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J. Biol. Chem., Vol. 279, Issue 29, 30369-30374, July 16, 2004

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Hyperglycemia Promotes Oxidative Stress through Inhibition of Thioredoxin Function by Thioredoxin-interacting Protein^*

P. Christian Schulze, Jun Yoshioka, Tomosaburo Takahashi, Zhiheng He, George L. King, and Richard T. Lee¶

From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School and Vascular Cell Biology & Complications, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02139

Increased intracellular reactive oxygen species (ROS) contribute to vascular disease and pro-atherosclerotic effects of diabetes mellitus may be mediated by oxidative stress. Several ROS-scavenging systems tightly control cellular redox balance; however, their role in hyperglycemia-induced oxidative stress is unclear. A ubiquitous antioxidative mechanism for regulating cellular redox balance is thioredoxin, a highly conserved thiol reductase that interacts with an endogenous inhibitor, thioredoxin-interacting protein (Txnip). Here we show that hyperglycemia inhibits thioredoxin ROS-scavenging function through p38 MAPK-mediated induction of Txnip. Overexpression of Txnip increased oxidative stress, while Txnip gene silencing restored thioredoxin activity in hyperglycemia. Diabetic animals exhibited increased vascular expression of Txnip and reduced thioredoxin activity, which normalized with insulin treatment. These results provide evidence for the impairment of a major ROS-scavenging system in hyperglycemia. These studies implicate reduced thioredoxin activity through interaction with Txnip as an important mechanism for vascular oxidative stress in diabetes mellitus.

Received for publication, January 18, 2004 , and in revised form, March 23, 2004.

^* This work was supported by grants from the NHLBI, National Institutes of Health, the Deutsche Akademie der Naturforscher Leopoldina (to P. C. S.), and the Banyu-Merck Fellowship in Cardiovascular Medicine (to T. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Cardiovascular Division, Brigham and Women's Hospital, 65 Landsdowne St., Cambridge, MA 02139. Tel.: 617-768-8272; Fax: 617-768-8270; E-mail: rlee{at}rics.bwh.harvard.edu.

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