Gene expression from healthy male and female porcine aortic valve leaflets
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ABSTRACT:
ORGANISM(S): Sus scrofa
PROVIDER: GSE33654 | GEO | 2013/01/02
SECONDARY ACCESSION(S): PRJNA148639
REPOSITORIES: GEO
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Project description:Calcific aortic valvular disease (CAVD) is characterized by sclerosis of the aortic valve leaflets and recent clinical studies have linked several other risk factors to this disease, including male sex. In this study we examined potential sex-related differences in gene expression profiles between porcine male and female valvular interstitial cells (VICs) to explore possible differences in CAVD propensity on the cellular level. RNA samples from three male and three female healthy porcine aortic valve leaflets (denuded of endothelial cells) were isolated, processed, and hybridized to AffymetrixM-BM-. GeneChip Porcine Genome microarrays according to manufacturerM-bM-^@M-^Ys instructions. Mean expression values of each probe set in the male samples were compared with those in the female samples.
2013-01-02 | E-GEOD-33654 | 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:Calcific aortic valve disease (CAVD) is the most common valvular heart disease in the aging population, ranging from initial aortic valve sclerosis to advanced aortic valve stenosis (AVS), but its underlying mechanism remains poorly understood. The present study aimed to explore the differentially expressed long non-coding RNAs and genes in CAVD.
2023-05-31 | GSE233819 | GEO
Project description:Purpose:To explore the the function and underlying mechanisms of basic fibroblast growth factor (BFGF) on calcific aortic valve disease (CAVD) a. Methods: The valvular interstitial cells were isolated from porcine aortic valve leaflets. To investigate the effect of BFGF on osteogenic differentiation of VICs, the osteogenic induced medium (OIM) and BFGF were added. RNA sequencing is used to identify changes in gene proffles. Results:This analysis completed the full transcriptome sequencing of 9 samples, with a total of 2 differentially expressed gene groups. The number of differentially expressed genes detected was 2526, 159. 6596 lncRNAs were identified, and the number of differentially expressed lncRNAs detected was 349,100. 6179 new circRNAs were predicted, and the number of differentially expressed circRNAs detected was 4,243. Conclusions:This study completed for the first time to the sequencing of the full transcriptome expression of valve interstitial cells under the action of BFGF, and has proved that BFGF can inhibit the calcification process of valve interstitial cells, our study suggests that bFGF has important value in the prevention and treatment of CAVD.
2023-05-01 | GSE225698 | GEO
Project description:A disease driver population within interstitial cells of human calcific aortic valves identified via single-cell and proteomic profiling Cellular heterogeneity of aortic valves complicates mechanistic evaluation of the calcification processes in calcific aortic valve disease (CAVD), and animal disease models are lacking. In this study, we identify a disease driver population (DDP) within valvular interstitial cells (VICs). Through stepwise single-cell analysis, phenotype-guided -OMIC profiling, and network-based analysis, we characterize DDP fingerprint as CD44highCD29+CD59+CD73+CD45low and discover potential key regulators of human CAVD. These DDP-VICs demonstrate multi-lineage differentiation and osteogenic properties. Temporal proteomic profiling of DDP-VICs identifies potential targets for therapy, including MAOA and CTHRC1. In vitro loss-of-function experiments confirm our targets. Such a stepwise strategy may be advantageous for therapeutic target discovery in other disease contexts.
2022-01-24 | GSE194180 | 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: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
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:Aortic valve stenosis (AVS) is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain under explored. Hydrogel scaffolds were designed to recapitulate key aspects of the valve tissue microenvironment and serve as a platform for culture of sex-specific valvular interstitial cells (VICs; precursors to pro-fibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA-seq was used to define pathways likely to be involved in driving sex-dependent activation. Interventions using small molecule inhibitors were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors. In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker, α-smooth muscle actin (α-SMA), compared to male leaflets. When isolated and cultured, female VICs had higher levels of basal α-SMA stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase (RhoA/ROCK) signaling as a potential driver of this sex-dependent myofibroblast activation. Further, we found that genes that escape X-chromosome inactivation, such as BMX and STS (encoding for Bmx non-receptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation via RhoA/ROCK signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation via RhoA/ROCK signaling. Together, in vivo and in vitro results confirm sex-dependencies in myofibroblast activation pathways, and transcriptome analyses and small molecule interventions implicate genes that escape X-chromosome inactivation in regulating sex differences in AVS progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of AVS and help guide sex-based precision therapies.
2022-05-01 | GSE174817 | 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