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(Circulation Research. 2007;101:1328.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Targeted Deletion of Thioredoxin-Interacting Protein Regulates Cardiac Dysfunction in Response to Pressure Overload

Jun Yoshioka, Kenichi Imahashi, Scott A. Gabel, William A. Chutkow, Aurora A. Burds, Joseph Gannon, P. Christian Schulze, Catherine MacGillivray, Robert E. London, Elizabeth Murphy, Richard T. Lee

From the Cardiovascular Division (J.Y., W.A.C., J.G., P.C.S., C.M., R.T.L.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; the Laboratory of Signal Transduction and Laboratory of Structural Biology (K.I., S.A.G., R.E.L., E.M.), National Institute of Environmental Health Sciences, Research Triangle Park, NC; and the Center for Cancer Research (A.A.B.), Massachusetts Institute of Technology, Cambridge, Mass.

Correspondence to Richard T. Lee, MD, 65 Landsdowne Street, #279, Cambridge, MA 02139. E-mail rlee{at}partners.org

Biomechanical overload induces cardiac hypertrophy and heart failure, and reactive oxygen species (ROS) play a role in both processes. Thioredoxin-Interacting Protein (Txnip) is encoded by a mechanically-regulated gene that controls cell growth and apoptosis in part through interaction with the endogenous dithiol antioxidant thioredoxin. Here we show that Txnip is a critical regulator of the cardiac response to pressure overload. We generated inducible cardiomyocyte-specific and systemic Txnip-null mice (Txnip-KO) using Flp/frt and Cre/loxP technologies. Compared with littermate controls, Txnip-KO hearts had attenuated cardiac hypertrophy and preserved left ventricular (LV) contractile reserve through 4 weeks of pressure overload; however, the beneficial effects were not sustained and Txnip deletion ultimately led to maladaptive LV remodeling at 8 weeks of pressure overload. Interestingly, these effects of Txnip deletion on cardiac performance were not accompanied by global changes in thioredoxin activity or ROS; instead, Txnip-KO hearts had a robust increase in myocardial glucose uptake. Thus, deletion of Txnip plays an unanticipated role in myocardial energy homeostasis rather than redox regulation. These results support the emerging concept that the function of Txnip is not as a simple thioredoxin inhibitor but as a metabolic control protein.

Key Words: cardiac hypertrophy • reactive oxygen species • glucose

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