Class II HDACs mediate CaMK-dependent signaling to NRSF in ventricular myocytes
Class II HDACs mediate CaMK-dependent signaling to NRSF in ventricular myocytes
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DOI：
10.1016/j.yjmcc.2006.08.010
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发表时间：
2006-12-01
影响因子：
5
通讯作者：
Nakao, Kazuwa
中科院分区：
文献类型：
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作者：
Nakagawa, Yasuaki;Kuwahara, Koichiro;Nakao, Kazuwa
我们最近报道，转录抑制因子神经元限制性沉默因子（NRSF）通过招募 I 类历史性脱乙酰酶（HDAC）来抑制胎儿心脏基因的表达，包括心房和脑钠肽（ANP 和 BNP），并且 NRSF 介导的抑制的减弱有助于心脏肥大期间胎儿基因表达的重新激活。然而，在心脏肥大中 NRSF-HDAC 复合物的活性受到抑制的分子机制仍未解决。在本研究中，我们发现 II 类 HDAC（HDAC4 和 5）是肥大信号的 Ca/钙调蛋白依赖性激酶 (CaMK) 反应性抑制因子，与 NRSF 相关并参与 NRSF 介导的抑制。使用 CaMK 抗性 HDAC5 突变体、CaMK 抑制剂 (KN62) 或显性失活 CaMK 突变体阻断 CaMK-II 类 HDAC 信号通路可抑制 ET-1 诱导的 ANP 和 BNP 启动子活性，但该抑制作用因 ANP 和 BNP 启动子内的神经元限制性沉默元件 (NRSE) 的突变而消除。此外，腺病毒介导的显性失活NRSF突变体的表达消除了KN62对心室肌细胞中ET-1诱导的内源ANP基因表达的抑制作用。最后，在心脏肥大的体外和体内模型中，NRSF 和 II 类 HDAC 之间的相互作用均减少。这些发现表明，ET-1 诱导的 CaMK 信号传导破坏 II 类 HDAC-NRSF 阻遏复合物，从而激活心室肌细胞中的 ANP 和 BNP 基因转录，并揭示了重新激活胎儿心脏基因程序的新机制。 (C) 2006 Elsevier Inc. 保留所有权利。
We recently reported that a transcriptional repressor, neuron-restrictive silencer factor (NRSF), represses expression of fetal cardiac genes, including atrial and brain natriuretic peptide (ANP and BNP), by recruiting class I historic deacetylase (HDAC) and that attenuation of NRSF-mediated repression contributes to the reactivation of fetal gene expression during cardiac hypertrophy. The molecular mechanism by which the activity of the NRSF-HDAC complex is inhibited in cardiac hypertrophy remains unresolved, however. In the present study, we show that class II HDACs (HDAC4 and 5), which are Ca/calmodulin-dependent kinase (CaMK)-responsive repressors of hypertrophic signaling, associate with NRSF and participate in NRSF-mediated repression. Blockade of the CaMK-class II HDAC signaling pathway using a CaMK-resistant HDAC5 mutant, a CaMK inhibitor (KN62) or a dominant-negative CaMK mutant inhibited ET-1-inducible ANP and BNP promoter activity, but that inhibitory effect was abolished by mutation of the neuron-restrictive silencer element (NRSE) within the ANP and BNP promoter. In addition, adenovirus-mediated expression of a dominant-negative NRSF mutant abolished the inhibitory effect of KN62 on ET-1-inducible endogenous ANP gene expression in ventricular myocytes. Finally, the interaction between NRSF and class II HDACs was decreased in both in vitro and in vivo models of cardiac hypertrophy. These findings show that ET-1-induced CaMK signaling disrupts class II HDAC-NRSF repressor complexes, thereby enabling activation of ANP and BNP gene transcription in ventricular myocytes, and shed light on a novel mechanism by which the fetal cardiac gene program is reactivated. (C) 2006 Elsevier Inc. All rights reserved.