NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function
NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function
复制标题
DOI：
10.1093/emboj/cdg601
复制
发表时间：
2003-12-01
期刊：
影响因子：
11.4
通讯作者：
Nakao, K
中科院分区：
文献类型：
--
作者：
Kuwahara, K;Saito, Y;Nakao, K
胎儿心脏基因程序的重新激活是肥大和衰竭心脏的特征，与心脏功能受损和预后不良相关。然而，胎儿心脏基因的可逆表达的机制仍然没有得到解决。在这里，我们表明，神经元限制性沉默因子（NRSF），一种转录抑制因子，选择性地调节多个胎儿心脏基因的表达，包括心钠素，脑钠素和α-骨骼肌动蛋白，并发挥作用的分子途径，导致这些基因在心室肌细胞的重新表达。此外，在心脏中表达NRSF显性阴性突变体的转基因小鼠表现出扩张型心肌病、心律失常和猝死的高易感性。我们证明，基因编码的两个离子通道，携带胎儿心脏电流I-f和I-Ca，I-T，这是在这些小鼠中诱导的，并可能负责心功能障碍和心肌梗死，由NRSF调节。我们的研究结果表明，NRSF是一个关键的转录调控胎儿心脏基因程序，并建议NRSF在维持正常的心脏结构和功能的重要作用。
Reactivation of the fetal cardiac gene program is a characteristic feature of hypertrophied and failing hearts that correlates with impaired cardiac function and poor prognosis. However, the mechanism governing the reversible expression of fetal cardiac genes remains unresolved. Here we show that neuron-restrictive silencer factor (NRSF), a transcriptional repressor, selectively regulates expression of multiple fetal cardiac genes, including those for atrial natriuretic peptide, brain natriuretic peptide and alpha-skeletal actin, and plays a role in molecular pathways leading to the re-expression of those genes in ventricular myocytes. Moreover, transgenic mice expressing a dominant-negative mutant of NRSF in their hearts exhibit dilated cardiomyopathy, high susceptibility to arrhythmias and sudden death. We demonstrate that genes encoding two ion channels that carry the fetal cardiac currents I-f and I-Ca,I-T, which are induced in these mice and are potentially responsible for both the cardiac dysfunction and the arrhythmogenesis, are regulated by NRSF. Our results indicate NRSF to be a key transcriptional regulator of the fetal cardiac gene program and suggest an important role for NRSF in maintaining normal cardiac structure and function.