteine
nitric-oxide synthesis
organ failure
Oxygen Consumption
ph
Reinhart K
relaxing factor
Schaffartzik W
sepsis
septic
Shock
skeletal-muscle
Spies C D
tissue oxygenation
Witt I