Microbiota exploring in CAVD: the potential fil rouge from aortic valve calcification to infiltrating bacteria
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ABSTRACT:
PROVIDER: PRJNA835844 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19123151_1.fastq.gz | Fastqsanger.gz | |||
| SRR19123151_2.fastq.gz | Fastqsanger.gz | |||
| SRR19123152_1.fastq.gz | Fastqsanger.gz | |||
| SRR19123152_2.fastq.gz | Fastqsanger.gz | |||
| SRR19123153_1.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Sex differences in aortic valve stenosis (AVS) progression have been documented clinically, but the underlying cellular mechanisms that drive sex-dependent calcification in aortic valve tissue remain poorly understood. Here, we harnessed single cell and spatial transcriptomics to investigate mechanisms that drive sex dependent spatial organization of valvular interstitial cell (VIC) and macrophage gene expression near calcification sites in human male and female aortic valve tissue. Histological analyses of aortic valve tissues stratified into healthy and diseased cohorts based on degree of calcification reveal increased valve calcification area in diseased male aortic valves relative to female, and increased valve thickening in diseased female aortic valves. Single cell sequencing analysis of heterogeneous valvular interstitial cell (VIC) populations reveals male-dependent gene expression of the Activator Protein 1 (AP-1) transcription factor complex. Spatial transcriptomics and RNA-FISH analyses of VIC populations near sites of calcification revealed male-dependent gene expression localization of Cartilage Oligomeric Matrix Protein (COMP), as opposed to diffuse COMP expression in female VICs. Cell-cell communication analyses were used to determine female-specific macrophage-VIC interactions. Secreted phosphoprotein 1 (also known as osteopontin) expressed from macrophages interacts with the cell surface receptor CD44 expressed by VICs to drive a pro-fibrotic phenotype in female aortic valves. Together, our results reveal sex differences in VIC and macrophage heterogeneity and functions near sites of calcification in aortic valve tissue. Our results highlight the importance of sex-based transcriptomics analyses to understand the cellular phenotypes responsible for causing sex differences in aortic valve fibrosis calcification.
2026-06-03 | GSE306288 | GEO
Project description:The study of the RNF130 gene induces valve calcification in HVIC, which correlates the proteome
2025-07-28 | PXD066642 |
Project description:Aortic valve calcification is a significant and serious clinical problem for which there are no effective medical treatments. Individuals born with bicuspid aortic valves, 1-2% of the population, are at the highest risk of developing aortic valve calcification. Aortic valve calcification involves increased levels of calcification and inflammatory genes. Bicuspid aortic valve leaflets experience increased strain. The molecular mechanisms involved in the pathogenesis of calcification of BAVs are not well understood, especially the molecular response to mechanical stretch. HOTAIR is a long non-coding RNA (lncRNA) that has been implicated with cancer but has not been studied in cardiac disease. We have found that HOTAIR levels are decreased in BAVs and in human aortic interstitial cells (AVICs) exposed to cyclic stretch. Reducing HOTAIR levels via siRNA in AVICs results in increased expression of calcification genes.
2014-05-02 | E-MTAB-2409 | biostudies-arrayexpress
Project description:Aortic valve calcific disease (CAVD) is a common heart valve condition typically characterized by severe narrowing of the aortic valve. Our previous research has shown that circHIPK3 is downregulated in calcified aortic valve tissues and plays a role in regulating the progression of CAVD. To further investigate how circHIPK3 exerts its inhibitory effects on aortic valve calcification, we overexpressed circHIPK3 in aortic valve interstitial cells and conducted RNA-seq analysis, revealing that circHIPK3 regulates key factors in the Wnt signaling pathway. These findings contribute to a deeper understanding of the molecular mechanisms underlying CAVD, particularly the potential involvement of circRNAs in this disease.
2024-02-02 | GSE254394 | GEO
Project description:Calcific aortic valve disease (CAVD) is an increasingly prevalent condition and endothelial dysfunction is implicated in its etiology. We previously identified nitric oxide (NO) as a calcification inhibitor by its activation of NOTCH1, which is genetically linked to human CAVD. Here, we show that NO rescues calcification by a S-nitrosylation-mediated mechanism in porcine aortic valve interstitial cells (pAVICs) and single cell RNA-seq demonstrated regulation of NOTCH pathway by NO. A unbiased proteomic approach to identify S-nitrosylated proteins in valve cells found enrichment of the ubiquitin proteasome pathway and implicated S-nitrosylation of USP9X in NOTCH regulation during calcification. Furthermore, S-nitrosylated USP9X was shown to deubiquitinate and stabilize MIB1 for NOTCH1 activation. Consistent with this, genetic deletion of Usp9x in mice demonstrated aortic valve disease and human calcified aortic valves displayed reduced S-nitrosylation of USP9X. These results demonstrate a novel mechanism by which S-nitrosylation dependent regulation of ubiquitin-associated pathway prevents CAVD.
2020-12-22 | GSE161123 | 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. 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:Calcific aortic valve disease (CAVD) is a leading cause of cardiovascular morbidity and mortality with no effective medical therapy. We previously identified carnitine O-octanoyltransferase (CROT) as a mediator of mitochondrial dysfunction and vascular calcification. However, its role in CAVD remains unexplored. Here, we investigate whether CROT contributes to CAVD progression by promoting the release of pro-calcific mitochondria-derived extracellular vesicles (mitoEVs). Methods and Results: Human valvular interstitial cells (VICs) were isolated from aortic valves obtained from patients with aortic stenosis (AS; n=34 donors). VICs were cultured in osteogenic medium (OM) to induce calcification, which was evaluated by Alizarin Red staining. Proteomic analysis was performed to identify differentially abundant proteins between VICs cultured in normal medium (NM) and OM, with the goal of elucidating mechanisms linking CROT to VIC calcification. Mitochondrial function was assessed using the Seahorse XF Analyzer to measure oxygen consumption rate (OCR), and mitochondrial morphology was examined by MitoTracker staining. Extracellular vesicles (EVs) were isolated from VIC-conditioned media by ultracentrifugation and characterized for particle size and concentration using NanoSight Pro. In vivo, AS was induced in C57BL/6J, Ldlr⁻/⁻ Crot (Sham, n=12), Ldlr-/- Crot+/+ (Aortic valve wire injury; AVWI, n=19) and Ldlr-/- Crot-/- (AVWI, n=23). Disease progression was monitored by echocardiography, and aortic valve calcification was visualized using OsteoSense 680EX near-infrared fluorescence-based molecular imaging. OM–induced calcification in VICs was reduced by siRNA-mediated CROT silencing (siCROT; p<0.05). Proteomic analysis revealed that mitochondrial-associated proteins were markedly altered following siCROT silencing. Examination of mitochondrial morphology showed that OM culture induced marked mitochondrial fragmentation, which was restored by siCROT treatment. Western blotting and flow cytometry analyses indicated that OM-induced mitochondrial fragmentation promotes the release of mitoEVs from VICs, which in turn contributes to calcification. Immunofluorescence revealed mitoEVs within the extracellular space, colocalizing with calcification. In vivo, CROT deficiency attenuated the progression of AS in AVWI mouse model by reducing valvular calcification. Conclusion: Osteogenic stimulation disrupts mitochondrial dynamics in VICs, promoting the release of pro-calcific mitoEVs. This study identifies CROT as a key regulator of this process, where CROT inhibition restores mitochondrial homeostasis and suppresses VIC calcification. These findings highlight CROT as a promising therapeutic target for the treatment of CAVD.
2026-05-13 | PXD072508 | Pride
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