%0 Journal Article
%A Lehmann, Lorenz H
%A Jebessa, Zegeye H
%A Kreusser, Michael M
%A Horsch, Axel
%A He, Tao
%A Kronlage, Mariya
%A Dewenter, Matthias
%A Sramek, Viviana
%A Oehl, Ulrike
%A Krebs-Haupenthal, Jutta
%A von der Lieth, Albert H
%A Schmidt, Andrea
%A Sun, Qiang
%A Ritterhoff, Julia
%A Finke, Daniel
%A Völkers, Mirko
%A Jungmann, Andreas
%A Sauer, Sven W
%A Thiel, Christian
%A Nickel, Alexander
%A Kohlhaas, Michael
%A Schäfer, Michaela
%A Sticht, Carsten
%A Maack, Christoph
%A Gretz, Norbert
%A Wagner, Michael
%A El-Armouche, Ali
%A Maier, Lars S
%A Londoño, Juan E Camacho
%A Meder, Benjamin
%A Freichel, Marc
%A Gröne, Hermann-Josef
%A Most, Patrick
%A Müller, Oliver J
%A Herzig, Stephan
%A Furlong, Eileen E M
%A Katus, Hugo A
%A Backs, Johannes
%T A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway.
%J Nature medicine
%V 24
%N 1
%@ 1546-170X
%C New York, NY
%I Nature America Inc.
%M DKFZ-2018-00131
%P 62 - 72
%D 2018
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:29227474
%R 10.1038/nm.4452
%U https://inrepo02.dkfz.de/record/132443