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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2666.)
© 2006 American Heart Association, Inc.

Vascular Biology

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

P. Christian Schulze; Heling Liu; Elizabeth Choe; Jun Yoshioka; Anath Shalev; Kenneth D. Bloch; Richard T. Lee

From Cardiovascular Division (P.C.S., J.Y., R.T.L.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Cardiovascular Research Center (H.L., E.C., K.D.B.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass; Department of Medicine (A.S.), University of Wisconsin-Madison, Madison, Wis.

Correspondence to P. Christian Schulze, MD, PhD, Department of Medicine, Boston University Medical Center, 80 E Concord St, Evans 124, Boston, MA 02115-2526. E-mail christian.schulze{at}bmc.org

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<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.

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.

Cellular redox balance is tightly regulated and nitric oxide (NO) promotes antioxidative mechanisms. We show the NO-dependent transcriptional regulation of the antioxidative thioredoxin system through suppression of Txnip and induction of thioredoxin reductase. NO also increased thioredoxin activity. These findings represent a novel antioxidative mechanism of NO.

Key Words: atherosclerosis • diabetes mellitus • nitric oxide • oxidative stress • thioredoxin

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