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(Circulation. 2004;109:2581-2586.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Thioredoxin-Interacting Protein Controls Cardiac Hypertrophy Through Regulation of Thioredoxin Activity

Jun Yoshioka, MD, PhD; P. Christian Schulze, MD, PhD; Mihaela Cupesi, MD; Jeremy D. Sylvan, BS; Catherine MacGillivray, AD; Joseph Gannon; Hayden Huang, PhD; Richard T. Lee, MD

From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Richard T. Lee, MD, 65 Landsdowne St, No. 279, Cambridge, MA 02139. E-mail rlee{at}rics.bwh.harvard.edu

Received September 2, 2003; de novo received December 29, 2003; accepted February 4, 2004.

Background— Although cellular redox balance plays an important role in mechanically induced cardiac hypertrophy, the mechanisms of regulation are incompletely defined. Because thioredoxin is a major intracellular antioxidant and can also regulate redox-dependent transcription, we explored the role of thioredoxin activity in mechanically overloaded cardiomyocytes in vitro and in vivo.

Methods and Results— Overexpression of thioredoxin induced protein synthesis in cardiomyocytes (127±5% of controls, P<0.01). Overexpression of thioredoxin-interacting protein (Txnip), an endogenous thioredoxin inhibitor, reduced protein synthesis in response to mechanical strain (89±5% reduction, P<0.01), phenylephrine (80±3% reduction, P<0.01), or angiotensin II (80±4% reduction, P<0.01). In vivo, myocardial thioredoxin activity increased 3.5-fold compared with sham controls after transverse aortic constriction (P<0.01). Aortic constriction did not change thioredoxin expression but reduced Txnip expression by 40% (P<0.05). Gene transfer studies showed that cells that overexpress Txnip develop less hypertrophy after aortic constriction than control cells in the same animals (28.1±5.2% reduction versus noninfected cells, P<0.01).

Conclusions— Thus, even though thioredoxin is an antioxidant, activation of thioredoxin participates in the development of pressure-overload cardiac hypertrophy, demonstrating the dual function of thioredoxin as both an antioxidant and a signaling protein. These results also support the emerging concept that the thioredoxin inhibitor Txnip is a critical regulator of biomechanical signaling.

Key Words: hypertrophy • mechanics • stress

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