Deterioration of Myocardial Energy Consumption Mechanism During the Course of Heart Failure

一种转录抑制因子，神经元限制性沉默因子（NRSF），通过募集I类组蛋白脱乙酰酶（HDAC）来抑制胎儿心脏基因（包括心房和脑钠肽（ANP和BNP））的表达，并且NRSF介导的抑制的减弱有助于心脏肥大或心力衰竭期间胎儿基因表达的重新激活。在心脏中表达显性阴性NRSF突变体（dnNRSF）的转基因小鼠表现出扩张型心肌病和猝死。总之，NRSF-HDAC阻遏物活性的调节在参与心力衰竭和猝死进展的信号传导通路中起关键作用。在这项研究中，发现II类HDAC（HDAC 4和5），这是钙/钙调蛋白依赖性激酶（CaMK）的肥大信号应答阻遏物，也与NRSF和参与NRSF介导的抑制。使用CaMK抗性突变体、CaMK抑制剂（KN 62）或显性负性CaMK突变体阻断CaMK II类HDAC信号通路抑制内皮素-1诱导的ANP启动子活性，但该抑制作用被ANP启动子内NRSE的突变所消除。此外，腺病毒介导的显性负性NRSF突变体的表达取消了KN 62对内皮素-1诱导的内源性心钠素基因表达的抑制作用。最后，NRSF和II类HDAC之间的相互作用在压力超负荷诱导的心脏肥大的小鼠模型中被破坏。

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 histone deacetylase (HDAC), and the attenuation of NRSF-mediated repression contributes to the reactivation of fetal gene expression during cardiac hypertrophy or heart failure. Transgenic mice expressing a dominant-negative NRSF mutant (dnNRSF) in their hearts exhibit dilated cardiomyopathy and sudden arrhythmic death. Taken together, the regulation of NRSF-HDAC repressor activity plays a key role in the signaling pathways involved in the progression of heart failure and sudden death. In this research, it was revealed that class II HDACs (HDAC4 and 5), which are Ca/calmodulin-dependent kinase (CaMK)-responsive repressors of hypertrophic signaling, also associate with NRSF and participate in NRSF-mediated repression. Blockade of the CaMK-class II HDAC signaling pathway using a CaMK-resistant mutant, a CaMK inhibitor (KN62) or a dominant-negative CaMK mutant inhibited endothelin-1-induced ANP promotor activity, but that inhibitory effect was abolished by mutation of the NRSE within the ANP promoter. In addition, adenovirus-mediated expression of a dominant negative NRSF mutant abolished the inhibitory effect of KN62 on endothelin-1-inducible endogenous ANP gene expression in cultured ventricular myocytes. Finally, the interaction between NRSF and class II HDACs was disrupted in a mouse model of pressure overload-induced cardiac hypertrophy.