Nitric Oxide–Dependent Suppression of Thioredoxin-Interacting Protein Expression Enhances Thioredoxin Activity

Abstract
Objective— 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. Methods and Results— Incubation of rat pulmonary artery smooth muscle cells (RPaSMC) with the NO donor compound S -nitroso-glutathione (GSNO, 100 μmol/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 P cis -regulatory elements between −1777 and −1127 bp upstream of the start codon. Hyperglycemia induced Txnip promoter activity (3.9±0.2-fold; P P Conclusions— 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.