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Interstitial cells in calcified aortic valves have reduced differentiation potential and stem cell-like properties.

ABSTRACT: Valve interstitial cells (VICs) are crucial in the development of calcific aortic valve disease. The purpose of the present investigation was to compare the phenotype, differentiation potential and stem cell-like properties of cells from calcified and healthy aortic valves. VICs were isolated from human healthy and calcified aortic valves. Calcification was induced with osteogenic medium. Unlike VICs from healthy valves, VICs from calcified valves cultured without osteogenic medium stained positively for calcium deposits with Alizarin Red confirming their calcific phenotype. Stimulation of VICs from calcified valves with osteogenic medium increased calcification (p = 0.02), but not significantly different from healthy VICs. When stimulated with myofibroblastic medium, VICs from calcified valves had lower expression of myofibroblastic markers, measured by flow cytometry and RT-qPCR, compared to healthy VICs. Contraction of collagen gel (a measure of myofibroblastic activity) was attenuated in cells from calcified valves (p = 0.04). Moreover, VICs from calcified valves, unlike cells from healthy valves had lower potential to differentiate into adipogenic pathway and lower expression of stem cell-associated markers CD106 (p = 0.04) and aldehyde dehydrogenase (p = 0.04). In conclusion, VICs from calcified aortic have reduced multipotency compared to cells from healthy valves, which should be considered when investigating possible medical treatments of aortic valve calcification.

SUBMITTER: Bogdanova M

PROVIDER: S-EPMC6736931 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Differential gene expression in human valve interstitial cells of normal aortic valves and calcified aortic valves

Project description:Valve interstial cells(VICs) are the major cellular compents in the aortic valve. Under pathological circumstances, normal VICs differentiate into myofibroblasts or osteoblast-like phentotypes, which play important roles in the pathogenesis of calcified aortic valve disease. We used micrroarrary analysis to compare the global programme of gene expression in normal and calcified human aortic valve intersitial cells (VICs), in order to find out some key factors that mediate the phenotype change of VICs.

2016-10-23 | GSE88803 | GEO

ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells.

Project description:ObjectiveExtracellular matrix proteinases are implicated in the pathogenesis of calcific aortic valve disease. The ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) enzyme is secreted, matrix-associated metalloendopeptidase, capable of degrading extracellular matrix proteins, particularly matrilin 2. We sought to determine the role of the ADAMTS5/matrilin 2 axis in mediating the phenotype transition of valvular interstitial cells (VICs) associated with calcific aortic valve disease.Approach and resultsLevels of ADAMTS5, matrilin 2, and α-SMA (α-smooth muscle actin) were evaluated in calcified and normal human aortic valve tissues and VICs. Calcified aortic valves have reduced levels of ADAMTS5 and higher levels of matrilin 2 and α-SMA. Treatment of normal VICs with soluble matrilin 2 caused an increase in α-SMA level through Toll-like receptors 2 and 4, which was accompanied by upregulation of runt-related transcription factor 2 and alkaline phosphatase. In addition, ADAMTS5 knockdown in normal VICs enhanced the effect of matrilin 2. Matrilin 2 activated nuclear factor (NF) κB and NF of activated T cells complex 1 and induced the interaction of these 2 NFs. Inhibition of either NF-κB or NF of activated T cells complex 1 suppressed matrilin 2's effect on VIC phenotype change. Knockdown of α-SMA reduced and overexpression of α-SMA enhanced the expression of pro-osteogenic factors and calcium deposit formation in human VICs.ConclusionsMatrilin 2 induces myofibroblastic transition and elevates pro-osteogenic activity in human VICs via activation of NF-κB and NF of activated T cells complex 1. Myofibroblastic transition in human VICs is an important mechanism of elevating the pro-osteogenic activity. Matrilin 2 accumulation associated with relative ADAMTS5 deficiency may contribute to the mechanism underlying calcific aortic valve disease progression.

| S-EPMC5516888 | biostudies-literature

Altered MicroRNA Expression Is Responsible for the Pro-Osteogenic Phenotype of Interstitial Cells in Calcified Human Aortic Valves.

Project description:The transition of aortic valve interstitial cells (AVICs) to myofibroblastic and osteoblast-like phenotypes plays a critical role in calcific aortic valve disease progression. Several microRNAs (miRs) are implicated in stem cell differentiation into osteoblast. We hypothesized that an epigenetic mechanism regulates valvular pro-osteogenic activity. This study examined miR profile in AVICs of calcified valves and identified miRs responsible for AVIC phenotypic transition. AVICs were isolated from normal and diseased valves. The miR microarray analysis revealed 14 upregulated and 12 downregulated miRs in diseased AVICs. Increased miR-486 and decreased miR-204 levels were associated with higher levels of myofibroblastic biomarker α-smooth muscle actin and osteoblastic biomarkers runt-related transcription factor 2 (Runx2) and osterix (Osx). Cotransfection of miR-486 antagomir and miR-204 mimic in diseased AVICs reduced their ability to express Runx2 and Osx. The miR-486 mimic upregulated α-smooth muscle actin expression in normal AVICs through the protein kinase B pathway and moderately elevated Runx2 and Osx levels. Knockdown of α-smooth muscle actin attenuated Runx2 and Osx expression induced by miR-486. The miR-486 mimic and miR-204 antagomir synergistically promoted Runx2 and Osx expression and calcium deposition in normal AVICs and normal aortic valve tissue. In AVICs of calcified valves, increased levels of miR-486 induce myofibroblastic transition to upregulate Runx2 and Osx expression and synergize with miR-204 deficiency to elevate cellular and valvular pro-osteogenic activity. These novel findings indicate that modulation of the epigenetic mechanism underlying valvular pro-osteogenic activity has therapeutic potential for prevention of calcific aortic valve disease progression.

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Proteoglycan 4 is Increased in Human Calcified Aortic Valves and Enhances Valvular Interstitial Cell Calcification.

Project description:Aortic valve stenosis (AVS), a consequence of increased fibrosis and calcification of the aortic valve leaflets, causes progressive narrowing of the aortic valve. Proteoglycans, structural components of the aortic valve, accumulate in regions with fibrosis and moderate calcification. Particularly, proteoglycan 4 (PRG4) has been identified in fibrotic parts of aortic valves. However, the role of PRG4 in the context of AVS and aortic valve calcification has not yet been determined. Here, transcriptomics, histology, and immunohistochemistry were performed in human aortic valves from patients undergoing aortic valve replacement. Human valve interstitial cells (VICs) were used for calcification experiments and RNA expression analysis. PRG4 was significantly upregulated in thickened and calcified regions of aortic valves compared with healthy regions. In addition, mRNA levels of PRG4 positively associated with mRNA for proteins involved in cardiovascular calcification. Treatment of VICs with recombinant human PRG4 enhanced phosphate-induced calcification and increased the mRNA expression of bone morphogenetic protein 2 and the runt-related transcription factor 2. In summary, PRG4 was upregulated in the development of AVS and promoted VIC osteogenic differentiation and calcification. These results suggest that an altered valve leaflet proteoglycan composition may play a role in the progression of AVS.

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Expression of uPA, tPA, and PAI-1 in Calcified Aortic Valves.

Project description:Purpose. Our physiopathological assumption is that u-PA, t-PA, and PAI-1 are released by calcified aortic valves and play a role in the calcification of these valves. Methods. Sixty-five calcified aortic valves were collected from patients suffering from aortic stenosis. Each valve was incubated for 24 hours in culture medium. The supernatants were used to measure u-PA, t-PA, and PAI-1 concentrations; the valve calcification was evaluated using biphotonic absorptiometry. Results. Aortic stenosis valves expressed normal plasminogen activators concentrations and overexpressed PAI-1 (u-PA, t-PA, and PAI-1 mean concentrations were, resp., 1.69 ng/mL ± 0.80, 2.76 ng/mL ± 1.33, and 53.27 ng/mL ± 36.39). There was no correlation between u-PA and PAI-1 (r = 0.3) but t-PA and PAI-1 were strongly correlated with each other (r = 0.6). Overexpression of PAI-1 was proportional to the calcium content of the AS valves. Conclusions. Our results demonstrate a consistent increase of PAI-1 proportional to the calcification. The overexpression of PAI-1 may be useful as a predictive indicator in patients with aortic stenosis.

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Gene expression profile of normal and calcified stenotic human aortic valves

Project description: Not available

| S-DIXA-D-1010 | biostudies-other

Gene expression profile of normal and calcified stenotic human aortic valves

Project description:We explored gene expression profile of human aortic valves in patients with or without aortic stenosis. The dataset that we generated constitutes a large-scale quantitative measurements of gene expression in normal and stenotic human valves. The goal was to compare gene expression levels between the two groups and identified a list of genes that are up- or down-regulated in aortic stenosis. Keywords: disease state analysis Gene expression was performed on ten normal and ten aortic stenosis valves

2009-07-09 | E-GEOD-12644 | biostudies-arrayexpress

Gene expression profile of normal and calcified stenotic human aortic valves

2009-07-09 | GSE12644 | GEO

Gene expression profile of calcified bicuspid, tricuspid and normal human aortic valves

Project description:The objective of this study was to identify genes differentially expressed between calcified bicuspid aortic valves (BAV) and tricuspid valves with (TAVc) and without (TAVn) aortic valve stenosis. Ten human BAV and nine TAVc were collected from male who underwent primary aortic valve replacement. Eight TAVn were obtained from male who underwent heart transplantation. mRNA levels were measured using Illumina HumanHT-12 v4 Expression BeadChip and compared between valve groups.

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