P4485The number of lipoprotein(a) kringle IV-type 2 repeats is associated with the osteogenic profile of aortic valvular interstitial cells induced by plasma from patients with calcific aortic stenosis

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D A Arangalage ◽  
T S Simon ◽  
M V Varret ◽  
M C Croyal ◽  
B A Arsenault ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Interstitial Cells ◽  
Calcium Deposition ◽  
Valvular Interstitial Cells ◽  
Pathogenic Role ◽  
Alizarin Red ◽  
Calcific Aortic Stenosis ◽  
Lipoprotein A ◽  
Osteoblastic Phenotype

Abstract Background Considerable progresses have been made in the invasive treatment of calcific aortic stenosis (AS), but there is still no pharmacological treatment available because the exact mechanism leading to the initiation of valvular calcification remains unknown. An increasing number of evidences, including large-scale genetic studies, have linked Lipoprotein(a) (Lp(a)) to AS but its pathogenic role in the osteoblastic transition of valvular interstitial cells (VIC) has remained undeciphered. Objective We sought to study the mechanistic link between the transition of VICs towards an osteoblastic phenotype leading to intraleaflet calcium deposition and the type of Lp(a) isoform, defined by the number of kringle IV-type 2 (KIV 2) repeats, in the plasma of patients with AS compared with healthy controls. Methods VICs isolated from healthy aortic valves were cultured in the presence of plasma samples deriving from 100 patients with severe AS included in the prospective cohort GENERAC and 50 matched control patients exempt from any aortic valve disease. We evaluated the number of Lp(a) KIV 2 repeats of each plasma preparation by liquid chromatography-mass spectrometry. The phenotypic changes of VICs towards an osteoblastic phenotype were assessed by immunofluorescence microscopy (osteocalcin expression) and Alizarin red staining (calcium deposition). Results Incubation of VICs with the plasma of AS patients triggered their transformation towards an osteoblastic phenotype, evidenced by the production of osteocalcin, and calcium deposition. There was no association between the plasma levels of Lp(a) and the extent of calcium deposition in the study population. However, a negative and significant correlation was found between calcium deposition and the number of KIV-2 repeats in the Lp(a) of the different plasma preparations (r=−0.20, p=0.038). A direct, causal role of Lp(a) isoforms containing a low number of KIV-2 repeats (5 to 6) in the transition of VICs towards an osteoblastic phenotype was supported by experiments performed with preparations of these isoforms, isolated from the plasma of blood donors. Conclusion A low number of KIV–2 repeats in plasma Lp(a) triggers the acquisition of an osteoblastic phenotype by VICs. The isoform, rather than the concentration of Lp(a) may play a pathogenic role in AS. Determining the number of KIV-2 repeats in the Lp(a) of patients may allow to identify subgroups of patients with an increased risk of developing AS. Acknowledgement/Funding ANR-16-RHUS-0003_STOP-AS. PHRC National 2005 and 2010, and PHRC regional 2007.

scholarly journals Molecular aspects of the pathological activation and differentiation of valvular interstitial cells during the development of calcific aortic stenosis

2019 ◽  
Vol 34 (3) ◽  
pp. 66-72
Author(s):  
A. E. Kostyunin
Keyword(s):  
Aortic Stenosis ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Interstitial Cells ◽  
Valvular Interstitial Cells ◽  
Calcific Aortic Stenosis ◽  
Valve Tissue ◽  
Pathological Differentiation ◽  
Molecular Aspects ◽  
Atherosclerotic Process

Calcific aortic stenosis is the most common valvular heart disease. The pathogenesis of this disease is complex and resembles the atherosclerotic process in the blood vessels. It is known that valvular interstitial cell activation and subsequent differentiation into osteoblast- and myofibroblast-like cells is the main driving force of fibrous and calcified aortic valve tissue. However, the molecular mechanisms behind these processes are still not fully understood. Current information on this issue is collected and analyzed in this article. The main molecular pathways mediating the pathological differentiation of the valvular interstitial cells and the reasons for their activation are considered.

scholarly journals A Coupled Multiscale Approach to Modeling Aortic Valve Mechanics in Health and Disease

2021 ◽  
Vol 11 (18) ◽  
pp. 8332
Author(s):  
Ahmed A. Bakhaty ◽  
Sanjay Govindjee ◽  
Mohammad R. K. Mofrad
Keyword(s):  
Aortic Valve ◽  
Aortic Stenosis ◽  
Mechanical Behavior ◽  
Three Dimensional ◽  
Interstitial Cells ◽  
Multiscale Approach ◽  
Valvular Interstitial Cells ◽  
Calcific Aortic Stenosis ◽  
Multiple Length Scales ◽  
Health And Disease

Mechano-biological processes in the aortic valve span multiple length scales ranging from the molecular and cell to tissue and organ levels. The valvular interstitial cells residing within the valve cusps sense and actively respond to leaflet tissue deformations caused by the valve opening and closing during the cardiac cycle. Abnormalities in these biomechanical processes are believed to impact the matrix-maintenance function of the valvular interstitial cells, thereby initiating valvular disease processes such as calcific aortic stenosis. Understanding the mechanical behavior of valvular interstitial cells in maintaining tissue homeostasis in response to leaflet tissue deformation is therefore key to understanding the function of the aortic valve in health and disease. In this study, we applied a multiscale computational homogenization technique (also known as “FE2”) to aortic valve leaflet tissue to study the three-dimensional mechanical behavior of the valvular interstitial cells in response to organ-scale mechanical loading. We further considered calcific aortic stenosis with the aim of understanding the likely relationship between the valvular interstitial cell deformations and calcification. We find that the presence of calcified nodules leads to an increased strain profile that drives further growth of calcification.

scholarly journals Midkine Prevents Calcification of Aortic Valve Interstitial Cells via Intercellular Crosstalk

2021 ◽  
Vol 9 ◽  
Author(s):  
Qian Zhou ◽  
Hong Cao ◽  
Xiaoyi Hang ◽  
Huamin Liang ◽  
Miaomiao Zhu ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Quantitative Polymerase Chain Reaction ◽  
Treatment Options ◽  
Cell Communication ◽  
Interstitial Cells ◽  
Cellular Heterogeneity ◽  
Valvular Interstitial Cells ◽  
Alizarin Red ◽  
Mesenchymal Transition

Calcified aortic valve disease (CAVD), the most common valvular heart disease, lacks pharmaceutical treatment options because its pathogenesis remains unclear. This disease with a complex macroenvironment characterizes notable cellular heterogeneity. Therefore, a comprehensive understanding of cellular diversity and cell-to-cell communication are essential for elucidating the mechanisms driving CAVD progression and developing therapeutic targets. In this study, we used single-cell RNA sequencing (scRNA-seq) analysis to describe the comprehensive transcriptomic landscape and cell-to-cell interactions. The transitional valvular endothelial cells (tVECs), an intermediate state during the endothelial-to-mesenchymal transition (EndMT), could be a target to interfere with EndMT progression. Moreover, matrix valvular interstitial cells (mVICs) with high expression of midkine (MDK) interact with activated valvular interstitial cells (aVICs) and compliment-activated valvular interstitial cells (cVICs) through the MK pathway. Then, MDK inhibited calcification of VICs that calcification was validated by Alizarin Red S staining, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting assays in vitro. Therefore, we speculated that mVICs secreted MDK to prevent VICs’ calcification. Together, these findings delineate the aortic valve cells’ heterogeneity, underlining the importance of intercellular cross talk and MDK, which may offer a potential therapeutic strategy as a novel inhibitor of CAVD.

scholarly journals Can a Valve Become Resistant to Insulin? - Influence of Type 2 Diabetes Mimicking Conditions on Valvular Interstitial Cells

2017 ◽  
Vol 65 (S 01) ◽  
pp. S1-S110
Author(s):  
J.I. Selig ◽  
S. Raschke ◽  
D.M. Ouwens ◽  
A. Lichtenberg ◽  
P. Akhyari ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Interstitial Cells ◽  
Valvular Interstitial Cells

Abstract 303: CD44 Activation Protects Human Sclerotic-derived Valvular Interstitial Cells from Calcification

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Paolo Poggio ◽  
Emanuela Branchetti ◽  
Rachana Sainger ◽  
Juan Grau ◽  
Eric Lai ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Early Stage ◽  
Interstitial Cells ◽  
Calcium Deposition ◽  
Proximity Ligation Assay ◽  
Valvular Interstitial Cells ◽  
Direct Role ◽  
Aortic Sclerosis

Introduction. The activation of Valvular Interstitial Cells (VIC) towards an osteoblast-like phenotype is a cellular hallmark of pathological progression towards Aortic Stenosis (AS). In recent years several clinical trials have failed to halt or revert the progression of this prevalent disease. The ability to prevent end-stage AS requires the understanding of the molecular events associated with the early phase of valve degeneration, a condition known as Aortic Sclerosis (ASc). In the last few years the transmembrane receptor CD44 has been studied as a putative molecule for cardiovascular drug therapy. We reported that the functional interaction between CD44 and one of its ligand, Osteopontin (OPN), protects vascular smooth muscle cells from calcification. More recently, we demonstrated that sclerotic tissues show increased expression of Bone Morphogenetic Protein 4 (BMP4) and BMP4 directly stimulates osteoblast-like transdifferentiation and calcification of VICs. Therefore we hypothesized a direct role of CD44 activation in protecting human Aortic Sclerosis-derived VICs from calcification. Methods. Human VICs from Control, ASc, and AS (n=5 each group) were isolated. Histological, cellular and molecular analysis, and in situ Proximity Ligation Assay were used to investigate the role of CD44 and OPN in VIC calcification. BMP4 treatments were used to promote VIC activation. Osteoblast-like transdifferentiation was analyzed using Alkaline Phosphatase (ALP) expression. Results. CD44 and OPN, as well as their functional binding, were increased in sclerotic and stenotic tissues compared to healthy controls in vitro and ex vivo. CD44-OPN binding prevented in vitro calcification induced by inorganic phosphate on human ASc-derived VICs. A neutralizing antibody against CD44, under BMP4 treatments, promoted calcium deposition along with increased expression of OPN and ALP. Conclusion. Our results generate an important insight into the molecular mechanism of VIC calcification. We proved that CD44-OPN direct interaction inhibits calcification of Aortic Sclerosis-derived VICs, suggesting that CD44 activation could have a protective role against VIC osteoblast-like transdifferentiation and calcification in the early stage of the disease.

Abstract 15192: Leptin Effects on Osteoblast Differentiation of Human Valvular Interstitial Cells: New Insight Into Calcific Aortic Valve Disease

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Mickael Rosa ◽  
Rodrigo Lorenzi ◽  
Madjid Tagzirt ◽  
Francis Juthier ◽  
Antoine Rauch ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Osteoblast Differentiation ◽  
Interstitial Cells ◽  
Valve Disease ◽  
Calcium Deposition ◽  
Valvular Interstitial Cells ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Alp Activity

Introduction: Calcific aortic valve disease (CAVD) affects 2% to 6% of the population over 65 years and results from dysregulated processes such as calcification, supported in part by the osteoblast differentiation of valvular interstitial cells (VIC), the most prevalent cell type in the human aortic valves. Leptin has recently been linked to aortic valve calcification in ApoE-/- mice. Hypothesis: Our hypothesis is that leptin could play a role in the calcifying processes implicated in CAVD via direct effects on human VIC. Methods: Patients who underwent aortic valve replacement for severe CAVD (n=43) or with coronary artery disease (CAD) but without CAVD (n=129) were included in this study. Presence of leptin was analyzed in human explanted calcified aortic valves and blood samples. Leptin receptors expression was analyzed in aortic valves and VIC isolated from aortic valves. Leptin effects on osteoblast differentiation of VIC in presence or not of Akt and ERK inhibitors were investigated by alizarin red staining, alkaline phosphatase (ALP) activity, and RT-qPCR analysis for osteopontin, ALP, bone morphogenetic protein BMP-2, and RUNX2. Results: Patients with CAVD have significant higher serum leptin concentration than CAD patients (p=0.002). The presence of leptin was observed by immunochemistry in human calcified aortic valves, with higher concentrations in calcified vs non-calcified zones (p=0.01). Both short and long leptin receptor isoforms were expressed in VIC. Chronic leptin stimulation of VIC enhanced ALP, BMP-2 and RUNX2 expression and decreased osteopontin expression. This treatment led to a higher, dose dependent, ALP activity and calcium deposition in VIC. Inhibiting Akt or ERK during leptin stimulation led to a reduced calcification by bringing the expression of calcification genes to the control levels. Conclusions: Together, these novel findings depict the potential role of leptin in the process of CAVD by triggering calcification processes in human VIC.

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