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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
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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
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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]
Identifier
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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