• Left ventricular hypertrophy (LVH) is an adaptive pathological response to increased workload, stress or injury •Sustained LVH is associated with decompensation and is a major cause of cardiac disease leading to heart failure •We have identified a gene (Abra) that is acutely induced in the initial stage of pressure overloadinduced LVH, before any cardiac structural changes1 •Recent studies suggests that Abra may play a broad role in biological processes such as myogenic proliferation and differentiation, arteriogenesis and the inhibition of apoptosis •However, the molecular mechanism whereby Abra senses and responds to cardiac stress is still unclear
The most common disorder causing sudden cardiac death in young people is the cardiac disease, hypertrophic cardiomyopathy (HCM). HCM is characterised by cardiac hypertrophy (an abnormal thickening of the heart muscle) and high levels of brain and atrial natriuretic peptides (BNP and ANP). REST is an important transcriptional repressor of ANP and BNP expression and lower levels of REST in hypertrophic, compared to normal hearts, may contribute to the disease phenotype. The aim of this study was to investigate the molecular mechanisms of REST-mediated repression and its potential role in the control of hypertrophy. Inhibition of REST function resulted in an increase in ANP and BNP gene expression that correlated with increases in histone acetylation and dimethylation of H3 lysine 4 at the ANP and BNP promoters. Additionally, increasing REST expression in adult cardiomyocytes prevented increases in ANP and BNP expression by the hypertrophic agonist, endothelin-1. This data provides evidence that a therapeutic strategy aimed at augmenting REST and/or the action of its corepressors may be effective in treating cardiac hypertrophy. This work was supported by the British Heart Foundation.
In vascular injury, the mechanisms responsible for contractile smooth muscle phenotype is altered, leading to vascular smooth muscle cell (VSMC) proliferation and vascular diseases such as neointimal hyperplasia. Analysis of mouse VSMC mRNA revealed the selective upregulation of KCNA3 gene (encoding KV1.3) when the cells switch phenotype. We here provide evidence for its role in vascular proliferation. Using a linear wound assay, we show that KV1.3 blockers margatoxin and correolide compound C inhibited cell motility in both mouse and human VSMC. Furthermore KV1.3 protein is selectively localised to smooth muscle cells grown in situ as neointimal formations in human saphenous veins obtained at coronary artery bypass surgery. Application of KV1.3 blockers reduced the neointimal formation and inhibited a voltage-dependent potassium current in human VSMC. We previously showed that downregulated REST transcription factor during phenotypic switching enables KCNN4 expression (Cheong et al, 2005). Here we reveal that KCNA3 also has a REST binding site and that there is enhanced KCNA3 expression in response to dominant-negative REST mutant. These data indicate that KV1.3 is upregulated in VSMC proliferation and that existing blockers of KV1.3 might have a therapeutic role in diseases caused or exacerbated by VSMC proliferation. Funded by the BHF, MRC and Wellcome Trust.
A region with a major effect on blood pressure (BP) is located on rat chromosome 1. We have previously isolated this region in reciprocal congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and shown that there are 2 distinct BP quantitative trait loci, BP1 and BP2, in this region. Sisa1, a congenic substrain from the SHR.WKY-Sa animals carrying an introgressed segment of 4.3Mb, contains BP1. Here, we report further dissection of BP1 by the creation of 2 new mutually exclusive congenic substrains (Sisa1a and Sisa1b) and interrogation of candidate genes by expression profiling and targeted transcript sequencing. Only 1 of the substrains (Sisa1a) continued to demonstrate a BP difference but with a reduced introgressed segment of 3Mb. Exonic sequencing of the 20 genes located in the Sisa1a region did not identify any major differences between SHR and WKY. However, microarray expression profiling of whole kidney samples and subsequent quantitative RT-PCR identified a single gene, Spon1 that exhibited significant differential expression between the WKY and SHR genotypes at both 6 and 24 weeks of age. Western blot analysis confirmed an increased level of the Spon1 gene product in SHR kidneys. Spon1 belongs to a family of genes with antiangiogenic properties. These findings justify further investigation of this novel positional candidate gene in BP control in hypertensive rat models and humans.
Cardiac hypertrophy is associated with a dramatic change in the gene expression profile of cardiac myocytes. Many genes important during development of the fetal heart but repressed in the adult tissue are reexpressed, resulting in gross physiological changes that lead to arrhythmias, cardiac failure, and sudden death. One transcription factor thought to be important in repressing the expression of fetal genes in the adult heart is the transcriptional repressor REST (repressor element 1-silencing transcription factor). Although REST has been shown to repress several fetal cardiac genes and inhibition of REST function is sufficient to induce cardiac hypertrophy, the molecular mechanisms employed in this repression are not known. Here we show that continued REST expression prevents increases in the levels of the BNP (Nppb) and ANP (Nppa) genes, encoding brain and atrial natriuretic peptides, in adult rat ventricular myocytes in response to endothelin-1 and that inhibition of REST results in increased expression of these genes in H9c2 cells. Increased expression of Nppb and Nppa correlates with increased histone H4 acetylation and histone H3 lysine 4 methylation of promoter-proximal regions of these genes. Furthermore, using deletions of individual REST repression domains, we show that the combined activities of two domains of REST are required to efficiently repress transcription of the Nppb gene; however, a single repression domain is sufficient to repress the Nppa gene. These data provide some of the first insights into the molecular mechanism that may be important for the changes in gene expression profile seen in cardiac hypertrophy.
Cardiac hypertrophy is an increase in the size of cardiac myocytes to generate increased muscle mass, usually driven by increased workload for the heart. Although important during postnatal development and an adaptive response to physical exercise, excessive hypertrophy can result in heart failure. One characteristic of hypertrophy is the re-expression of genes that are normally only expressed during foetal heart development. Although the involvement of these changes in gene expression in hypertrophy has been known for some years, the mechanisms involved in this re-expression are only now being elucidated and the transcription factor REST (repressor element 1-silencing transcription factor) has been identified as an important repressor of hypertrophic gene expression.
Copy number variation has emerged recently as an important genetic mechanism leading to phenotypic heterogeneity. The aim of our study was to determine whether copy number variants (CNVs) exist between the spontaneously hypertensive rat (SHR) and its control strain, the Wistar-Kyoto rat, whether these map to quantitative trait loci in the rat and whether CNVs associate with gene expression or blood pressure differences between the 2 strains. We performed a comparative genomic hybridization assay between SHR and Wistar-Kyoto strains using a whole-genome array. In total, 16 CNVs were identified and validated (6 because of a relative loss of copy number in the SHR and 10 because of a relative gain). CNVs were present on rat autosomes 1, 3, 4, 6, 7, 10, 14, and 17 and varied in size from 10.0 kb to 1.6 Mb. Most of these CNVs mapped to chromosomal regions within previously identified quantitative trait loci, including those for blood pressure in the SHR. Transcriptomic experiments confirmed differences in the renal expression of several genes (including Ms4a6a, Ndrg3, Egln1, Cd36, Sema3a, Ugt2b, and Idi21) located in some of the CNVs between SHR and Wistar-Kyoto rats. In F(2) animals derived from an SHRxWistar-Kyoto cross, we also found a significant increase in blood pressure associated with an increase in copy number in the Egln1 gene. Our findings suggest that CNVs may play a role in the susceptibility to hypertension and related traits in the SHR.
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