Toll-like receptor 3 mediates calcific aortic valve disease via a conserved mechanism of calcification
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA926670 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23195664_1.fastq.gz | Fastqsanger.gz | |||
| SRR23195664_2.fastq.gz | Fastqsanger.gz | |||
| SRR23195665_1.fastq.gz | Fastqsanger.gz | |||
| SRR23195665_2.fastq.gz | Fastqsanger.gz | |||
| SRR23195666_1.fastq.gz | Fastqsanger.gz |
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Project description:Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of expression Sox9 has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism. 3 samples of aortic valve interstitial cells treated with DAPT were compared with 3 samples of aortic valve interstitial cells treated with DMSO
2011-08-25 | E-GEOD-31668 | biostudies-arrayexpress
Project description:Calcification of the aortic valve leads to increased leaflet stiffness resulting in development of calcific aortic valve disease (CAVD); however, the underlying molecular and cellular mechanisms of calcification are poorly understood. Here, we investigated gene expressions in relation to valvular calcification and promotion of CAVD progression.
2016-01-28 | GSE77287 | GEO
Project description:Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of expression Sox9 has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism.
2011-08-26 | GSE31668 | GEO
Project description:Although calcific aortic valve stenosis (CAVS) is the most prevalent valvular heart disease, the molecular mechanisms underlying aortic valve calcification remain unknown. Here, we found a significant elevation in stanniocalcin-1 (STC1) expression in the valve interstitial cells (VICs) of calcific aortic valves by combined analysis of our comprehensive gene expression data and microarray datasets reported previously. Immunohistochemical staining showed that STC1 was located around the calcific area in the aortic valves of patients with CAVS. In vitro experiments using inhibitors and siRNA targeting osteoblast differentiation signaling revealed that activation of the Akt/STC1 axis was essential for runt-related transcription factor 2 (RUNX2) induction in the VICs. RNA sequencing and bioinformatics analysis of STC1-knocked down VICs in osteoblast differentiation medium resulted in silencing of the induction of osteoarthritis signaling-related genes, including RUNX2 and COL10A1. STC1 depletion in the murine CAVS model improved aortic valve dysfunction with high peak velocity and valve thickening and suppressed the appearance of osteochondrocytes. STC1-deficient mice also exhibited complete calcification abolishment, although partial valve thickening by aortic valve injury was observed. Our findings suggest that STC1 may be a critical factor in determining valve calcification and a novel target for preventing the transition to severe CAVS with calcification. We analyzed the gene expression profiles of the valve interstitial cells (VICs) isolated from noncalcific and calcific areas in calcific aortic valve stenosis (CAVS) donors using a gene microarray.
2023-12-31 | GSE226781 | GEO
Project description:We report transcriptional profiles of aortic valve tissue from calcific aortic valve disease (CAVD) and normal control (non-CAVD). We collected the aortic valve tissues from five patients with CAVD who underwent aortic valve replacement due to severe aortic valve stenosis. Aortic valve samples from patients with non-calcified aortic valve resection due to heart transplantation (recipient heart) or aortic dissection were collected as the control (non-CAVD). The inclusion criteria for CAVD group were as follows: 50-75 years old; undergoing aortic valve replacement due to severe AVS with significantly valvular calcification. The inclusion criteria for non-CAVD group were as follows: non-calcified aortic valve resection due to heart transplantation (recipient heart) or aortic dissection. For each sample, total RNA was extracted, a cDNA library was generated, and an Illumina NovaSeq 6000 was used to sequence each sample. Stringtie software was used to count the fragment within each gene, and TMM algorithm was used for normalization. Differential expression analysis was performed using R package edgeR. Differentially expressed RNAs with |log2(FC)| value >1, q value [false discovery rate (FDR) adjusted P-value] <0.05, and one group’s mean fragments per kilobase of exon per million reads mapped (FPKM) >1, were assigned as differentially-expressed genes (DEGs).
2023-06-28 | GSE235995 | GEO
Project description:Toll-like receptor 3 mediates calcific aortic valve disease via a conserved mechanism of calcification
| PRJNA575565 | ENA
Project description:Calcific aortic valve disease is the most common form of valvular heart disease in the Western World. Milder degrees of aortic valve calcification is called aortic sclerosis and severe calcification with impaired leaflet motion is called aortic stenosis. We used microarrays to detail the global programme of gene expression underlying cdevelopment of calcified aortic valve disease in humans.
2015-10-01 | GSE51472 | GEO
Project description:The aim of the present study was to gain insights on the pathological process of Calcific Aortic Valve Disease in CHIP carriers. To uncover molecular pathways that could link CHIP to CAVD, we exanimated the aortic valve transcriptome from CHIP, non-CHIP patients, or non-calcific controls with RNAseq.
2022-08-02 | E-MTAB-11354 | biostudies-arrayexpress
Project description:Calcific aortic valve disease (CAVD) is a common heart valve disease, yet its underlying mechanism remains pooly understood. We aimed to explore the microRNAs funtion in CAVD and to develop novel miRNA therapy for CAVD.
2019-10-10 | GSE87885 | GEO
Project description:The role of long noncoding RNAs (lncRNAs) in calcific aortic valve disease (CAVD) remains largely elusive. This study aims to report a novel therapeutic lncRNA, SNHG3, and elucidate its role in CAVD. Based on high-throughput transcriptomic sequencing of human aortic valves, SNHG3 is among the most highly expressed lncRNAs in CAVD. Furthermore, SNHG3 upregulation is verified in human calcified aortic valves, osteoblastic human aortic valve interstitial cells (hVICs), and aortic valve tissues in CAVD mice. Moreover, knockdown of SNHG3 with antisense oligonucleotide markedly ameliorates aortic valve calcification in high cholesterol diet-treated ApoE-/- mice, as evidenced by reduced calcium deposition in the aortic valve leaflets, improved echocardiographic parameters, and decreased osteogenic differentiation markers (RUNX2, osteopontin, and osteocalcin) in aortic valves. Consistent with these in vivo findings, SNHG3 overexpression aggravates the calcification of hVICs, while knockdown of SNHG3 alleviates the process of differential calcification. Transcriptomics sequencing, gene set enrichment analyses, RNA-pull down, RNA immunoprecipitation and chromatin immunoprecipitation-qPCR show that SNHG3 physically interacts with polycomb repressive complex 2 to suppress the H3K27 tri-methylation BMP2 locus, which in turn activates BMP2 expression and signaling pathways. Taken together, SNHG3 promotes aortic valve calcification by upregulating BMP2, which might be a novel therapeutic target in human CAVD.
2022-10-01 | GSE199718 | GEO