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@ARTICLE{Lehmann:132443,
      author       = {L. H. Lehmann and Z. H. Jebessa and M. M. Kreusser and A.
                      Horsch and T. He and M. Kronlage and M. Dewenter and V.
                      Sramek and U. Oehl and J. Krebs-Haupenthal and A. H. von der
                      Lieth and A. Schmidt and Q. Sun and J. Ritterhoff and D.
                      Finke and M. Völkers and A. Jungmann and S. W. Sauer and C.
                      Thiel and A. Nickel and M. Kohlhaas and M. Schäfer and C.
                      Sticht and C. Maack and N. Gretz and M. Wagner and A.
                      El-Armouche and L. S. Maier and J. E. C. Londoño and B.
                      Meder and M. Freichel and H.-J. Gröne$^*$ and P. Most and
                      O. J. Müller and S. Herzig$^*$ and E. E. M. Furlong and H.
                      A. Katus and J. Backs},
      title        = {{A} proteolytic fragment of histone deacetylase 4 protects
                      the heart from failure by regulating the hexosamine
                      biosynthetic pathway.},
      journal      = {Nature medicine},
      volume       = {24},
      number       = {1},
      issn         = {1546-170X},
      address      = {New York, NY},
      publisher    = {Nature America Inc.},
      reportid     = {DKFZ-2018-00131},
      pages        = {62 - 72},
      year         = {2018},
      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.},
      cin          = {G130},
      ddc          = {610},
      cid          = {I:(DE-He78)G130-20160331},
      pnm          = {322 - Genetics and Pathophysiology (POF3-322)},
      pid          = {G:(DE-HGF)POF3-322},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29227474},
      doi          = {10.1038/nm.4452},
      url          = {https://inrepo02.dkfz.de/record/132443},
}