scholarly journals Asporin Reduces Adult Aortic Valve Interstitial Cell Mineralization Induced by Osteogenic Media and Wnt Signaling Manipulation In Vitro

2020 ◽  
Vol 2020 ◽  
pp. 1-19
Author(s):  
Anisha Polley ◽  
Riffat Khanam ◽  
Arunima Sengupta ◽  
Santanu Chakraborty
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Interstitial Cell ◽  
Valve Disease ◽  
Periodontal Ligament Cells ◽  
Calcific Aortic Valve Disease ◽  
Disease Manifestation ◽  
Regulatory Pathways ◽  
Replacement Surgery

Worldwide, calcific aortic valve disease is one of the leading causes of morbidity and mortality among patients with cardiac abnormalities. Aortic valve mineralization and calcification are the key events of adult calcific aortic valve disease manifestation and functional insufficiency. Due to heavy mineralization and calcification, adult aortic valvular cusps show disorganized and dispersed stratification concomitant with deposition of calcific nodules with severely compromised adult valve function. Interestingly, shared gene regulatory pathways are identified between bone-forming cells and heart valve cells during development. Asporin, a small leucine-rich proteoglycan (43 kDa), acts to inhibit mineralization in periodontal ligament cells and is also detected in normal murine adult aortic valve leaflets with unknown function. Therefore, to understand the Asporin function in aortic cusp mineralization and calcification, adult avian aortic valvular interstitial cell culture system is established and osteogenesis has been induced in these cells successfully. Upon induction of osteogenesis, reduced expression of Asporin mRNA and increased expression of bone and osteogenesis markers are detected compared to cells maintained without osteogenic induction. Importantly, treatment with human recombinant Asporin protein reduces the mineralization level in osteogenic media-induced aortic valvular interstitial cells with the concomitant decreased level of Wnt/β-catenin signaling. Overall, all these data are highly indicative that Asporin might be a novel biomolecular target to treat patients of calcific aortic valve disease over current cusp replacement surgery.

scholarly journals Creation of disease-inspired biomaterial environments to mimic pathological events in early calcific aortic valve disease

2017 ◽  
Vol 115 (3) ◽  
pp. E363-E371 ◽  
Author(s):  
Ana M. Porras ◽  
Jennifer A. Westlund ◽  
Austin D. Evans ◽  
Kristyn S. Masters
Keyword(s):  
Aortic Valve ◽  
Disease Progression ◽  
Aortic Valve Disease ◽  
Low Density Lipoprotein ◽  
Treatment Strategies ◽  
Density Lipoprotein ◽  
Valve Disease ◽  
Calcific Aortic Valve Disease ◽  
Valve Lesion

An insufficient understanding of calcific aortic valve disease (CAVD) pathogenesis remains a major obstacle in developing treatment strategies for this disease. The aim of the present study was to create engineered environments that mimic the earliest known features of CAVD and apply this in vitro platform to decipher relationships relevant to early valve lesion pathobiology. Glycosaminoglycan (GAG) enrichment is a dominant hallmark of early CAVD, but culture of valvular interstitial cells (VICs) in biomaterial environments containing pathological amounts of hyaluronic acid (HA) or chondroitin sulfate (CS) did not directly increase indicators of disease progression such as VIC activation or inflammatory cytokine production. However, HA-enriched matrices increased production of vascular endothelial growth factor (VEGF), while matrices displaying pathological levels of CS were effective at retaining lipoproteins, whose deposition is also found in early CAVD. Retained oxidized low-density lipoprotein (oxLDL), in turn, stimulated myofibroblastic VIC differentiation and secretion of numerous inflammatory cytokines. OxLDL also increased VIC deposition of GAGs, thereby creating a positive feedback loop to further enrich GAG content and promote disease progression. Using this disease-inspired in vitro platform, we were able to model a complex, multistep pathological sequence, with our findings suggesting distinct roles for individual GAGs in outcomes related to valve lesion progression, as well as key differences in cell–lipoprotein interactions compared with atherosclerosis. We propose a pathogenesis cascade that may be relevant to understanding early CAVD and envision the extension of such models to investigate other tissue pathologies or test pharmacological treatments.

scholarly journals Simulating early calcific aortic valve disease within novel in vitro 3D tissue platform

2013 ◽  
Vol 34 (suppl 1) ◽  
pp. P3908-P3908 ◽  
Author(s):  
J. Hjortnaes ◽  
G. Gamci-Unal ◽  
C. Goettsch ◽  
K. Scherer ◽  
L. Lax ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
Calcific Aortic Valve Disease

scholarly journals 16 Investigating calcific aortic valve disease using novel immortalised sheep and rat valve interstitial cell lines

1997 ◽  
Author(s):  
Hiu-Gwen Tsang ◽  
Lin Cui ◽  
Colin Farquharson ◽  
Brendan M Corcoran ◽  
Kim M Summers ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Cell Lines ◽  
Aortic Valve Disease ◽  
Interstitial Cell ◽  
Valve Disease ◽  
Calcific Aortic Valve Disease

scholarly journals Reproducible In Vitro Tissue Culture Model to Study Basic Mechanisms of Calcific Aortic Valve Disease: Comparative Analysis to Valvular Interstitials Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 474
Author(s):  
Andreas Weber ◽  
Melissa Pfaff ◽  
Friederike Schöttler ◽  
Vera Schmidt ◽  
Artur Lichtenberg ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
Natural Conditions ◽  
Calcific Aortic Valve Disease ◽  
Culture Model ◽  
3D Environments ◽  
Tissue Culture Model

The hallmarks of calcific aortic valve disease (CAVD), an active and regulated process involving the creation of calcium nodules, lipoprotein accumulation, and chronic inflammation, are the significant changes that occur in the composition, organization, and mechanical properties of the extracellular matrix (ECM) of the aortic valve (AV). Most research regarding CAVD is based on experiments using two-dimensional (2D) cell culture or artificially created three-dimensional (3D) environments of valvular interstitial cells (VICs). Because the valvular ECM has a powerful influence in regulating pathological events, we developed an in vitro AV tissue culture model, which is more closely able to mimic natural conditions to study cellular responses underlying CAVD. AV leaflets, isolated from the hearts of 6–8-month-old sheep, were fixed with needles on silicon rubber rings to achieve passive tension and treated in vitro under pro-degenerative and pro-calcifying conditions. The degeneration of AV leaflets progressed over time, commencing with the first visible calcified domains after 14 d and winding up with the distinct formation of calcium nodules, heightened stiffness, and clear disruption of the ECM after 56 d. Both the expression of pro-degenerative genes and the myofibroblastic differentiation of VICs were altered in AV leaflets compared to that in VIC cultures. In this study, we have established an easily applicable, reproducible, and cost-effective in vitro AV tissue culture model to study pathological mechanisms underlying CAVD. The valvular ECM and realistic VIC–VEC interactions mimic natural conditions more closely than VIC cultures or 3D environments. The application of various culture conditions enables the examination of different pathological mechanisms underlying CAVD and could lead to a better understanding of the molecular mechanisms that lead to VIC degeneration and AS. Our model provides a valuable tool to study the complex pathobiology of CAVD and can be used to identify potential therapeutic targets for slowing disease progression.

scholarly journals Cellular and molecular mechanisms of calcific aortic valve disease

2019 ◽  
pp. 86-91
Author(s):  
E. V. Shcheglova ◽  
M. Kh. Baykulova ◽  
O. I. Boeva
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Molecular Mechanisms ◽  
Current Data ◽  
Valve Disease ◽  
Ectopic Calcification ◽  
Calcific Aortic Valve Disease ◽  
Initiation Phase ◽  
Replacement Surgery ◽  
Leading Role

The review provides current data on the pathogenesis of calcific aortic valve disease (CAVD) — a widespread disease with unfavorable prognosis. Currently, there are no effective therapeutic methods for the prevention and treatment of this pathology with the exception of valve replacement surgery. The role of genetic and hereditary factors in the occurrence of CAVD is considered, the leading pathogenetic mechanisms are described taking into account the stage of the disease. In particular, in the initiation phase of calcification, deposition of oxidized lipoproteins in the cusps and local inflammation plays the leading role. In the progression phase, active ectopic calcification dominates, similar to the process of bone formation. The study of the pathogenesis of CAVD seems appropriate taking into account the prospect of developing new effective therapeutic and prophylactic approaches.

scholarly journals Calcific Aortic Valve Disease: Molecular Mechanisms And Therapeutic Approaches

2015 ◽  
Vol 10 (2) ◽  
pp. 108 ◽  
Author(s):  
Daniel Alejandro Lerman ◽  
Sai Prasad ◽  
Nasri Alotti ◽  
◽  
◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Molecular Mechanisms ◽  
Cell Model ◽  
Human Monoclonal Antibody ◽  
Valve Disease ◽  
Vascular Lesions ◽  
Calcium Deposition ◽  
Calcific Aortic Valve Disease

Calcification occurs in atherosclerotic vascular lesions and in the aortic valve. Calcific aortic valve disease (CAVD) is a slow, progressive disorder that ranges from mild valve thickening without obstruction of blood flow, termed aortic sclerosis, to severe calcification with impaired leaflet motion, termed aortic stenosis. In the past, this process was thought to be ‘degenerative’ because of time-dependent wear and tear of the leaflets, with passive calcium deposition. The presence of osteoblasts in atherosclerotic vascular lesions and in CAVD implies that calcification is an active, regulated process akin to atherosclerosis, with lipoprotein deposition and chronic inflammation. If calcification is active, via pro-osteogenic pathways, one might expect that development and progression of calcification could be inhibited. The overlap in the clinical factors associated with calcific valve disease and atherosclerosis provides further support for a shared disease mechanism. In our recent research we used an in vitro porcine valve interstitial cell model to study spontaneous calcification and potential promoters and inhibitors. Using this model, we found that denosumab, a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand may, at a working concentration of 50 μg/mL, inhibit induced calcium deposition to basal levels.

scholarly journals Standardization of Human Calcific Aortic Valve Disease in vitro Modeling Reveals Passage-Dependent Calcification

2019 ◽  
Vol 6 ◽  
Author(s):  
Shinji Goto ◽  
Maximillian A. Rogers ◽  
Mark C. Blaser ◽  
Hideyuki Higashi ◽  
Lang H. Lee ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
Calcific Aortic Valve Disease ◽  
In Vitro Modeling

scholarly journals Human Aortic Valve Interstitial Cells Display Proangiogenic Properties During Calcific Aortic Valve Disease

2020 ◽  
Author(s):  
Nicolas Gendron ◽  
Mickael Rosa ◽  
Adeline Blandinieres ◽  
Yoann Sottejeau ◽  
Elisa Rossi ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Conditioned Media ◽  
Valve Disease ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Endothelial Colony Forming Cells

Objective: The study’s aim was to analyze the capacity of human valve interstitial cells (VICs) to participate in aortic valve angiogenesis. Approach and Results: VICs were isolated from human aortic valves obtained after surgery for calcific aortic valve disease and from normal aortic valves unsuitable for grafting (control VICs). We examined VIC in vitro and in vivo potential to differentiate in endothelial and perivascular lineages. VIC paracrine effect was also examined on human endothelial colony-forming cells. A pathological VIC (VIC p ) mesenchymal-like phenotype was confirmed by CD90 + /CD73 + /CD44 + expression and multipotent-like differentiation ability. When VIC p were cocultured with endothelial colony-forming cells, they formed microvessels by differentiating into perivascular cells both in vivo and in vitro. VIC p and control VIC conditioned media were compared using serial ELISA regarding quantification of endothelial and angiogenic factors. Higher expression of VEGF (vascular endothelial growth factor)-A was observed at the protein level in VIC p -conditioned media and confirmed at the mRNA level in VIC p compared with control VIC. Conditioned media from VIC p induced in vitro a significant increase in endothelial colony-forming cell proliferation, migration, and sprouting compared with conditioned media from control VIC. These effects were inhibited by blocking VEGF-A with blocking antibody or siRNA approach, confirming VIC p involvement in angiogenesis by a VEGF-A dependent mechanism. Conclusions: We provide here the first proof of an angiogenic potential of human VICs isolated from patients with calcific aortic valve disease. These results point to a novel function of VIC p in valve vascularization during calcific aortic valve disease, with a perivascular differentiation ability and a VEGF-A paracrine effect. Targeting perivascular differentiation and VEGF-A to slow calcific aortic valve disease progression warrants further investigation.

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