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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.

SUBMITTER: Kuwahara K

PROVIDER: S-EPMC291842 | biostudies-literature | 2003 Dec

REPOSITORIES: biostudies-literature

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NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function.

Kuwahara Koichiro K 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

The EMBO journal 20031201 23

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 natriureti ...[more]

PMID: 14633990

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Project description:Subclinical hypothyroidism and low T3 syndrome are commonly associated with an increased risk of cardiovascular disease (CVD) and mortality. We examined effects of T3 on T-tubule (TT) structures, Ca2+ mobilization and contractility, and clustering of dyadic proteins. Thyroid hormone (TH) deficiency was induced in adult female rats by propyl-thiouracil (PTU; 0.025%) treatment for 8 weeks. Rats were then randomized to continued PTU or triiodo-L-thyronine (T3; 10 μg/kg/d) treatment for 2 weeks (PTU + T3). After in vivo echocardiographic and hemodynamic recordings, cardiomyocytes (CM) were isolated to record Ca2+ transients and contractility. TT organization was assessed by confocal microscopy, and STORM images were captured to measure ryanodine receptor (RyR2) cluster number and size, and L-type Ca2+ channel (LTCC, Cav1.2) co-localization. Expressed genes including two integral TT proteins, junctophilin-2 (Jph-2) and bridging integrator-1 (BIN1), were analyzed in left ventricular (LV) tissues and cultured CM using qPCR and RNA sequencing. The T3 dosage used normalized serum T3, and reversed adverse effects of TH deficiency on in vivo measures of cardiac function. Recordings of isolated CM indicated that T3 increased rates of Ca2+ release and re-uptake, resulting in increased velocities of sarcomere shortening and re-lengthening. TT periodicity was significantly decreased, with reduced transverse tubules but increased longitudinal tubules in TH-deficient CMs and LV tissue, and these structures were normalized by T3 treatment. Analysis of STORM data of PTU myocytes showed decreased RyR2 cluster numbers and RyR localizations within each cluster without significant changes in Cav1.2 localizations within RyR clusters. T3 treatment normalized RyR2 cluster size and number. qPCR and RNAseq analyses of LV and cultured CM showed that Jph2 expression was T3-responsive, and its increase with treatment may explain improved TT organization and RyR-LTCC coupling.

Project description:BackgroundThe study of fetal heart is receiving increasing attention. Fetal heart quantification (Fetal HQ) technology is a new speckle tracking technology that can analyze the 24-segment morphology and function of fetal ventricles. This study aims to use Fetal HQ to assess the changes in the structure and function of the fetal heart in normal mid to late pregnancy, providing a foundation for the clinical application of fetal cardiac speckle tracking technology.MethodsThe heart size, global sphericity index (GSI), left ventricular [stroke volume (SV)], cardiac output (CO), ejection fraction (EF), global longitudinal strain (GLS), fractional area change (FAC), 24-segment end-diastolic diameter (EDD), sphericity index (SI) and fractional shortening (FS) of the two ventricles of 500 normal pregnant fetuses were evaluated by Fetal HQ. The subjects were divided into 5 groups according to gestational weeks (GA), and the changes of fetal heart morphology and function were observed. P<0.05 indicated the statistically significant difference.ResultsThe fetal heart rate decreased gradually with the increase of GA (P<0.05). The size parameters of the fetal heart and two ventricles gradually increased with increasing GA (P<0.05). The 24 segments EDD of both ventricles increased with increasing GA (P<0.05), while the EDD increased first and then decreased from the ventricle base to the apex. The GSI and the 24 segments SI of two ventricles were basically not significantly different among the groups (P>0.05). The EF, GLS, FAC of the left ventricle and the GLS, FAC of the right ventricle decreased with the increase of GA (P<0.05), and SV and CO increased with increasing GA (P<0.05). The 24 segments FS of the left ventricle showed a downward trend with the increase of GA and gradually increased from the base to the apex. The FS of most segments of the right ventricle decreased with the increase of the GA and increased first and then decreased from the base to the apex.ConclusionsThe whole and segmental size parameters of fetal heart can quantitatively evaluate the growth and development of fetal heart; the GSI and segmental SI are reliable morphological indexes for evaluating fetal heart; fetal ventricular function parameters EF, FAC, GLS and segmental FS can evaluate fetal cardiac function. The Fetal HQ technique can help us to evaluate the heart growth and development of normal fetuses in the second and third trimester of pregnancy.

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NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function.

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NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function.

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