Shear Stress and NOTCH1 Regulate Calcification Related Genes in Human Aortic Valve Endothelium (ChIP-Seq)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE47152 | GEO | 2015/05/16
SECONDARY ACCESSION(S): PRJNA204502
REPOSITORIES: GEO
Similar Datasets
Project description:We are interested in the role of NOTCH1 and Shear Stress in Aortic Valve Endothelium. Primary human aortic valve endothelium was subjected to 4 conditions in vitro. 1) Control siRNA, No shear stress. 2) NOTCH1 siRNA, No shear stress. 3) Control siRNA, 15 dynes/cm2 shear stress. 4) NOTCH1 siRNA, 15 dynes/cm2 shear stress. Triplicates of each condition were pooled for library perp and sequencing
2015-05-16 | E-GEOD-47157 | biostudies-arrayexpress
Project description:We are interested in the role of NOTCH1 and Shear Stress in Aortic Valve Endothelium.
2015-05-16 | GSE47157 | GEO
Project description:Porcine aortic and aortic valve endothelial cells were exposed to 20 dynes/cm2 steady laminar shear stress with static cultures serving as controls. Total RNA was hybridized to Agilent Human 1 cDNA arrays and processed using the Agilent Feature Extraction Software Keywords = aortic valve Keywords = endothelial Keywords = shear stress Keywords: other
2005-07-30 | GSE1637 | 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:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-05-16 | E-GEOD-47160 | biostudies-arrayexpress
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:This SuperSeries is composed of the SubSeries listed below.
2015-05-16 | GSE47160 | 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: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:Continuous-flow left ventricular assist devices commonly lead to aortic regurgitation, which results in decreased pump efficiency and worsening heart failure. We hypothesized that non-physiological wall shear stress and oscillatory shear index alter the abundance of structural proteins in aortic valves of left ventricular assist device (LVAD) patients. Doppler images of aortic valves of patients undergoing heart transplants were obtained. Eight patients had been supported with LVADs, whereas 10 were not. Aortic valve tissue was collected and protein levels were analyzed using mass spectrometry. Echocardiographic images were analyzed and wall shear stress and oscillatory shear index were calculated. The relationship between normalized levels of individual proteins and in vivo echocardiographic measurements was evaluated. Of the 57 proteins of interest, there was a strong negative correlation between levels of 15 proteins and the wall shear stress (R < -0.500, p ? 0.05), and a moderate negative correlation between 16 proteins and wall shear stress (R ?0.500 to ?0.300, p ? 0.05). Gene ontology analysis demonstrated clusters of proteins involved in cellular structure. Proteins negatively correlated with WSS included those with cytoskeletal, actin/myosin, cell-cell junction and extracellular functions. In aortic valve tissue, 31 proteins were identified involved in cellular structure and extracellular junctions with a negative correlation between their levels and wall shear stress. These findings suggest an association between the forces acting on the aortic valve (AV) and leaflet protein abundance, and may form a mechanical basis for the increased risk of aortic leaflet degeneration in LVAD patients.
2021-02-23 | MSV000086941 | MassIVE