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Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2666-72. Epub 2006 Oct 5.

Nitric oxide-dependent suppression of thioredoxin-interacting protein expression enhances thioredoxin activity.

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Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, USA.



Cellular redox balance is regulated by enzymatic and nonenzymatic systems and freely diffusible nitric oxide (NO) promotes antioxidative mechanisms. We show the NO-dependent transcriptional regulation of the antioxidative thioredoxin system.


Incubation of rat pulmonary artery smooth muscle cells (RPaSMC) with the NO donor compound S-nitroso-glutathione (GSNO, 100 micromol/L) suppressed thioredoxin-interacting protein (Txnip), an inhibitor of thioredoxin function, by 71+/-18% and enhanced thioredoxin reductase 2.7+/-0.2 fold (n=6; both P<0.001 versus control). GSNO increased thioredoxin activity (1.9+/-0.5-fold after 4 hours; P<0.05 versus control). Promoter deletion analysis revealed that NO suppression of Txnip transcription is mediated by cis-regulatory elements between -1777 and -1127 bp upstream of the start codon. Hyperglycemia induced Txnip promoter activity (3.9+/-0.2-fold; P<0.001) and abolished NO effects (-37.4+/-1.0% at 5.6 mmol/L glucose versus 12.4+/-2.1% at 22.4 mmol/L glucose; P<0.05). Immunoprecipitation experiments demonstrated that GSNO stimulation and mutation of thioredoxin at Cys69, a site of nitrosylation, had no effect on the Txnip/thioredoxin interaction.


NO can regulate cellular redox state by changing expression of Txnip and thioredoxin reductase. This represents a novel antioxidative mechanism of NO independent of posttranslational protein S-nitrosylation of thioredoxin.

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