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

心力衰竭过程中心肌能量消耗机制的恶化

基本信息

批准号：
17590729
负责人：
HARADA Masaki
金额：
$ 2.24万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590729/
关键词：
heart failure energy consumption mitochondria NRSF PPAR

项目摘要

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.

通过募集I类组蛋白脱乙酰基酶（HDAC），以及在NRSF的衰减期间，通过招募I类组蛋白脱乙酰基酶（HDAC），通过募集I类组蛋白脱乙酰酶（HDAC）的NRSFERTIVAT在fIFTRAIN的反应术中，一种转录的压抑剂，神经限制性沉默因子（NRSF）抑制胎儿心脏基因的表达，包括心房和脑纳他蛋白肽（ANP和BNP），通过募集I类组蛋白脱乙酰酶（HDAC）的表达。失败。表达主导性NRSF突变体（DNNRSF）的转基因小鼠表现出扩张的心肌病和突然心律不齐的死亡。综上所述，NRSF-HDAC抑制剂活性的调节在涉及心力衰竭和猝死的信号传导途径中起着关键作用。在这项研究中，揭示了II类HDAC（HDAC4和5），它们是CA/CALSODULIN依赖蛋白依赖性激酶（CAMK） - 肥厚信号的反应性抑制剂，也与NRSF相关并参与NRSF介导的抑制作用。使用CAMK耐药突变体，CAMK抑制剂（KN62）或显性阴性CAMK突变体抑制CAMK级II HDAC信号通路，抑制了内皮素-1诱导的ANP启动子的活性，但是通过在ANP促进者中的NRSE突变消除了抑制作用。此外，腺病毒介导的显性负NRSF突变体的表达消除了KN62对培养的心室肌细胞中内皮素-1可诱导的内源性ANP基因表达的抑制作用。最后，在压力超负荷诱导的心肥大的小鼠模型中，NRSF和II类HDAC之间的相互作用被破坏。