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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
6R01HL091469-07
Application #
8714713
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
2008-01-15
Project End
2018-02-28
Budget Start
2013-07-01
Budget End
2014-02-28
Support Year
7
Fiscal Year
2013
Total Cost
$395,422
Indirect Cost
$146,728
Name
Rutgers University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
Matsushima, Shouji; Kuroda, Junya; Zhai, Peiyong et al. (2016) Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling. J Clin Invest 126:3403-16
Nah, Jihoon; Fernández, Álvaro F; Kitsis, Richard N et al. (2016) Does Autophagy Mediate Cardiac Myocyte Death During Stress? Circ Res 119:893-5
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
Maejima, Yasuhiro; Isobe, Mitsuaki; Sadoshima, Junichi (2016) Regulation of autophagy by Beclin 1 in the heart. J Mol Cell Cardiol 95:19-25
Shirakabe, Akihiro; Ikeda, Yoshiyuki; Sciarretta, Sebastiano et al. (2016) Aging and Autophagy in the Heart. Circ Res 118:1563-76
Nakamura, Michinari; Zhai, Peiyong; Del Re, Dominic P et al. (2016) Mst1-mediated phosphorylation of Bcl-xL is required for myocardial reperfusion injury. JCI Insight 1:
Tong, Mingming; Sadoshima, Junichi (2016) Mitochondrial autophagy in cardiomyopathy. Curr Opin Genet Dev 38:8-15
Shirakabe, Akihiro; Zhai, Peiyong; Ikeda, Yoshiyuki et al. (2016) Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure. Circulation 133:1249-63
Nagarajan, Narayani; Oka, Shinichi; Sadoshima, Junichi (2016) Modulation of signaling mechanisms in the heart by thioredoxin 1. Free Radic Biol Med :
Shirakabe, Akihiro; Zhai, Peiyong; Ikeda, Yoshiyuki et al. (2016) Response by Shirakabe et al to Letter Regarding Article, ""Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure"". Circulation 134:e75-6

Showing the most recent 10 out of 108 publications