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

神经元限制性沉默因子(NRSF)是一种转录活性很强的沉默蛋白，它与位于多种心脏胚胎基因转录调控区域的神经元限制性沉默元件(NRSE)结合。由α-MHC(α-MHC-dnNRSF-TG)驱动的过表达显性负型NRSF突变体的转基因小鼠表现出左室扩张、心功能不全和致死性室性心律失常，类似于扩张型心肌病。对α-MHC-dnNRSF-TG小鼠左心室的基因芯片分析表明，与正常对照组小鼠相比，TG小鼠的几个基因表达显著上调。其中一些，如心钠素、脑钠素、GOα、CACNA1H、神经降压素受体2和多巴胺受体2，在其5‘端印花区或内含子中含有NRSE。在急性心肌梗死或横断性主动脉带的实验性心力衰竭模型中，ANP和BNP基因表达上调，但上述其他基因的改变并不一致，提示NRSF在心力衰竭的发生发展过程中不是唯一的转录调节因子。在a-MHC控制下过表达GoA或CACNA1H的转基因小鼠表现出与野生型小鼠相似的表型。需要进一步的研究来阐明NRSF在心力衰竭发展中的重要作用。

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.