Unknown,Transcriptomics,Genomics,Proteomics

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RNA-seq of the atrioventricular node from a model of heart failure

ABSTRACT: Heart failure is associated with atrioventricular (AV) node dysfunction, and AV node dysfunction in the setting of heart failure is associated with an increased risk of mortality and heart failure hospitalisation. This study aims to understand the causes of AV node dysfunction in heart failure by studying changes in the whole nodal transcriptome. The mouse transverse aortic constriction model of heart failure was studied; functional changes were assessed using electrocardiography and echocardiography and the transcriptome of the AV node was quantified using RNA-seq. Heart failure was associated with a significant increase in the PR interval, indicating a slowing of AV node conduction and AV node dysfunction, and significant changes in 3,077 transcripts (5.6% of the transcriptome). Many systems were affected: transcripts supporting AV node conduction were downregulated and there were changes in transcripts identified by GWAS as determinants of the PR interval. In addition, there was evidence of remodelling of the sarcomere, a shift from fatty acid to glucose metabolism, and remodelling of the extracellular matrix. There was evidence of the causes of this widespread remodelling of the AV node: evidence of dysregulation of multiple intracellular signalling pathways, dysregulation of 109 protein kinases and 148 transcription factors, and an immune response with a proliferation of neutrophils, monocytes, macrophages and B lymphocytes and a dysregulation of 40 cytokines. In conclusion, inflammation and a widespread transcriptional remodelling of the AV node underlies AV node dysfunction in heart failure.

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Mus musculus

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PROVIDER: E-MTAB-12384 | biostudies-arrayexpress |

SECONDARY ACCESSION(S): ERP143409

REPOSITORIES: biostudies-arrayexpress

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Project description:E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells; In the study we demonstrated shared gene expression in embryonic heart valve development and Osteoblast progenitor cells. The atrioventricular (AV) valves of the heart develop from undifferentiated mesenchymal endocardial cushions, that later remodel into stratified valves with diversified extracellular matrix (ECM). Because the mature valves express genes associated with osteogenesis and exhibit disease-associated calcification, we hypothesized the existence of shared regulatory pathways active in the remodeling AV valves and in bone progenitor cells. In order to define gene regulatory programs of valvulogenesis relative to osteoblast progenitors, we undertook Affymetrix gene expression profiling analysis of murine embryonic day (E)12.5 AV cushions compared to E17.5 remodeled AV valves (mitral and tri-cuspid) and to pre-osteoblast MC3T3-E1 (subclone4) cells. Overall MC3T3 cells were significantly more similar to E17.5 valves than to E12.5 cushions, supporting the hypothesis that valve remodeling involves the expression of many genes also expressed in osteoblasts. Several transcription factors characteristic of mesenchymal and osteoblast precursor cells, including Twist1 are predominant in E12.5 cushion. Valve remodeling also includes differential regulation of matrix metalloproteinases and their inhibitors as well as characteristic collagen isoform switching. Among the most highly enriched genes during valvulogenesis were members of the small leucine-rich proteoglycan (SLRP) family including Asporin, a known negative regulator of osteoblast differentiation and mineralization. Together, these data support shared gene expression profiles of the remodeling valves and osteoblast bone precursor cells in normal valve development and homeostasis with potential functions in calcific valve disease. Experiment Overall Design: In the study, we hybridized RNA from E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells to Affymetrix MOE430 2 GeneChipÂ® arrays.

Project description:Rationale: A critical step in heart development is the coordinated formation of nodal myocardium and cushion tissue from the atrioventricular canal (AVC). After its specification, the myocardium of the AVC aligns the chambers, forms the AV node, and induces the formation of the mesenchymal AV cushions, primordia of valves and septa, while it resists working myocardial differentiation. Objective: To assess what roles Tbx2 and Tbx3, two closely related T-box transcription factors expressed in the AVC, play in these processes. Methods and Results: We analyzed mice ectopically expressing Tbx3 in the atrial myocardium by genome-wide microarray and expression analysis. We found a prominent role for Tbx3 in defining the nodal phenotype by repressing working myocardial genes (sarcomeric, mitochondrial, fast conduction) and cell proliferation regulators, and in inducing node-associated genes. Moreover, there was a striking induction of genes associated with endocardial cushions and mesenchyme. Using gain-of-function models, we found that in the developing heart both Tbx2 and Tbx3 induce ectopic Bmp2 and Tgfb2 expression and endocardial cushion formation. Analysis of compound Tbx2/Tbx3 mutant embryos revealed that upon loss of more than two functional alleles, expansion of the AV myocardium does not occur and AV cushions fail to form. Conclusions: Tbx2 and Tbx3 locally stimulate development of the AVC myocardium, induce the AV nodal phenotype therein and trigger AV cushion formation from the overlying AV endocardium, providing a mechanism for the colocalization and coordination of these two important processes in heart development. Nppa-Cre4 (Cre4) mice were crossed with CT mice to obtain efficient activation of Tbx3 in atria of double transgenic Cre4-CT mice, as previously described (Hoogaars et al., 2007). To investigate the gene expression profile of atria of Cre4-CT mice, we performed whole genome microarray analysis using Sentrix Mouse-6 oligonucleotide beadchips. We compared the atrial gene expression profiles of six male double transgenic Cre4-CT mice and six male Cre4 control mice.

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RNA-seq of the atrioventricular node from a model of heart failure

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