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Stanniocalcin-1 mediates aortic valve calcification via promoting osteochondrogenic differentiation from valve interstitial cells

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226781 | GEO | 2023/12/31

REPOSITORIES: GEO

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Metabolomics Characterization of Human Calcific Aortic Valve Stenosis

Project description:BACKGROUND: Calcific aortic valve stenosis (CAVS) is the most prevalent valvular heart disease in developed countries with significant morbidity and mortality. Given the poor understanding of the pathophysiological processes leading to CAVS, we utilized a joint non-targeted metabolomics and targeted lipidomics approach to better characterize the metabolic perturbations involved in its development and progression.METHODS: We collected human aortic valve tissue from 106 patients undergoing aortic valve replacement surgery. Our cohort represented aortic valvular hemodynamics from mild to severe aortic stenosis with varying degrees of valvular calcification.RESULTS: Seventy-two significantly differential (p<0.01) metabolites across different stages of CAVS severity were filtered and identified from the tissue metabolome. Each stage of valvular stenosis was characterized by a distinct metabolic signature. The top three perturbed metabolic pathways in the setting of CAVS involved glycerophospholipid metabolism, linoleic acid metabolism and primary bile acid biosynthesis. The lysophosphatidic acid species (LysoPA) exhibited significant (p<0.05) association with CAVS severity and were also found to select patients with accelerated rate of CAVS progression. Two LysoPA species namely, 18:2 LysoPA and 20:4 LysoPA, exhibited potential to serve as biomarkers of CAVS severity.CONCLUSIONS: The present study reports the largest and most comprehensive metabolomics analysis of human aortic valve stenosis that highlights the dysregulated LysoPA pathway involved in the pathogenesis of CAVS.

2020-02-03 | MTBLS1267 | MetaboLights

Expression data of human aortic valve cusps

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

Inhibitory Role of Notch1 in Calcific Aortic Valve Disease

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

Super-Enhancer-Associated Aortic Valve Stenosis Risk Locus 1p21.2 Alters NFATC2 Binding Site and Promotes Fibrogenesis [H3K27ac HiChIP]

Project description:Genome-wide association studies identified a strong signal for non coding variants at the 1p21.2 locus associated with calcific aortic valve stenosis (CAVS). Regulation at the locus and impact on the biology of the aortic valve is presently unknown. Integrative mapping of genetic association data was performed. The locus was evaluated by 3D genome mapping, analysis of atomic resolution data, DNA-binding assay and CRISPR activation (CRISPRa). Weighted gene co-expression network analysis (WGCNA) was performed to determine regulatory network in CAVS. The functional impact of the locus was assessed in isolated VICs. Fine-grained mapping at 1p21.2 risk locus identified rs6702619 as being located in open chromatin and a distant-acting super-enhancer including chromatin interaction with the promoter of PALMD in VICs. Atomic-level data showed that the risk variant modified base readout and DNA shape, which prevented the recruitment of NFATC2, a transcription factor involved in heart valve morphogenesis, and lowered the expression of PALMD. CRISPRa confirmed that rs6702619 exerts a control on the expression of PALMD. WGCNA performed in 233 calcified aortic valves identified a co-expression network encompassing PALMD, which was enriched in actin-based process. In LC-MS/MS and co-immunoprecipitation assay, actin was identified as a protein interacting with PALMD. Lower expression of PALMD in VICs promoted the polymerization of actin, the activation of myocardin-related transcription factor and fibrogenesis. Risk allele at rs6702619 disrupts a NFATC2 binding site and decreases enhancer-mediated expression of PALMD, which results in actin polymerization, a myofibroblast-like phenotype in VICs and fibrogenesis, a key underpinning process in the pathogenesis of CAVS.

2020-07-16 | GSE154512 | GEO

Super-Enhancer-Associated Aortic Valve Stenosis Risk Locus 1p21.2 Alters NFATC2 Binding Site and Promotes Fibrogenesis [ATAC-Seq]

2020-07-16 | GSE154510 | GEO

Super-Enhancer-Associated Aortic Valve Stenosis Risk Locus 1p21.2 Alters NFATC2 Binding Site and Promotes Fibrogenesis [ChIP-Seq]

2020-07-16 | GSE154511 | GEO

Sortilin Drives Valvular Interstitial Cells to a Combined Inflammatory Myofibroblast-Osteogenic Phenotype in Calcific Aortic Valve Disease as Revealed by Single-cell Analysis

Project description:Background: Calcific aortic valve disease (CAVD), the most common valve disease is comprised of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored. Methods: An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14 and 21 days; and processed for imaging, proteomics, transcriptomics and single-cell RNA sequencing (scRNA-seq). Results: The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice versus littermate controls. We identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin and p-38 MAPK signaling. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq identified 12 differentially expressed cell clusters in human VIC samples, where a novel combined inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) phenotype was detected with increased expression of SORT1, COL1A1, WNT5A, IL-6 and SAA1. VICs sequenced with sortilin deficiency showed decreased IMO-VIC phenotype. Conclusions: Sortilin promotes experimental CAVD by mediating valvular fibrosis and calcification, and newly identified phenotype (IMO-VIC). This is the first study to examine the role of sortilin in aortic valve calcification and it may render it a therapeutic target to inhibit IMO-VIC emergence by simultaneously reducing inflammation, fibrosis, and calcification, the three key pathological processes underlying CAVD.

2024-01-03 | PXD038117 | Pride

Inhibitory Role of Notch1 in Calcific Aortic Valve Disease

2011-08-26 | GSE31668 | GEO

A novel long noncoding RNA SNHG3 promotes osteoblast differentiation through BMP2 upregulation in calcific aortic valve disease

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

Single cell RNA sequencing of valvular interstitial cells and adipose derived mesenchymal stem cells

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