Title |
A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway
|
---|---|
Published in |
Nature Medicine, December 2017
|
DOI | 10.1038/nm.4452 |
Pubmed ID | |
Authors |
Lorenz H Lehmann, Zegeye H Jebessa, Michael M Kreusser, Axel Horsch, Tao He, Mariya Kronlage, Matthias Dewenter, Viviana Sramek, Ulrike Oehl, Jutta Krebs-Haupenthal, Albert H von der Lieth, Andrea Schmidt, Qiang Sun, Julia Ritterhoff, Daniel Finke, Mirko Völkers, Andreas Jungmann, Sven W Sauer, Christian Thiel, Alexander Nickel, Michael Kohlhaas, Michaela Schäfer, Carsten Sticht, Christoph Maack, Norbert Gretz, Michael Wagner, Ali El-Armouche, Lars S Maier, Juan E Camacho Londoño, Benjamin Meder, Marc Freichel, Hermann-Josef Gröne, Patrick Most, Oliver J Müller, Stephan Herzig, Eileen E M Furlong, Hugo A Katus, Johannes Backs |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Australia | 2 | 10% |
Spain | 2 | 10% |
United States | 2 | 10% |
Germany | 1 | 5% |
France | 1 | 5% |
New Zealand | 1 | 5% |
Unknown | 12 | 57% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 12 | 57% |
Scientists | 8 | 38% |
Science communicators (journalists, bloggers, editors) | 1 | 5% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 109 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 24 | 22% |
Researcher | 13 | 12% |
Student > Bachelor | 11 | 10% |
Student > Master | 11 | 10% |
Professor | 8 | 7% |
Other | 14 | 13% |
Unknown | 28 | 26% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 27 | 25% |
Medicine and Dentistry | 23 | 21% |
Agricultural and Biological Sciences | 13 | 12% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 2% |
Physics and Astronomy | 2 | 2% |
Other | 10 | 9% |
Unknown | 32 | 29% |