Involvement of NRSF-mediated Transcriptional Silencing System in Molecular Mechanism of Chronic Heart Failure

神经元限制性沉默因子（Neuron Restrictive Silencer Factor，NRSF）是一种强转录沉默蛋白，与位于心脏胚胎基因转录调控区的神经元限制性沉默元件（Neuron Restrictive Silencer Element，NRSE）结合。过表达α-MHC驱动的显性阴性NRSF突变体（α-MHC-dnNRSF-Tg）的转基因小鼠表现出类似扩张型心肌病的左心室扩张、心室功能不全和致死性室性心律失常。基因芯片分析表明，与正常对照组相比，Tg小鼠左心室多个基因表达显著上调。其中包括ANP、BNP、Goα、CACNA 1H、神经降压素受体2和多巴胺受体2型等，其5'端的侧翼区或内含子含有NRSE。在急性心肌梗死或横主动脉带的实验性心力衰竭模型中，ANP和BNP基因上调，但上述其他基因的变化并不一致，表明NRSF不是心力衰竭发生的唯一转录调控因子。在α-MHC控制下过表达果阿或CACNA 1H的转基因小鼠显示出与野生型小鼠相似的表型。NRSF在心力衰竭发生发展中的重要作用有待进一步研究。

Neuron Restrictive Silencer Factor (NRSF), a strong transcriptional silencer protein, binds Neuron Restrictive Silencer Element (NRSE) that is located in the transcriptional regulating region of a number of cardiac embryonic genes. Transgenic mice overexpressing dominant negative form of NRSF mutant driven by α-MHC (α-MHC-dnNRSF-Tg) showed left ventricular dilation, ventricular dysfunction and fatal ventricular arrhythmia, which resemble dilated cardiomyopathy.The present study has investigated which genes regulated by NRSF during development of heart failure. According to the cDNA array analyses of the left ventricle of α-MHC-dnNRSF-Tg, several genes are significantly up-regulated in Tg mice compared with normal control mice. Some of them, such as ANP,BNP,Goα,CACNA1H, neurotensin receptor 2, and dopamine receptor type 2, contain NRSE in their 5' franking region or intron. In experimental heart failure model of acute myocardial infarction or transverse aortic band, ANP and BNP genes were upregulated but, other genes listed above were not uniformly altered, suggesting NRSF is not a solely transcriptional regulator in development of heart failure. Transgenic mice overexpressing either Goa or CACNA1H under control of a-MHC showed similar phenotypes to those of wild type mice. Further studies are necessary to elucidate important roles of NRSF in development of heart failure.