A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway
A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway
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DOI：
10.1038/nm.4452
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发表时间：
2018-01-01
期刊：
影响因子：
82.9
通讯作者：
Backs, Johannes
中科院分区：
文献类型：
--
作者：
Lehmann, Lorenz H.;Jebessa, Zegeye H.;Backs, Johannes
应激反应性表观遗传阻遏物组蛋白脱乙酰酶 4 (HDAC4) 调节心脏基因表达。在这里，我们发现衰竭小鼠心脏中 HDAC4 N 端蛋白水解衍生片段（称为 HDAC4-NT）的水平低于健康对照心脏中的水平。通过病毒介导将编码 HDAC4-NT 的 Hdac4 基因部分转移到小鼠心肌中，可保护心脏免于重塑和衰竭；这与编码核孤儿受体的 Nr4a1 表达减少以及己糖胺生物合成途径 (HBP) 的 NR4A1 依赖性激活减少有关。相反，运动会增强 HDAC4-NT 水平，而心肌细胞特异性缺失 Hdac4 的小鼠则表现出运动能力下降，其特点是心脏疲劳和 Nr4a1 表达增加。从机制上讲，我们发现 NR4A1 以依赖于 HBP 和钙传感器 STIM1 的方式负向调节收缩功能。我们的工作描述了一个新的调控轴，其中代谢途径的表观遗传调控影响钙处理。在间歇性生理应激期间该轴的激活可促进心脏功能，而在持续病理性心脏应激期间该轴的损伤会导致心力衰竭。
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.