A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway
2018
Authors: Lehmann LH, Jebessa ZH, Kreusser MM, Horsch A, He T, Kronlage M, Dewenter M, Sramek V, Oehl U, Krebs-Haupenthal J, von der Lieth AH, Schmidt A, Sun Q, Ritterhoff J, Finke D, Völkers M, Jungmann A, Sauer SW, Thiel C, Nickel A, Kohlhaas M, Schäfer M, Sticht C, Maack C, Gretz N, Wagner M, El-Armouche A, Maier LS, Londoño JEC, Meder B, Freichel M, Gröne HJ, Most P, Müller OJ, Herzig S, Furlong EEM, Katus HA, Backs J
CellNetworks People: Freichel Marc
Journal: Nat Med. 2018 Jan;24(1):62-72. doi: 10.1038/nm.4452

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.