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Lehmann, L.H.* ; Jebessa, Z.H.* ; Kreusser, M.M.* ; Horsch, A.* ; He, T.* ; Kronlage, M.* ; Dewenter, M.* ; Sramek, V.* ; Oehl, U.* ; Krebs-Haupenthal, J.* ; Von Der Lieth, A.H.* ; Schmidt, A.* ; Sun, Q.* ; Ritterhoff, J.* ; Finke, D.* ; Völkers, M.* ; Jungmann, A.* ; Sauer, S.W.* ; Thiel, C.* ; Nickel, A.* ; Kohlhaas, M.* ; Schäfer, M ; Sticht, C.* ; Maack, C.* ; Gretz, N.* ; Wagner, M.* ; El-Armouche, A.* ; Maier, L.S.* ; Londoño, J.E.C.* ; Meder, B.* ; Freichel, M.* ; Gröne, H.J.* ; Most, P.* ; Müller, O.J.* ; Herzig, S. ; Furlong, E.E.M.* ; Katus, H.A.* ; Backs, J.*

A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway.

Nat. Med. 24, 62-72 (2018)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 1078-8956
e-ISSN 1546-170X
Journal Nature medicine
Quellenangaben Volume: 24, Issue: 1, Pages: 62-72 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)