RNF130 induces aortic valve calcification by promoting SPR ubiquitinationin human valvular interstitial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Haijian Sun
PROVIDER: PXD066641 | iProX | Sun Jul 27 00:00:00 BST 2025
REPOSITORIES: iProX
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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:Arterial media calcification caused by diabetes is an important cause of vascular calcification. Dipeptidyl peptidase-4 (DPP4) is associated with diabetic arterial media calcification. At the same time, long non-coding RNA(lncRNA) is closely related to the evolution of a variety of cardiovascular diseases, but the involvement of lncRNA in vascular calcification induced by DPP4 has not been reported in details. In this study, we established a model of human aortic smooth muscle cells (HASMCs) calcification induced by DPP4. There was a significant difference in the expression of lncRNAs and mRNAs between normal and calcified vascular smooth muscle cells detected by gene chip technology. Based on the results of microarray detection, we found that lncRNA may be involved in vascular calcification induced by DPP4 through regulating target genes.
2021-12-03 | GSE189923 | 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:Cardiovascular calcification can occur in vascular and valvular structures and is commonly associated with calcium deposition and tissue mineralization leading to stiffness and dysfunction. Based on shared risk factors and end stage pathologies, calcific aortic valve disease (CAVD) and coronary artery calcification (CAC) are often considered as one disease, and similarly treated. However, the clinical conditions associated with each phenotype can be different, suggesting multifaceted pathologies. To better understand diversity in molecular and cellular processes that underlie calcification in vascular and valvular structures, we exposed aortic vascular smooth muscle cells (AVSMCs) and aortic valve interstitial cells (AVICs) to calcific stimuli including high (2.5mM) phosphate and osteogenic media (OM) treatments in vitro. Consistent with clinical observations made by others, we show that AVSMCs are more susceptible to calcification than AVICs, and this process is mediated by cell-specific and treatment-specific molecular responses. RNA-seq analysis demonstrates that in response to calcific-stimuli, both AVSMCs and AVICs activate a robust ossification-program, although the signaling pathways, cellular processes and osteogenic-associated markers involved are diverse. In addition, VIC-mediated calcification appears to involve biological processes related to osteo-chondro differentiation and down regulation of actin cytoskeleton genes, that are not observed in VSMCs. Furthermore, are findings suggest that signaling pathways involved in cardiovascular cell calcification are dependent on the calcific-stimuli, including a requirement of PI3K signaling for OM-induced calcification, and not 2.5mM Phosphate. Together, this study provides a wealth of information suggesting that the pathogenesis of cardiovascular calcifications may be significantly more diverse than previously appreciated.
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Project description:Vascular calcification is a common manifestation of atherosclerosis and involves cell-mediated processes similar to the formation of bone (osteogenesis). Elevated plasma levels of homocysteine are an independent risk factor for atherosclerotic vascular disease but the underlying mechanisms remain unclear. We postulated that hcy can modulate the cells involved in atherosclerosis to promote calcification. Cell experiments were performed to assess the effect of homocysteine on the osteogenic differentiation of aortic smooth muscle cells (AoSMC). Keywords: dose repsonse comparison To study the ability of homocysteine to induce osteogenic differentiation, AoSMC were cultured in T75 flasks (7.5x10E5 /mL) in growth medium with 0, 10 and 100 μmol/L DL-homocysteine. Four biological replicates were prepared for each condition. After 14 days, RNA was extracted from cells and the expression levels of osteogenic genes were compared between the different conditions of homocysteine concentration.
2008-10-21 | E-GEOD-9490 | biostudies-arrayexpress
Project description:To explore the miR expression profile of calcified valve interstitial cells (VICs) induced by high calcium/phosphate, identify the key miRNA in the calcification process of VICs, and probe effect of miRs in regulating valve calcification.
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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:Klotho knock-out mice are an important model for CKD-induced calcification. In CKD, serum magnesium (Mg2+) inversely correlates with vascular calcification. This study aims to determine the effects of Mg2+ on aortic calcification in Klotho knock-out mice. Klotho knock-out mice were treated with either a minimal or a high Mg2+ diet from birth. After eight weeks, serum biochemistry was studied and organs were harvested. Protective effects of Mg2+ were characterized by RNA-sequencing of aortic tissue. Micro-CT analysis was performed to study bone integrity. High Mg2+ diet prevented vascular calcification and reduced aortic gene expression of Runx2 and matrix Gla protein, demonstrating the protective effect on pro-osteogenic signaling. Differential expression of inflammation and extracellular matrix remodeling genes accompany the beneficial effects of Mg2+ on calcification. High dietary Mg2+ did not affect serum parathyroid hormone, vitamin D3 and calcium. High Mg2+ intake prevented calcification despite increasing fibroblast growth factor-23 and phosphate concentration in knock-out mice. In addition, mice on the high Mg2+ diet had a 20% reduced femoral bone mineral density and increased osteoid formation indicating osteomalacia, while osteoclast activity was decreased in Klotho knock-out mice. In Saos-2 osteoblasts, Mg2+ supplementation reduced mineralization independent of osteoblastic matrix production, alkaline phosphatase activity and maturation markers alpha-1 type-I collagen and sclerostin. In conclusion, high dietary Mg2+ prevents calcification in Klotho knock-out mice. These effects are potentially mediated by reduction of inflammatory and extracellular matrix remodeling pathways in the aorta. Mg2+ treatment is promising to prevent vascular calcification, but the risk for osteomalacia should be considered.
2019-11-04 | GSE136593 | GEO
Project description:Vascular calcification is a common manifestation of atherosclerosis and involves cell-mediated processes similar to the formation of bone (osteogenesis). Elevated plasma levels of homocysteine are an independent risk factor for atherosclerotic vascular disease but the underlying mechanisms remain unclear. We postulated that hcy can modulate the cells involved in atherosclerosis to promote calcification. Cell experiments were performed to assess the effect of homocysteine on the osteogenic differentiation of aortic smooth muscle cells (AoSMC). Keywords: dose repsonse comparison
2008-10-21 | GSE9490 | GEO
Project description:Aortic valve calcifications are often associated with calcium deposition and tissue mineralization, resulting in stiffness and dysfunction. To better understand the diversity of molecular and cellular processes for calcification in valve structures, we isolated human aortic valve interstitial cells (AVICs) and exposed them to calcification stimulation. RNA-seq revealed that in response to calcified stimuli, AVIC activates a robust ossification program, although the signaling pathways, cellular processes, and osteogenesis-related markers involved are diverse. In conclusion, this study provides a wealth of information suggesting that the pathogenesis of aortic valve calcification may be much more than previously understood.
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