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 #
5R01HL091469-05
Application #
8206722
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2008-01-15
Project End
2013-02-28
Budget Start
2012-01-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$527,236
Indirect Cost
$189,264
Name
University of Medicine & Dentistry of NJ
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Maejima, Yasuhiro; Chen, Yun; Isobe, Mitsuaki et al. (2015) Recent progress in research on molecular mechanisms of autophagy in the heart. Am J Physiol Heart Circ Physiol 308:H259-68
Matsushima, Shouji; Tsutsui, Hiroyuki; Sadoshima, Junichi (2014) Physiological and pathological functions of NADPH oxidases during myocardial ischemia-reperfusion. Trends Cardiovasc Med 24:202-5
Yamamoto, Takanobu; Byun, Jaemin; Zhai, Peiyong et al. (2014) Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. PLoS One 9:e98972
Maejima, Yasuhiro; Sadoshima, Junichi (2014) SUMOylation: a novel protein quality control modifier in the heart. Circ Res 115:686-9
Maejima, Yasuhiro; Usui, Soichiro; Zhai, Peiyong et al. (2014) Muscle-specific RING finger 1 negatively regulates pathological cardiac hypertrophy through downregulation of calcineurin A. Circ Heart Fail 7:479-90
Sciarretta, Sebastiano; Yee, Derek; Shenoy, Varun et al. (2014) The importance of autophagy in cardioprotection. High Blood Press Cardiovasc Prev 21:21-8
Sciarretta, Sebastiano; Volpe, Massimo; Sadoshima, Junichi (2014) Mammalian target of rapamycin signaling in cardiac physiology and disease. Circ Res 114:549-64
Del Re, Dominic P; Matsuda, Takahisa; Zhai, Peiyong et al. (2014) Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL. Mol Cell 54:639-50
Shao, Dan; Oka, Shin-Ichi; Liu, Tong et al. (2014) A redox-dependent mechanism for regulation of AMPK activation by Thioredoxin1 during energy starvation. Cell Metab 19:232-45
Yu, Qiujun; Lee, Chi Fung; Wang, Wang et al. (2014) Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury. J Am Heart Assoc 3:e000555

Showing the most recent 10 out of 74 publications