Induction of high STAT1 expression in transgenic mice with LQTS and heart failure

Abstract

Cardiac-specific expression of the N1325S mutation of SCN5A in transgenic mouse hearts (TG-NS) resulted in long QT syndrome (LQTS), ventricular arrhythmias (VT), and heart failure. In this study we carried out oligonucleotide mircoarray analysis to identify genes that are differentially expressed in the TG-NS mouse hearts. We identified 33 genes in five different functional groups that showed differential expression. None of the 33 genes are ion channel genes. STAT1, which encodes a transcription factor involved in apoptosis and interferon response, showed the most significant difference of expression between TG-NS and control mice (a nearly 10-fold increase in expression, P = 4 × 10 −6 ). The results were further confirmed by quantitative real-time PCR and Western blot analyses. Accordingly, many interferon response genes also showed differential expression in TG-NS hearts. This study represents the first microarray analysis for LQTS and implicates STAT1 in the pathogenesis and progression of LQTS and heart failure. KeywordsCardiac sodium channel gene SCN5A mutation N1325S; Long QT syndrome (LQTS) and ventricular tachycardia; Microarray analysis; Dilated cardiomyopathy and heart failure; STAT1The long QT syndrome (LQTS) is characterized by prolongation of the QT interval and T wave abnormalities on electrocardiograms (ECG) [1,2]. LQTS is associated with symptoms including syncope, seizures and sudden death caused by a specific ventricular arrhythmia, torsade de pointes [1,2]. One of the major genes identified for LQTS is the SCN5A gene on chromosome 3p21-23 (LQT3), which accounts for 10-20% LQTS cases [2,3]. SCN5A © 2007 Elsevier Inc. All rights reserved. * Corresponding author. Address: Center for Cardiovascular Genetics/NE4-202, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA. Fax: +1 216 636 1231 wangq2@ccf.org. . Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The N1325S mutation in SCN5A is a substitution of an asparagine residue by a serine at position 1325 in the intercellular region of domain III S4-S5 of Na v 1.5, and is one of the earliest mutations identified in LQT3 families [3]. It disrupts the Na + channel inactivation and generates the late persistent I Na inward current. Overexpression of the N1325S mutation in Xenopus oocytes and HEK293 cells induced dispersed reopening in the late inactivation phase, which produced a late persistent inward sodium current [10][11][12]. We have expressed the SCN5A N1325S mutation in the mouse heart (TG-NS mice) [13]. The TG-NS transgenic mice showed prolongation of the QT in...

Identification of biomarkers for ischemic cardiomyopathy based on microarray data analysis

“…The apoptotic response to IFIT2 may contribute to other functions, including translational regulation, inhibition of tumor colonization, and protection against a lethal viral infection [47]. IFIT2 and IFIT3 are the interferon-related genes and are found to be differentially expressed in heart failure mice [48]. In this study, STAT1, IFIT2, and IFIT3 were identified as hub nodes and showed multiple interactions with other genes/proteins.…”

LQTS mutation N1325S in cardiac sodium channel gene SCN5A causes cardiomyocyte apoptosis, cardiac fibrosis and contractile dysfunction in mice

“…Although the detailed mechanism for apoptosis in TG-NS hearts is not known, activation of caspases 3 and 9, but not caspase-8, suggests that cardiomyocyte apoptosis in these mice is via the mitochondrial apoptotic pathway. An extensive microarray study revealed that expression of STAT1 was markedly increased in TG-NS hearts[23] and such an increase may contribute to increased cardiomyocyte apoptosis[24]. Furthermore, we showed that compared to TG-WTL10 mice, expression of L-type Ca 2+ channel, RYR2, and NCX was increased in TG-NS mice (Fig.…”

Microarray Analysis in Cardiac Arrhythmias: A New Perspective?

“…Wu et al using the transgenic mice with SCN5A N1325S mutation in the mouse heart (TG‐NS), a mouse model for LQTS, studied global gene expression reprogramming in these mice. Differentially expressed genes between TG‐NS and nontransgenic control mice were determined using mouse oligonucleotide microarrays with 22,690 unique transcripts . Researchers reported a large number of genes with altered expression between these two types of mice.…”

“…At P value of 10 −4 , there were 11 differentially expressed genes with fold change values more than 5: nine were activated and two were inhibited (9↑, 2↓). At P value of 10 −3 , there were 33 differentially expressed (31↑, 2↓) genes with ≥ 5‐fold . When the cut off was set to twofold, the number of genes increased to 14 at P ≤ 10 −4 and 65 at P ≤ 10 −3 .…”

“…Finally, in TG‐NS mice, 31 genes were found to be activated and two genes were inhibited. These genes were classified into five functional groups: 11 genes were associated with interferon‐responses, four genes were involved in inflammation and apoptosis, four genes mediated other immune responses, four genes encoded enzymes, and there was a group of 11 genes with yet unknown function …”