Localized Prox1 regulates aortic valve endothelial cell diversity and extracellular matrix stratification
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE231336 | GEO | 2023/06/29
REPOSITORIES: GEO
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Project description:Localized Prox1 regulates aortic valve endothelial cell diversity and extracellular matrix stratification
| PRJNA963866 | ENA
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:In order to analyze molecular changes in response to endothelial injury, the aortic valve in wild type mice was injured by inserting a thin anigoplasty guidewire into the mouse carotid artery and advancing the wire through the aortic valve opening. This procedure produced damage to the layer of valve endothelial cells surroung the outer edge of the valve leaflet. Sham surgery consisted of the same wire insertion prcoedure but the wire was not advanced to the level of the valve. The surgical procedure was performed in young (3-4 month old) and aging (16-18 month old) mice. Individual sham and injured aortic valves were collected 48 hours after surgery and submitted for sequencing (one valve per biological replicate).
2021-05-07 | GSE169034 | GEO
Project description:Bicuspid aortic valve is well known as a risk factor of dilation of ascending aorta. But the mechanisms of dialation are unknown. Morever, patients with bicuspid aortic valve tend to be aortic valve disease at younger age. After aortic valve surgery, if ascending aorta is dilated, the patient must be performed re-operation. For that reason, surgery for aortic root or ascending aorta is recommended to patient with bicuspid aortic valve with dilated ascending aorta. We thought that abnormality of cell cycle of the structure protein participated in ascending aorta dilation of patient with bicuspid aortic valve. We resected the wall of the ascending aota from patient undergoing aortic valve replacement for aortic valve stenosis during operation, and performed immunohistochemical staining for akt. Anti Akt antibodys were stained much on aortic media with bicuspoed aortic valve. Akt is a protein that is involved in mTOR / PI3K, and modulate the cell differenciation and proliferation. Further, the same samples were analyzed using a microarray method. On bicuspid aortic valve patients, the expression of TSC2 is reduced, and GβL is increased. TSC2 inhibit this pathway, and MLST8 activate this pathway. In the ascending aorta of BAV patients, PI3K / mTOR system is considered to be activated. When this pathway is activated, cell proliferation and cytodifferentiation are promoted abnormally,
2017-06-30 | GSE83675 | GEO
Project description:Calcific Aortic Valve Disease (CAVD) is a common heart valve condition, often characterized by severe narrowing of the aortic valve. It lacks pharmaceutical treatments and typically requires aortic valve replacement surgery, imposing a significant burden on healthcare resources.This study reports the expression profile of circRNAs in the aortic valve tissues of CAVD patients and a normal control group (non-CAVD). We collected aortic valve tissue samples from three CAVD patients who underwent aortic valve replacement surgery due to severe aortic valve stenosis, as well as aortic valve samples from non-CAVD patients who either received heart transplant surgery (recipient heart) or had their aortic valve removed due to aortic dissection. Overall, our research reveals the significant role of circRNAs in the progression of CAVD. CircRNAs, a class of circular non-coding RNA molecules, are actively studied for their functions and regulatory mechanisms within cells. 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 | GSE254393 | GEO
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
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: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 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:BackgroundSpecialized valve endothelial cell (VEC) populations are localized oriented to blood flow in developing aortic and mitral valves, but their roles in valve development and disease are unknown. In the aortic valve (AoV), a population of VECs on the fibrosa side expresses the transcription factor Prox1 together with genes found in lymphatic ECs. In this study, we examine Prox1's role in regulating a lymphatic-like gene network and promoting VEC diversity required for the development of the stratified trilaminar extracellular matrix (ECM) of murine AoV leaflets.MethodsTo determine whether disruption of Prox1 localization affects heart valve development, we generated mice (NFATc1enCre Prox1 gain-of-function) in which Prox1 is overexpressed on the ventricularis side of the AoV beginning in embryonic development. To identify potential targets of Prox1, we performed cleavage under targets and release using nuclease on wild-type and NFATc1enCre Prox1 gain-of-function AoVs with validation by colocalization in vivo using RNA in situ hybridization in NFATc1enCre Prox1 gain-of-function AoVs. Natural induction of Prox1 and target gene expression was evaluated in myxomatous AoVs in a mouse model of Marfan syndrome (Fbn1C1039G/+).ResultsThe overexpression of Prox1 is sufficient to cause enlargement of AoVs by postnatal day (P)0, as well as a decrease in ventricularis-specific gene expression and disorganized interstitial ECM layers at P7. We identified potential targets of Prox1 known to play roles in lymphatic ECs including Flt1, Efnb2, Egfl7, and Cx37. Ectopic Prox1 colocalized with induced Flt1, Efnb2, and Cx37 expression in NFATc1enCre Prox1 gain-of-function AoVs. Moreover, in Marfan syndrome myxomatous AoVs, endogenous Prox1, and its identified targets, were ectopically induced in ventricularis side VECs.ConclusionsOur results support a role for Prox1 in localized lymphatic-like gene expression on the fibrosa side of the AoV. Furthermore, localized VEC specialization is required for development of the stratified trilaminar ECM critical for AoV function and is dysregulated in congenitally malformed valves.
| S-EPMC10528305 | biostudies-literature