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.

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 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 Inhibition of Pathological Differentiation of Valvular Interstitial Cells by C-Type Natriuretic Peptide

2011 ◽  
Vol 31 (8) ◽  
pp. 1881-1889 ◽  
Author(s):  
Cindy Y.Y. Yip ◽  
Mark C. Blaser ◽  
Zahra Mirzaei ◽  
Xiao Zhong ◽  
Craig A. Simmons
Keyword(s):  
Natriuretic Peptide ◽  
Interstitial Cells ◽  
Valvular Interstitial Cells ◽  
Pathological Differentiation

scholarly journals Towards Personalized Therapy of Aortic Stenosis

2021 ◽  
Vol 11 (12) ◽  
pp. 1292
Author(s):  
Piotr Mazur ◽  
Magdalena Kopytek ◽  
Michał Ząbczyk ◽  
Anetta Undas ◽  
Joanna Natorska
Keyword(s):  
Aortic Stenosis ◽  
Molecular Mechanisms ◽  
Randomized Trials ◽  
Current Knowledge ◽  
Lipid Lowering ◽  
Advanced Glycation ◽  
Calcific Aortic Stenosis ◽  
Treatment Pathways ◽  
Glycation End Products ◽  
Coagulation Proteins

Calcific aortic stenosis (CAS) is the most common cause of acquired valvular heart disease in adults with no available pharmacological treatment to inhibit the disease progression to date. This review provides an up-to-date overview of current knowledge of molecular mechanisms underlying CAS pathobiology and the related treatment pathways. Particular attention is paid to current randomized trials investigating medical treatment of CAS, including strategies based on lipid-lowering and antihypertensive therapies, phosphate and calcium metabolism, and novel therapeutic targets such as valvular oxidative stress, coagulation proteins, matrix metalloproteinases, and accumulation of advanced glycation end products.

scholarly journals Secreted Factors From Proinflammatory Macrophages Promote an Osteoblast-Like Phenotype in Valvular Interstitial Cells

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Joseph C. Grim ◽  
Brian A. Aguado ◽  
Brandon J. Vogt ◽  
Dilara Batan ◽  
Cassidy L. Andrichik ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Stenosis ◽  
Proinflammatory Cytokines ◽  
Interstitial Cells ◽  
Fiber Formation ◽  
Conditioned Media ◽  
Valvular Interstitial Cells ◽  
M1 Macrophages ◽  
Antifibrotic Effect ◽  
Valve Tissue

Objective: Resident valvular interstitial cells (VICs) activate to myofibroblasts during aortic valve stenosis progression, which further promotes fibrosis or even differentiate into osteoblast-like cells that can lead to calcification of valve tissue. Inflammation is a hallmark of aortic valve stenosis, so we aimed to determine proinflammatory cytokines secreted from M1 macrophages that give rise to a transient VIC phenotype that leads to calcification of valve tissue. Approach and Results: We designed hydrogel biomaterials as valve extracellular matrix mimics enabling the culture of VICs in either their quiescent fibroblast or activated myofibroblast phenotype in response to the local matrix stiffness. When VIC fibroblasts and myofibroblasts were treated with conditioned media from THP-1-derived M1 macrophages, we observed robust reduction of αSMA (alpha smooth muscle actin) expression, reduced stress fiber formation, and increased proliferation, suggesting a potent antifibrotic effect. We further identified TNF (tumor necrosis factor)-α and IL (interleukin)-1β as 2 cytokines in M1 media that cause the observed antifibrotic effect. After 7 days of culture in M1 conditioned media, VICs began differentiating into osteoblast-like cells, as measured by increased expression of RUNX2 (runt-related transcription factor 2) and osteopontin. We also identified and validated IL-6 as a critical mediator of the observed pro-osteogenic effect. Conclusions: Proinflammatory cytokines in M1 conditioned media inhibit myofibroblast activation in VICs (eg, TNF-α and IL-1β) and promote their osteogenic differentiation (eg, IL-6). Together, our work suggests inflammatory M1 macrophages may drive a myofibroblast-to-osteogenic intermediate VIC phenotype, which may mediate the switch from fibrosis to calcification during aortic valve stenosis progression.

scholarly journals Calcific Aortic Stenosis—A Review on Acquired Mechanisms of the Disease and Treatments

2021 ◽  
Vol 8 ◽  
Author(s):  
Banafsheh Zebhi ◽  
Mohamad Lazkani ◽  
David Bark
Keyword(s):  
Aortic Stenosis ◽  
Molecular Mechanisms ◽  
Progressive Disease ◽  
Diagnostic Methods ◽  
Calcific Aortic Stenosis ◽  
Treatment Practices ◽  
Prosthetic Valves

Calcific aortic stenosis is a progressive disease that has become more prevalent in recent decades. Despite advances in research to uncover underlying biomechanisms, and development of new generations of prosthetic valves and replacement techniques, management of calcific aortic stenosis still comes with unresolved complications. In this review, we highlight underlying molecular mechanisms of acquired aortic stenosis calcification in relation to hemodynamics, complications related to the disease, diagnostic methods, and evolving treatment practices for calcific aortic stenosis.

Differential Osteogenic Marker Expression by Human Vascular and Valvular Cells in Tissue-Engineered Collagen Constructs

2010 ◽  
Author(s):  
Zannatul Ferdous ◽  
Hanjoong Jo ◽  
Robert M. Nerem
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Aortic Stenosis ◽  
Elderly Population ◽  
Cell Types ◽  
Cardiovascular Disorders ◽  
Valvular Interstitial Cells ◽  
Calcific Aortic Stenosis ◽  
High Prevalence ◽  
Calcium Deposits

Atherosclerosis and aortic stenosis are two of the most prevalent cardiovascular disorders and a major cause of death in elderly population. In atherosclerosis, plaques and calcium deposits build up inside major arteries, which lead to narrowing of the vessel lumens and limits or completely blocks blood flow. Similarly, in calcific aortic stenosis, calcium deposits on valve cusps and valve ring result in narrowing of valve lumen, eventually leading to impaired function and even valve failure. As the disease progresses, both diseases thus require expensive replacement/repair surgeries in most patients. However, in spite of the high prevalence, the causes and mechanisms of these diseases are still not clearly understood. Due to the similarities in diseased tissue pathology, atherosclerosis and aortic stenosis have been suggested to be continuum of the same disease [1] and mainly have been investigated for atherosclerosis. However, the prevalence of both diseases is not concurrent in most patients. Likewise, valvular interstitial cells (VICs) were thought to behave in a similar manner as smooth muscle cells (SMCs), but some recent studies suggest differences between the two cell types [2]. Therefore, unique mechanisms might be involved in how VICs and SMCs respond to an osteogenic environment.

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