title: NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function.
abstract: 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,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.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.forename: Makoto
authors.initials: M
authors.lastname: Takano
authors.forename: Yuji
authors.initials: Y
authors.lastname: Arai
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuno
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Nobuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Adachi
authors.forename: Genzo
authors.initials: G
authors.lastname: Takemura
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Morisaki
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kuratomi
authors.forename: Akinori
authors.initials: A
authors.lastname: Noma
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Yasunao
authors.initials: Y
authors.lastname: Yoshimasa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Rika
authors.initials: R
authors.lastname: Kawakami
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kishimoto
authors.forename: Michio
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Satoru
authors.initials: S
authors.lastname: Usami
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Saito
authors.forename: Masaki
authors.initials: M
authors.lastname: Harada
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000235:genetics; D004452:Echocardiography; D005786:Gene Expression Regulation; D006321:Heart / Q000196:embryology*; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D016276:Ventricular Function / Q000502:physiology; D000099229:RE1-Silencing Transcription Factor
chemical_list: D000199:Actins; D009320:Atrial Natriuretic Factor; D020097:Natriuretic Peptide, Brain; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor