Dataset Information

Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease.

ABSTRACT: Calcific aortic valve stenosis (AS) is a life-threatening disease with no medical therapy. The genetic architecture of AS remains elusive. This study combines genome-wide association studies, gene expression, and expression quantitative trait loci mapping in human valve tissues to identify susceptibility genes of AS.A meta-analysis was performed combining the results of 2 genome-wide association studies in 474 and 486 cases from Quebec City (Canada) and Paris (France), respectively. Corresponding controls consisted of 2988 and 1864 individuals with European ancestry from the database of genotypes and phenotypes. mRNA expression levels were evaluated in 9 calcified and 8 normal aortic valves by RNA sequencing. The results were integrated with valve expression quantitative trait loci data obtained from 22 AS patients. Twenty-five single-nucleotide polymorphisms had P<5×10(-6) in the genome-wide association studies meta-analysis. The calcium signaling pathway was the top gene set enriched for genes mapped to moderately AS-associated single-nucleotide polymorphisms. Genes in this pathway were found differentially expressed in valves with and without AS. Two single-nucleotide polymorphisms located in RUNX2 (runt-related transcription factor 2), encoding an osteogenic transcription factor, demonstrated some association with AS (genome-wide association studies P=5.33×10(-5)). The mRNA expression levels of RUNX2 were upregulated in calcified valves and associated with eQTL-SNPs. CACNA1C encoding a subunit of a voltage-dependent calcium channel was upregulated in calcified valves. The eQTL-SNP with the most significant association with AS located in CACNA1C was associated with higher expression of the gene.This integrative genomic study confirmed the role of RUNX2 as a potential driver of AS and identified a new AS susceptibility gene, CACNA1C, belonging to the calcium signaling pathway.

SUBMITTER: Guauque-Olarte S

PROVIDER: S-EPMC4934886 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease.

Guauque-Olarte Sandra S Messika-Zeitoun David D Droit Arnaud A Lamontagne Maxime M Tremblay-Marchand Joël J Lavoie-Charland Emilie E Gaudreault Nathalie N Arsenault Benoit J BJ Dubé Marie-Pierre MP Tardif Jean-Claude JC Body Simon C SC Seidman Jonathan G JG Boileau Catherine C Mathieu Patrick P Pibarot Philippe P Bossé Yohan Y

Circulation. Cardiovascular genetics 20151109 6

<h4>Background</h4>Calcific aortic valve stenosis (AS) is a life-threatening disease with no medical therapy. The genetic architecture of AS remains elusive. This study combines genome-wide association studies, gene expression, and expression quantitative trait loci mapping in human valve tissues to identify susceptibility genes of AS.<h4>Methods and results</h4>A meta-analysis was performed combining the results of 2 genome-wide association studies in 474 and 486 cases from Quebec City (Canada) ...[more]

PMID: 26553695

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Project description:Background: Calcific aortic valve disease is common in the aging population and is characterized by the histological changes of the aortic valves including extracellular matrix remodeling, osteochondrogenic differentiation, and calcification. Combined, these changes lead to aortic sclerosis, aortic stenosis (AS), and eventually to heart failure. Runt-related transcription factor 2 (Runx2) is a transcription factor highly expressed in the calcified aortic valves. However, its definitive role in the progression of calcific aortic valve disease (CAVD) has not been determined. In this study, we utilized constitutive and transient conditional knockout mouse models to assess the molecular, histological, and functional changes in the aortic valve due to Runx2 depletion. Methods: Lineage tracing studies were performed to determine the provenance of the cells giving rise to Runx2+ osteochondrogenic cells in the aortic valves of LDLr-/- mice. Hyperlipidemic mice with a constitutive or temporal depletion of Runx2 in the activated valvular interstitial cells (aVICs) and sinus wall cells were further investigated. Following feeding with a diabetogenic diet, the mice were examined for changes in gene expression, blood flow dynamics, calcification, and histology. Results: The aVICs and sinus wall cells gave rise to Runx2+ osteochondrogenic cells in diseased mouse aortic valves. The conditional depletion of Runx2 in the SM22α+ aVICs and sinus wall cells led to the decreased osteochondrogenic gene expression in diabetic LDLr-/- mice. The transient conditional depletion of Runx2 in the aVICs and sinus wall cells of LDLr-/-ApoB100 CAVD mice early in disease led to a significant reduction in the aortic peak velocity, mean velocity, and mean gradient, suggesting the causal role of Runx2 on the progression of AS. Finally, the leaflet hinge and sinus wall calcification were significantly decreased in the aortic valve following the conditional and temporal Runx2 depletion, but no significant effect on the valve cusp calcification or thickness was observed. Conclusions: In the aortic valve disease, Runx2 was expressed early and was required for the osteochondrogenic differentiation of the aVICs and sinus wall cells. The transient depletion of Runx2 in the aVICs and sinus wall cells in a mouse model of CAVD with a high prevalence of hemodynamic valve dysfunction led to an improved aortic valve function. Our studies also suggest that leaflet hinge and sinus wall calcification, even in the absence of significant leaflet cusp calcification, may be sufficient to cause significant valve dysfunctions in mice.

Project description:Calcific aortic valve disease (CAVD) is a highly prevalent condition that comprises a disease continuum, ranging from microscopic changes to profound fibro-calcific leaflet remodeling, culminating in aortic stenosis, heart failure, and ultimately premature death. Ferroptosis has been hypothesized to contribute to the pathogenesis of CAVD. We aimed to study the association between ferroptosis genes and CAVD and reveal the potential roles of ferroptosis in CAVD. CAVD-related differentially expressed genes (DEGs) were identified via bioinformatic analysis of Datasets GSE51472 and GSE12644 obtained from Gene Expression Omnibus. A ferroptosis dataset containing 259 genes was obtained from the Ferroptosis Database. We then intersected with CAVD-related DEGs to identify the ferroptosis DEGs. Subsequently, protein-protein interaction networks and functional enrichment analyses were performed for ferroptosis DEGs. Then, we used miRWalk3.0 to predict the target pivotal microRNAs. An in vitro model of CAVD was constructed using human aortic valve interstitial cells. The qRT-PCR and western blotting methods were used to validate the ferroptosis DEGs identified by the microarray data. A total of 21 ferroptosis DEGs in CAVD containing 12 upregulated and nine downregulated genes were identified. The results of the Gene Set Enrichment Analysis (GSEA) and analysis of the KEGG pathway by WebGestalt indicated that the ferroptosis DEGs were enriched in six signaling pathways among which NAFLD (including IL-6, BID, and PRKAA2 genes) and HIF-1 (including IL-6, HIF-1, and HMOX1 genes) signaling pathways were also verified by DAVID and/or Metascape. Finally, the in vitro results showed that the mRNA and protein expression levels of IL-6, HIF-1α, HMOX1, and BID were higher, while the levels of PRKAA2 were lower in the Pi-treated group than those in the control group. However, the addition of ferrostatin-1 (a selective ferroptosis inhibitor) significantly reversed the above changes. Therefore, IL-6, HIF-1α, HMOX1, BID, and PRKAA2 are potential key genes closely associated with ferroptosis in CAVD. Further work is required to explore the underlying ferroptosis-related molecular mechanisms and provide possible therapeutic targets for CAVD.

Dataset Information

Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease.

Publications

Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease.

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