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000132443 0247_ $$2doi$$a10.1038/nm.4452
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000132443 0247_ $$2ISSN$$a1546-170X
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000132443 037__ $$aDKFZ-2018-00131
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000132443 1001_ $$aLehmann, Lorenz H$$b0
000132443 245__ $$aA proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway.
000132443 260__ $$aNew York, NY$$bNature America Inc.$$c2018
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000132443 520__ $$aThe 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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000132443 7001_ $$aJebessa, Zegeye H$$b1
000132443 7001_ $$aKreusser, Michael M$$b2
000132443 7001_ $$aHorsch, Axel$$b3
000132443 7001_ $$aHe, Tao$$b4
000132443 7001_ $$aKronlage, Mariya$$b5
000132443 7001_ $$aDewenter, Matthias$$b6
000132443 7001_ $$aSramek, Viviana$$b7
000132443 7001_ $$aOehl, Ulrike$$b8
000132443 7001_ $$aKrebs-Haupenthal, Jutta$$b9
000132443 7001_ $$avon der Lieth, Albert H$$b10
000132443 7001_ $$aSchmidt, Andrea$$b11
000132443 7001_ $$aSun, Qiang$$b12
000132443 7001_ $$aRitterhoff, Julia$$b13
000132443 7001_ $$aFinke, Daniel$$b14
000132443 7001_ $$aVölkers, Mirko$$b15
000132443 7001_ $$aJungmann, Andreas$$b16
000132443 7001_ $$aSauer, Sven W$$b17
000132443 7001_ $$aThiel, Christian$$b18
000132443 7001_ $$aNickel, Alexander$$b19
000132443 7001_ $$aKohlhaas, Michael$$b20
000132443 7001_ $$aSchäfer, Michaela$$b21
000132443 7001_ $$aSticht, Carsten$$b22
000132443 7001_ $$aMaack, Christoph$$b23
000132443 7001_ $$aGretz, Norbert$$b24
000132443 7001_ $$aWagner, Michael$$b25
000132443 7001_ $$aEl-Armouche, Ali$$b26
000132443 7001_ $$aMaier, Lars S$$b27
000132443 7001_ $$aLondoño, Juan E Camacho$$b28
000132443 7001_ $$aMeder, Benjamin$$b29
000132443 7001_ $$aFreichel, Marc$$b30
000132443 7001_ $$0P:(DE-He78)00a2ea610aee4a8fca32908fc3d02e91$$aGröne, Hermann-Josef$$b31$$udkfz
000132443 7001_ $$aMost, Patrick$$b32
000132443 7001_ $$00000-0001-8223-2638$$aMüller, Oliver J$$b33
000132443 7001_ $$0P:(DE-He78)e527f794b23172e769c8904180546f57$$aHerzig, Stephan$$b34$$udkfz
000132443 7001_ $$00000-0002-9544-8339$$aFurlong, Eileen E M$$b35
000132443 7001_ $$aKatus, Hugo A$$b36
000132443 7001_ $$00000-0002-2322-2699$$aBacks, Johannes$$b37
000132443 773__ $$0PERI:(DE-600)1484517-9$$a10.1038/nm.4452$$gVol. 24, no. 1, p. 62 - 72$$n1$$p62 - 72$$tNature medicine$$v24$$x1546-170X$$y2018
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