Aortic Valve Tissue: Stenosis vs. Sclerosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE138531 | GEO | 2019/10/08
REPOSITORIES: GEO
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Project description:Aortic valve stenosis (AVS) is a prevailing and life-threatening cardiovascular disease in adults over 75 years of age. However, the molecular mechanisms governing the pathogenesis of AVS are yet to be fully unraveled. With accumulating evidence that Wnt signaling plays a key role in the development of AVS, the involvement of intracellular Wnt molecules has become an integral study target in AVS pathogenesis. Thus, we hypothesized that the Wnt/β‐catenin pathway Wnt intracellular mediators, SFRP2, DVL2, GSK3β and β‐catenin are dysregulated in patients with AVS. Using immunohistochemistry, Real‐Time qPCR and Western blotting, we investigated the presence of SFRP2, GSK‐3β, DVL2 and β‐catenin in normal and stenotic human aortic valves. Markedly higher mRNA and protein expression of GSK‐3β, DVL2, β‐catenin and SFRP2 were found in stenotic aortic valves. This was further corroborated by observation of their abundant immunostaining, which displayed strong immunoreactivity in diseased aortic valves. Proteomic analyses of selective GSK3b inhibition in calcifying human aortic valve interstitial cells (HAVICs) revealed enrichment of proteins involved organophosphate metabolism, while reducing the activation of pathogenic biomolecular processes. Lastly, use of the potent calcification inhibitor, Fetuin A, in calcifying HAVICs significantly reduced the expression of Wnt signaling genes Wnt3a, Wnt5a, Wnt5b and Wnt11. The current findings of altered expression of canonical Wnt signaling in AVS suggest a possible role for regulatory Wnts in AVS. Hence, future studies focused on targeting these molecules are warranted to underline their role in the pathogenesis of the disease.
2021-09-09 | PXD020783 | Pride
Project description:We compared 15 severely diseased aortic valve sample to 16 control aortic valve samples using microRNA microarrays (Affymetrix GeneChip miRNA 2.0). The diseased samples were taken from areas of severe disease of aortic valves removed at aortic valve replacement for severe aortic stenosis. Control samples were obtained from macroscopically normal post-mortem aortic valves. In addition, we compared areas of mild or moderate disease on valves from participants with severe aortic stenosis to the same participant's severely diseased sample in seven participants.
2017-04-27 | E-MTAB-2766 | biostudies-arrayexpress
Project description:Managing aortic valve stenosis (AVS) is challenging because of the lack of pharmacotherapies to halt/revert stenosis, deeming aortic valve replacement (AVR) the only effective treatment. AVS management is further confronted with staggering sexual dimorphism; women display more extensive fibrosis, while men present remarkably higher valve calcification. To accelerate the development of effective and sex-personalised pharmacotherapies, deeper molecular insights are needed. Hence, we aimed to characterise AVS sexual dimorphism using proteomics. Aortic valves were obtained from surgical AVR. Disease severity was assessed by echocardiography. Fifty valves (50% women) were homogenised, and the proteins were quantified by LC-MS/MS. The relevance of differentially expressed proteins (DEPs) in sexual dimorphism was appraised using protein-protein interaction (PPI) and functional enrichment analyses (FEA). DEPs were validated using immunohistochemistry, qRT-PCR and ELISA, with the aid of 30 additional independent valves.
2025-10-13 | PXD051201 | Pride
Project description:This study aimed to characterize transcriptomic alterations in murine aortic valves following conditional deletion of Hdac3 in valvular interstitial cells. By comparing gene expression profiles between control and Hdac3-deficient valves, we aimed to identify molecular pathways regulated by HDAC3 that are crucial for maintaining aortic valve structure and function. These data provide insights into the epigenetic and metabolic mechanisms underlying non-calcific aortic valve disease.
2025-07-18 | GSE302550 | GEO
Project description:Introduction: Calcific aortic stenosis (AS) is an age-related progressive disease with increasing global prevalence. Although chronic inflammation is a key factor in its pathogenesis, the detailed immune cell profiles and their interactions with non-immune cells remain poorly understood. This study aimed to characterize the immune cell landscape in calcific AS at a single-cell level and evaluate the potential of anti-inflammatory therapy. Methods: Human aortic valve samples were obtained from four patients with non-calcified aortic regurgitation (AR) and 11 patients with AS undergoing surgical aortic valve replacement. Single-cell 3’ gene expression sequencing (scRNA-seq (3’)) was performed on CD45+ immune cells, while single-cell RNA sequencing Flex (scRNA-seq (Flex)) and bulk RNA sequencing were conducted on unsorted cells. Additionally, an anti-TNFα antibody experiment was performed in a murine AS model induced by aortic valve wire injury. Results: In myeloid cells, LYVE1 resident macrophages were significantly decreased, whereas classical monocytes expressing pro-inflammatory genes and C1Q macrophages were increased in AS valves compared to AR valves. These macrophages exhibited strong interactions with valve interstitial cells, particularly with chondrogenic subtypes expressing COMP and SPARC. Anti-TNFα treatment in the murine model significantly reduced aortic valve calcification without hematopoietic complications. Conclusions: This study is the first to integrate scRNA-seq (3’) and scRNA-seq (Flex) analyses of human aortic valves, revealing single cell-level characteristics of immune cells and their interactions with non-immune cells in calcific AS. These findings suggest that anti-inflammatory therapy could be a therapeutic target for calcific AS.
2026-03-01 | GSE291890 | GEO
Project description:This study aimed to investigate epigenetic regulation in murine aortic valves by profiling H3K27ac enrichment in control and Hdac3-deficient valves, as well as HDAC3 and phosphorylated HDAC3 (Ser424) occupancy in control valves. Using CUT&Tag, we assessed genome-wide changes in enhancer activity and HDAC3 binding to identify regulatory elements and pathways disrupted by Hdac3 deletion in valvular interstitial cells. These data provide insight into the role of HDAC3 and its phosphorylation in maintaining epigenetic homeostasis and gene expression programs critical for aortic valve integrity.
2025-07-18 | GSE302552 | GEO
Project description:Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure. Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.
2010-05-11 | GSE21771 | GEO
Project description:To examine molecular mechanisms of aortic valve stenosis in mice with hypertension and hypercholesterolemia, RNA-Seq was used during the developmental phase of stenosis to identify new gene targets.
2016-03-07 | GSE71534 | 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: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