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

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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.