NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function.
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.
Kuwahara
Koichiro
K
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Saito
Yoshihiko
Y
Takano
Makoto
M
Arai
Yuji
Y
Yasuno
Shinji
S
Nakagawa
Yasuaki
Y
Takahashi
Nobuki
N
Adachi
Yuichiro
Y
Takemura
Genzo
G
Horie
Minoru
M
Miyamoto
Yoshihiro
Y
Morisaki
Takayuki
T
Kuratomi
Shinobu
S
Noma
Akinori
A
Fujiwara
Hisayoshi
H
Yoshimasa
Yasunao
Y
Kinoshita
Hideyuki
H
Kawakami
Rika
R
Kishimoto
Ichiro
I
Nakanishi
Michio
M
Usami
Satoru
S
Saito
Yoshitomo
Y
Harada
Masaki
M
Nakao
Kazuwa
K
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
D000199:Actins; D009320:Atrial Natriuretic Factor; D020097:Natriuretic Peptide, Brain; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor