TY  - JOUR
AU  - Lehmann, Lorenz H
AU  - Jebessa, Zegeye H
AU  - Kreusser, Michael M
AU  - Horsch, Axel
AU  - He, Tao
AU  - Kronlage, Mariya
AU  - Dewenter, Matthias
AU  - Sramek, Viviana
AU  - Oehl, Ulrike
AU  - Krebs-Haupenthal, Jutta
AU  - von der Lieth, Albert H
AU  - Schmidt, Andrea
AU  - Sun, Qiang
AU  - Ritterhoff, Julia
AU  - Finke, Daniel
AU  - Völkers, Mirko
AU  - Jungmann, Andreas
AU  - Sauer, Sven W
AU  - Thiel, Christian
AU  - Nickel, Alexander
AU  - Kohlhaas, Michael
AU  - Schäfer, Michaela
AU  - Sticht, Carsten
AU  - Maack, Christoph
AU  - Gretz, Norbert
AU  - Wagner, Michael
AU  - El-Armouche, Ali
AU  - Maier, Lars S
AU  - Londoño, Juan E Camacho
AU  - Meder, Benjamin
AU  - Freichel, Marc
AU  - Gröne, Hermann-Josef
AU  - Most, Patrick
AU  - Müller, Oliver J
AU  - Herzig, Stephan
AU  - Furlong, Eileen E M
AU  - Katus, Hugo A
AU  - Backs, Johannes
TI  - A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway.
JO  - Nature medicine
VL  - 24
IS  - 1
SN  - 1546-170X
CY  - New York, NY
PB  - Nature America Inc.
M1  - DKFZ-2018-00131
SP  - 62 - 72
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29227474
DO  - DOI:10.1038/nm.4452
UR  - https://inrepo02.dkfz.de/record/132443
ER  -