Journal Article

DKFZ-2018-00131

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway.

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.DKFZ* ; Most, P. ; Müller, O. J. ; Herzig, S.DKFZ* ; Furlong, E. E. M. ; Katus, H. A. ; Backs, J.

2018
Nature America Inc. New York, NY

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Please use a persistent id in citations: doi:10.1038/nm.4452

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.

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Contributing Institute(s):

1. Zelluläre und Molekulare Pathologie (G130)

Research Program(s):

1. 322 - Genetics and Pathophysiology (POF3-322) (POF3-322)

Appears in the scientific report 2018

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Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 30 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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