Exploring molecular profiles of calcification in aortic vascular smooth muscle cells and aortic valvular interstitial cells
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PROVIDER: PRJNA943271 | ENA |
REPOSITORIES: ENA
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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.
2023-08-01 | GSE227131 | 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.
2024-01-03 | GSE252266 | 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:Exploring molecular profiles of osteogenically differentiated aortic valvular interstitial cells
| PRJNA1059037 | ENA
Project description:To further elucidate the molecular mechanism by which piRNA AVCAPIR drives aortic valve calcification, we performed m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with input RNA sequencing (RNA-seq) in human valvular interstitial cells with or without AVCAPIR overexpression.
2025-10-02 | GSE214629 | GEO
Project description:Calcific aortic valve disease (CAVD) involves pathological crosstalk between human valvular endothelial cells (hVECs) and interstitial cells (hVICs), yet the role of this communication in pathogenesis remains poorly defined. Here, we identify a novel extracellular vesicle-derived circRNA, CircILRUN, originating from hVECs and demonstrate its critical function in promoting hVIC osteogenesis and CAVD progression in vitro and in vivo. CircILRUN expression is significantly elevated in extracellular vesicles from hVECs under oscillatory shear stress. Its deletion markedly attenuates aortic valve calcification (AVC) in mice, reducing valve thickness, calcium deposition, and improving echocardiographic parameters, findings corroborated in osteogenic medium-induced hVICs. Through unbiased protein-RNA screening and biochemical validation, we identify N-acetyltransferase 10 (NAT10) as a key target of CircILRUN. Nat10 depletion also effectively reduces AVC in vivo. Mechanistically, CircILRUN acts as a molecular scaffold facilitating the interaction between NAT10 and the deubiquitinase USP11, thereby stabilizing NAT10 protein. Integrated transcriptomic and ac4C epitranscriptomic profiling reveals that CircILRUN promotes NAT10-mediated acetylation of CD36 mRNA, stabilizing CD36 and accelerating AVC progression. Collectively, our findings establish an extracellular vesicle-mediated circILRUN–NAT10–CD36 axis driving CAVD pathogenesis and identify both circILRUN and NAT10 as promising therapeutic targets
2025-08-26 | GSE306211 | GEO
Project description:Calcific aortic valve disease (CAVD) involves pathological crosstalk between human valvular endothelial cells (hVECs) and interstitial cells (hVICs), yet the role of this communication in pathogenesis remains poorly defined. Here, we identify a novel extracellular vesicle-derived circRNA, CircILRUN, originating from hVECs and demonstrate its critical function in promoting hVIC osteogenesis and CAVD progression in vitro and in vivo. CircILRUN expression is significantly elevated in extracellular vesicles from hVECs under oscillatory shear stress. Its deletion markedly attenuates aortic valve calcification (AVC) in mice, reducing valve thickness, calcium deposition, and improving echocardiographic parameters, findings corroborated in osteogenic medium-induced hVICs. Through unbiased protein-RNA screening and biochemical validation, we identify N-acetyltransferase 10 (NAT10) as a key target of CircILRUN. Nat10 depletion also effectively reduces AVC in vivo. Mechanistically, CircILRUN acts as a molecular scaffold facilitating the interaction between NAT10 and the deubiquitinase USP11, thereby stabilizing NAT10 protein. Integrated transcriptomic and ac4C epitranscriptomic profiling reveals that CircILRUN promotes NAT10-mediated acetylation of CD36 mRNA, stabilizing CD36 and accelerating AVC progression. Collectively, our findings establish an extracellular vesicle-mediated circILRUN–NAT10–CD36 axis driving CAVD pathogenesis and identify both circILRUN and NAT10 as promising therapeutic targets
2025-09-30 | GSE306740 | GEO
Project description:Pharmacological interventions to treat valvular calcification are not currently part of clinical guidelines. Low-density lipoprotein lowering therapies to treat calcific aortic valve disease (CAVD) failed in clinical trials. However, apolipoproteins are known promotors of atherosclerosis and may play a role in CAVD pathogenesis beyond their lipid-binding capabilities. Lipoprotein particles carry oxidized lipids that promote valvular disease, but whether apolipoproteins themselves possess pathogenic properties in CAVD is less clear. We assessed 12 apolipoproteins in non-fibrotic/non-calcific (NF/NC), fibrotic (F) and calcific (C) aortic valve tissues by proteomics and immunohistochemistry and evaluated effects of enriched apolipoproteins on calcification. Eight apolipoproteins (apoA-I, apoA-II, apoA-IV, apoB, apoC-III, apoD, apoL-I and apoM) were enriched in the C vs. NF/NC tissues. Apo(a), apoB, apoC-III, apoE and apoJ colocalized with the disease-prone fibrosa and calcific regions on histological sections. Circulating apoC-III on lipoprotein(a) was identified as a potential biomarker of aortic stenosis incidence and progression, but whether apoC-III also contributes to CAVD is unknown. ApoC-III was increased in F and C tissues and observed within the calcification-prone fibrosa layer as well as around calcification and induced calcification in primary human valvular cell cultures via a mitochondrial dysfunction/inflammation-mediated calcification pathway. This study provides the first assessment of a broad array of apolipoproteins in CAVD tissues, demonstrates that specific apolipoproteins associate with valvular calcification, and implicates apoC-III as an active, modifiable driver of CAVD beyond its potential role as a biomarker.
2020-12-14 | PXD021858 | Pride
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: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