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）是一种强转录沉默蛋白，与位于许多心脏胚胎基因转录调控区的神经元限制性沉默元件（NRSE）结合。过表达α-MHC驱动的NRSF显性阴性突变体（α-MHC- dnnrsf - tg）的转基因小鼠表现出类似扩张型心肌病的左室扩张、心功能障碍和致死性室性心律失常。本研究探讨了在心力衰竭发生过程中哪些基因受NRSF调控。根据α-MHC-dnNRSF-Tg左心室cDNA阵列分析，Tg小鼠与正常对照小鼠相比，多个基因显著上调。其中一些如ANP、BNP、Goα、CACNA1H、神经紧张素受体2和多巴胺受体2在其5'区或内含子中含有NRSE。在急性心肌梗死或主动脉横带实验性心衰模型中，ANP和BNP基因上调，但上述列出的其他基因不均匀改变，提示NRSF在心衰发生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。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.