Journal
NATURE MEDICINE
Volume 24, Issue 1, Pages 62-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4452
Keywords
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Funding
- Deutsche Forschungsgemeinschaft [BA 2258/2-1, SFB 1118, He3260/8-1, He3260/7-1, SFB1118, TR-SFB 152, EL 270/7-1, WA 2586/4-1]
- European Commission [MEDIA-261409]
- Deutsches Zentrum fur Herz-Kreislauf-Forschung (DZHK
- German Centre for Cardiovascular Research)
- BMBF (German Ministry of Education and Research)
- Heidelberg Research Center for Molecular Medicine (HRCMM) Career Development Fellowship
- Helmholtz Cross-Program Topic Metabolic Dysfunction
- DZHK
- BMBF
- DFG (Heisenberg Programm) [SFB-894]
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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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