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Proteomics comparison of human valve interstitial cells from healthy patients and donors with CAVD

ABSTRACT: Calcific aortic valve disease (CAVD) is an slowly progressive calcification of heart valve which leads to aortic stenosis. The only existing treatment of CAVD is surgical replacment of calcified valve - development of anti-CAVD treatment is urgent task. For better understanding of molecular mechanisms of CAVD progression we performed proteomics analysis of osteogenic differentiation of human valve interstitial cells isolated from healthy humans or patients with CAVD.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart Valve Cell

DISEASE(S): Aortic Valve Stenosis

SUBMITTER: Arseniy Lobov

LAB HEAD: Anna Malashicheva

PROVIDER: PXD032212 | Pride | 2022-10-21

REPOSITORIES: Pride

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			Action	DRS
	BT_190226_Arsenii_01.raw	Raw
	BT_190226_Arsenii_02.raw	Raw
	BT_190226_Arsenii_03.raw	Raw
	BT_190226_Arsenii_04.raw	Raw
	BT_190226_Arsenii_05.raw	Raw

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Crenigacestat inhibits osteogenic differentiation of human valve interstitial cells and seems promising for treatment of cardiovascular calcification

Project description:Vascular calcification is common pathology various forms of which presented in the half of humans. Calcific aortic valve disease (CAVD) is one of the most dangerous forms of vascular calcification. Despite high mortality there is no target therapy against CAVD. Thus, we tested crenigacestat (LY3039478), inhibitor of Notch-signaling, and shRNA against RBPJk for inhibition of osteogenic differentiation of velve intersticial cells (VICs) in vitro. Both of them effectivelly enhibited osteogenic differentiation and we performed proteomics analysis do describe molecular mechanisms of their effect. Presented dataset contain results of shotgun proteomics analysis with ion mobility in TimsToF Pro instrument (in DDA PASEF mode) of VICs in classic osteogenic medium (OM) and OM supplemented with crenigacestat, DMSO or shCSL.

2022-10-04 | PXD029632 | Pride

Comparative analysis of DDA- and DIA-PASEF methods for proteomics analysis of human valve interstitial cells and osteoblasts during osteogenic differentiation

Project description:Shotgun proteomics is one of the key "omics" methods, the methodology of which is rapidly developing. Mass spectrometers of the TimsToF series (Bruker) with ion mobility are one of the young technological platforms for shotgun proteomics in which both data dependent (DDA) and data independent acquisition (DIA) proteomics methods might be performed. However, only a few comparisons of the effectiveness of DDA and DIA proteomics on TimsToF have been published, carried out mainly on the test samples. From the other hand, peculiarities of osteogenic differentiation of human valve interstitial cells (VICs) are fruitful therapeutic target for calcific aortic valve disease (CAVD) treatment. Still, there is no data whether pathological osteogenic differentiation of VICs similar to normal ossification. Combining this technical and biological tasks we performed comparative proteomics analysis of osteogenic differentiation of human VICs and osteoblasts by DIA- and DDA-PASEF proteomics on TimsToF Pro.

2024-11-12 | PXD036566 | Pride

Aortic valve transcriptome in CHIP, non-CHIP and non-calcific controls.

Project description:The aim of the present study was to gain insights on the pathological process of Calcific Aortic Valve Disease in CHIP carriers. To uncover molecular pathways that could link CHIP to CAVD, we exanimated the aortic valve transcriptome from CHIP, non-CHIP patients, or non-calcific controls with RNAseq.

2022-08-02 | E-MTAB-11354 | biostudies-arrayexpress

Sortilin Drives Valvular Interstitial Cells to a Combined Inflammatory Myofibroblast-Osteogenic Phenotype in Calcific Aortic Valve Disease as Revealed by Single-cell Analysis

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

ApoC-III is a novel inducer of human valvular calcification

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

Expression analysis of human aortic valve interstitial cells (hAVICs), mitral valve interstitial cells(hMVICs) and dermal firbroblasts (hDFs)

Project description:Investigation of whole genome gene expression level changes in hAVICs and hMVICs, compared to human dermal fibroblasts. A three chip assay using total RNA obtained from primary cultured normal valve interstital cells and human dermal fibroblasts was performed. Each chip measures the expression level of 45,033 genes from normal AVICs,MVICs and DFs.

2013-06-30 | E-GEOD-40801 | biostudies-arrayexpress

Genome-wide transcript profiling for native porcine valvular interstitial cells and those cultured on TCPS and treated with TGF-β1

Project description:Fibrotic diseases have significant health impact and have been associated with differentiation of the resident fibroblasts into myofibroblasts. In particular, stiffened extracellular matrix and TGF-β1 in fibrotic lesions have been shown to promote pathogenic myofibroblast activation and progression of fibrosis in various tissues. To better understand the roles of mechanical and chemical cues on myofibroblast differentiation and how they may crosstalk, we cultured primary valvular interstitial cells (VICs) isolated from porcine aortic valves and studied how traditional TCPS culture, which presents a non-physiologically stiff environment, and TGF-β1 affect native VIC phenotypes. We carried out gene expression profiling using porcine genome microarrays from Affymetrix and found that traditional TCPS culture induces major changes in gene expression of native VICs, rendering these cells more activated and similar to cells treated with TGF-β1. We also monitored time-dependent effects induced by TGF-β1 by examining gene expression changes induced by TGF-β1 at 8 hours and 24 hours. Porcine aortic VICs were isolated and cultured with or without TGF-β1 treatment for RNA extraction and hybridization on Affymetrix microarrays. We included 3 biological replicates for each condition. P0 VICs were freshly isolated cells which had not been cultured. P2 VICs were cells that had been passaged 2 times and cultured on plastic plates in low serum media. Some of the P2 VICs were treated with TGF-β1 at 5ng/ml for 8 hours or 24 hours. All the control and TGF-β1-treated conditions were collected at the same time on day 3 of culture.

2013-09-02 | E-GEOD-48839 | biostudies-arrayexpress

Cardiovascular gene expression

Project description:Comparison between neonatal and adult heart valve and vascular tissue Tissue engineering of blood vessels and heart valves aims to create high quality prostheses, with preservation of their growth potential. However, the current markers used to identify the necessary cell phenotypes might not take the developmental properties of such structures into account. 4 x 3 replicates

2011-12-14 | E-GEOD-34411 | biostudies-arrayexpress

Gene expression from healthy male and female porcine aortic valve leaflets

Project description:Calcific aortic valvular disease (CAVD) is characterized by sclerosis of the aortic valve leaflets and recent clinical studies have linked several other risk factors to this disease, including male sex. In this study we examined potential sex-related differences in gene expression profiles between porcine male and female valvular interstitial cells (VICs) to explore possible differences in CAVD propensity on the cellular level. RNA samples from three male and three female healthy porcine aortic valve leaflets (denuded of endothelial cells) were isolated, processed, and hybridized to AffymetrixM-BM-. GeneChip Porcine Genome microarrays according to manufacturerM-bM-^@M-^Ys instructions. Mean expression values of each probe set in the male samples were compared with those in the female samples.

2013-01-02 | E-GEOD-33654 | biostudies-arrayexpress

Inhibitory Role of Notch1 in Calcific Aortic Valve Disease

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

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