on May 3, 2004
Published online before print May 3, 2004, doi: 10.1161/01.CIR.0000129771.32215.44
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on September 2, 2003
From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. * To whom correspondence should be addressed. E-mail: rlee{at}rics.bwh.harvard.edu.
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.
Revised on December 29, 2003
Accepted on February 4, 2004
Thioredoxin-Interacting Protein Controls Cardiac Hypertrophy Through Regulation of Thioredoxin Activity
Jun Yoshioka MD, PhD,
Key words: hypertrophy • mechanics • stress
This article has been cited by other articles:
 |
|
 |
|
  S.-T. Pang, W.-C. Hsieh, C.-K. Chuang, C.-H. Chao, W.-H. Weng, and H.-H. Juang Thioredoxin-interacting protein: an oxidative stress-related gene is upregulated by glucose in human prostate carcinoma cells J. Mol. Endocrinol., March 1, 2009; 42(3): 205 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ebrahimian, M. R. Sairam, E. L. Schiffrin, and R. M. Touyz Cardiac hypertrophy is associated with altered thioredoxin and ASK-1 signaling in a mouse model of menopause Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1481 - H1488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Li, K. Tang, B. Xie, S. Li, and G. J. Rozanski Regulation of Kv4 channel expression in failing rat heart by the thioredoxin system Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H416 - H424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Davis Searching for Causality of Knocking Out Txnip: Is Txnip Missing in Action? Circ. Res., December 7, 2007; 101(12): 1216 - 1218. [Full Text] [PDF]
|
|
|
|
|
|
J. Yoshioka, K. Imahashi, S. A. Gabel, W. A. Chutkow, A. A. Burds, J. Gannon, P. C. Schulze, C. MacGillivray, R. E. London, E. Murphy, et al. Targeted Deletion of Thioredoxin-Interacting Protein Regulates Cardiac Dysfunction in Response to Pressure Overload Circ. Res., December 7, 2007; 101(12): 1328 - 1338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Lemmens, V. F.M. Segers, M. Demolder, M. Michiels, P. Van Cauwelaert, and G. W. De Keulenaer Endogenous inhibitors of hypertrophy in concentric versus eccentric hypertrophy Eur J Heart Fail, April 1, 2007; 9(4): 352 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K.C. Ng, J. Wu, E. Chang, B.-y. Wang, R. Katzenberg-Clark, A. Ishii-Watabe, and J. P. Cooke A Central Role for Nicotinic Cholinergic Regulation of Growth Factor-Induced Endothelial Cell Migration Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 106 - 112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Patwari, L. J. Higgins, W. A. Chutkow, J. Yoshioka, and R. T. Lee The Interaction of Thioredoxin with Txnip: EVIDENCE FOR FORMATION OF A MIXED DISULFIDE BY DISULFIDE EXCHANGE J. Biol. Chem., August 4, 2006; 281(31): 21884 - 21891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Jeong, H. Cha, E. Kim, M. Kang, D. K. Yang, J. M. Kim, P. O. Yoon, J. G. Oh, O. Y. Bernecker, S. Sakata, et al. PICOT Inhibits Cardiac Hypertrophy and Enhances Ventricular Function and Cardiomyocyte Contractility Circ. Res., August 4, 2006; 99(3): 307 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Filby, S. B. Hooper, F. Sozo, V. A. Zahra, S. J. Flecknoe, and M. J. Wallace VDUP1: a potential mediator of expansion-induced lung growth and epithelial cell differentiation in the ovine fetus Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L250 - L258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Fan, D. A. Iacobas, D. Zhou, Q. Chen, J. K. Lai, O. Gavrialov, and G. G. Haddad Gene expression and phenotypic characterization of mouse heart after chronic constant or intermittent hypoxia Physiol Genomics, August 11, 2005; 22(3): 292 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yoshioka, R. N. Prince, H. Huang, S. B. Perkins, F. U. Cruz, C. MacGillivray, D. A. Lauffenburger, and R. T. Lee Cardiomyocyte hypertrophy and degradation of connexin43 through spatially restricted autocrine/paracrine heparin-binding EGF PNAS, July 26, 2005; 102(30): 10622 - 10627. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Kuster, D. R. Pimentel, T. Adachi, Y. Ido, D. A. Brenner, R. A. Cohen, R. Liao, D. A. Siwik, and W. S. Colucci {alpha}-Adrenergic Receptor-Stimulated Hypertrophy in Adult Rat Ventricular Myocytes Is Mediated via Thioredoxin-1-Sensitive Oxidative Modification of Thiols on Ras Circulation, March 8, 2005; 111(9): 1192 - 1198. [Abstract] [Full Text] [PDF]
|
|