Whether or not heart failure (HF) develops from compensatory hypertrophy can be determined by the balance between the cell death promoting mechanism and the cell protective mechanism. Enhancing the endogenous mechanism of cardioprotection during cardiac hypertrophy may allow us to develop strategies to prevent the development of congestive HF. Thioredoxin1 (Trx1) is a 12 kD anti-oxidant, which is expressed in the heart and upregulated in response to stresses. Our studies thus far conducted have suggested that Trx1 is a negative regulator of pathological hypertrophy, and at the same time a positive mediator of cardioprotection, thereby possessing multiple potentially beneficial functions for the heart. Anti-hypertrophic effects of Trx1 are mediated by upregulation of Dnajb5, a member of the Hsp40 family, and subsequent formation of a multi-protein complex consisting of Trx1, TBP-2, importin alpha1, Dnajb5, and class II HDACs. Our preliminary results suggest that Dnajb5 plays an essential role in mediating the anti-hypertrophic effects of Trx1. Furthermore, redox regulation of Dnajb5 and HDAC4 by Trx1 through multi-protein complex formation mediates both subcellular localization and enzyme activity of HDAC4, which represents a novel mechanism of regulation of HDAC and cardiac hypertrophy by a redox-dependent mechanism. Furthermore, Trx1 upregulates PGC-1alpha, a master key gene regulating mitochondrial genes, and that Trx1 upregulates genes involved in mitochondrial oxidative phosphorylation and the TCA cycle, thereby enhancing mitochondrial function. Thus, the goal of this project is to further delineate the molecular mechanism by which Trx1 exert its cardioprotective effects, including anti-hypertrophic and anti-apoptotic effects and the enhancement of mitochondrial function.
Specific aims are: 1) To examine whether Trx1 inhibits cardiac hypertrophy/apoptosis through redox- sensitive regulation of Dnajb5 and HDAC4 and 2) To examine whether Trx1 rescues the mitochondrial function during pathological hypertrophy through upregulation of PGC-1 alpha. Our study will establish novel redox-dependent regulation of HDAC and the signaling mechanism by which Trx1 restores mitochondrial function in the failing heart. This project has significant implications for Public Health because knowledge obtained from this study should be useful for the development of a novel treatment for HF in patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Schwartz, Lisa
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University of Medicine & Dentistry of NJ
Anatomy/Cell Biology
Schools of Medicine
United States
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Ikeda, Shohei; Mizushima, Wataru; Sciarretta, Sebastiano et al. (2018) Hippo Deficiency Leads to Cardiac Dysfunction Accompanied by Cardiomyocyte De-Differentiation During Pressure Overload. Circ Res :
Sciarretta, Sebastiano; De Falco, Elena; Frati, Giacomo et al. (2017) How to be young at heart? miR-22 as a potential therapeutic target to boost autophagy and protect the old myocardium. Ann Transl Med 5:52
Nagarajan, Narayani; Oka, Shinichi; Sadoshima, Junichi (2017) Modulation of signaling mechanisms in the heart by thioredoxin 1. Free Radic Biol Med 109:125-131
Sadoshima, Junichi (2017) Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School. Circ Res 121:1127-1129
Sadoshima, Junichi; Tomoike, Hitonobu (2017) What Should We Learn From the Recent Decline of Basic Cardiovascular Science in Japan? Circ Res 121:314-316
Oka, Shin-Ichi; Hirata, Tsuyoshi; Suzuki, Wataru et al. (2017) Thioredoxin-1 maintains mechanistic target of rapamycin (mTOR) function during oxidative stress in cardiomyocytes. J Biol Chem 292:18988-19000
Saito, Toshiro; Sadoshima, Junichi (2017) Unexpected Functional Consequences of the Loss of the Autophagy-Related Conjugation System. Circ Res 120:610-612
Mizushima, Wataru; Sadoshima, Junichi (2017) BAG3 plays a central role in proteostasis in the heart. J Clin Invest 127:2900-2903
Matsuda, Takahisa; Zhai, Peiyong; Sciarretta, Sebastiano et al. (2016) NF2 Activates Hippo Signaling and Promotes Ischemia/Reperfusion Injury in the Heart. Circ Res 119:596-606
Matsushima, Shouji; Zablocki, Daniela; Tsutsui, Hiroyuki et al. (2016) Poldip2 negatively regulates matrix synthesis at focal adhesions. J Mol Cell Cardiol 94:10-12

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