Lehmann, Lorenz H. and Jebessa, Zegeye H. and Kreusser, Michael M. and Horsch, Axel and He, Tao and Kronlage, Mariya and Dewenter, Matthias and Sramek, Viviana and Oehl, Ulrike and Krebs-Haupenthal, Jutta and von der Lieth, Albert H. and Schmidt, Andrea and Sun, Qiang and Ritterhoff, Julia and Finke, Daniel and Voelkers, Mirko and Jungmann, Andreas and Sauer, Sven W. and Thiel, Christian and Nickel, Alexander and Kohlhaas, Michael and Schaefer, Michaela and Sticht, Carsten and Maack, Christoph and Gretz, Norbert and Wagner, Michael and El-Armouche, Ali and Maier, Lars S. and Londono, Juan E. Camacho and Meder, Benjamin and Freichel, Marc and Groene, Hermann-Josef and Most, Patrick and Mueller, Oliver J. and Herzig, Stephan and Furlong, Eileen E. M. and Katus, Hugo A. and Backs, Johannes (2018) A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. NATURE MEDICINE, 24 (1). 62-+. ISSN 1078-8956, 1546-170X
Full text not available from this repository. (Request a copy)Abstract
The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | STROMAL INTERACTION MOLECULE-1; CAM KINASE-II; PATHOLOGICAL CARDIAC-HYPERTROPHY; LINKED N-ACETYLGLUCOSAMINE; OPERATED CALCIUM-ENTRY; NEONATAL CARDIOMYOCYTES; PRESSURE-OVERLOAD; O-GLCNAC; TRANSCRIPTION FACTORS; CONTRACTILE FUNCTION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Mar 2020 12:00 |
| Last Modified: | 23 Mar 2020 12:00 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15281 |
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