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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Acknowledgements
We thank M. Oestringer, S. Harrack and X. Qi for technical help and M. Hagenmüller for organizational help. We thank Pineda antibody service (Berlin) for production of the HDAC4-NT-specific antibody. We thank M. Sussman for providing the NR4A1-expressing adenovirus, J. Hill for providing the Stim1-D76A adenovirus and E.N. Olson for the MEF2A, MEF2C and MEF2D expression constructs. We additionally thank M.D. Schneider for providing the Myh6–Cre transgenic mice, M. Ohora (Tokyo Medical and Dental University) for providing the Stim1- and Stim2-floxed mice, and S. Offermanns (Max-Planck Institute for Heart and Lung Research, Bad Nauheim) for providing the αMHC-CreER(T2) mice. We thank U. Haberkorn and W. Mier for synthesis of DIM-C-p-PhOH. J.B. was supported by grants from the Deutsche Forschungsgemeinschaft (BA 2258/2-1 and SFB 1118), the European Commission (FP7-Health-2010 and MEDIA-261409) and the Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK; German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). L.H.L. is recipient of the Heidelberg Research Center for Molecular Medicine (HRCMM) Career Development Fellowship. S.H. received grant support from the Deutsche Forschungsgemeinschaft (He3260/8-1, He3260/7-1 and SFB1118), and the Helmholtz Cross-Program Topic Metabolic Dysfunction. M.F. received grant support from the Deutsche Forschungsgemeinschaft (SFB1118 and TR-SFB 152), the DZHK and the BMBF. C.M. is supported by the DFG (Heisenberg Programm and SFB-894). M.W. and A.E.-A. are supported by the Deutsche Forschungsgemeinschaft (EL 270/7-1 (A.E.-A.) and WA 2586/4-1 (M.W.)). J.B. is in particular grateful to E.N. Olson who contributed to the inception of this work and to the Olson lab, where J.B. continued the generation of the conditional Hdac4 KO mice; work that was started by Junyoung Oh. This work is also dedicated to the memory of Junyoung Oh.
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J.B., L.H.L. and Z.H.J. designed the study; L.H.L., Z.H.J., M.M.K., A.H., T.H., M. Kronlage, C.S., V.S., U.O., J.K.-H., J.R., D.F., A.N., M.S., A.S., Q.S., A.J., M.V., M.W., S.W.S. and J.B. performed experiments; L.H.L., Z.H.J., M.M.K., M.D., A.H.v.d.L., A.H., C.T., A.N., M. Kohlhaas, N.G., J.E.C.L., B.M., M.F., C.M., H.-J.G., S.H. and J.B. analyzed and interpreted data; L.H.L., V.S. and E.E.M.F. designed, executed and analyzed the ChIP experiments; H.A.K., E.E.M.F., M.F., M.W., A.E.-A., L.S.M., O.J.M., P.M., S.H. and J.B. provided research support and conceptual advice; L.H.L. and J.B. wrote the paper; and E.E.M.F., N.G., C.M. and H.A.K. revised the paper.
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L.H.L., Z.H.J., H.A.K. and J.B. have filed a patent on HDAC4-NT gene therapy.
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Lehmann, L., Jebessa, Z., Kreusser, M. et al. A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. Nat Med 24, 62–72 (2018). https://doi.org/10.1038/nm.4452
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DOI: https://doi.org/10.1038/nm.4452
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