scholarly journals Zinc ameliorates human aortic valve calcification through GPR39 mediated ERK1/2 signalling pathway

2020 ◽  
Author(s):  
Ziying Chen ◽  
Flora Gordillo-Martinez ◽  
Lei Jiang ◽  
Pengcheng He ◽  
Wanzi Hong ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Osteogenic Differentiation ◽  
Zinc Supplementation ◽  
Zinc Transporter ◽  
Signalling Pathway ◽  
Valve Disease ◽  
Zinc Treatment ◽  
Aortic Valves ◽  
Human Aortic Valve

Abstract Aims Calcific aortic valve disease (CAVD) is the most common heart valve disease in the Western world. It has been reported that zinc is accumulated in calcified human aortic valves. However, whether zinc directly regulates CAVD is yet to be elucidated. The present study sought to determine the potential role of zinc in the pathogenesis of CAVD. Methods and results Using a combination of a human valve interstitial cell (hVIC) calcification model, human aortic valve tissues, and blood samples, we report that 20 μM zinc supplementation attenuates hVIC in vitro calcification, and that this is mediated through inhibition of apoptosis and osteogenic differentiation via the zinc-sensing receptor GPR39-dependent ERK1/2 signalling pathway. Furthermore, we report that GPR39 protein expression is dramatically reduced in calcified human aortic valves, and there is a significant reduction in zinc serum levels in patients with CAVD. Moreover, we reveal that 20 μM zinc treatment prevents the reduction of GPR39 observed in calcified hVICs. We also show that the zinc transporter ZIP13 and ZIP14 are significantly increased in hVICs in response to zinc treatment. Knockdown of ZIP13 or ZIP14 significantly inhibited hVIC in vitro calcification and osteogenic differentiation. Conclusions Together, these findings suggest that zinc is a novel inhibitor of CAVD, and report that zinc transporter ZIP13 and ZIP14 are important regulators of hVIC in vitro calcification and osteogenic differentiation. Zinc supplementation may offer a potential therapeutic strategy for CAVD.

scholarly journals Degenerative aortic valve disease and diabetes: Implications for a link between proteoglycans and diabetic disorders in the aortic valve

2018 ◽  
Vol 16 (3) ◽  
pp. 254-269 ◽  
Author(s):  
Mareike Barth ◽  
Jessica I Selig ◽  
Svenja Klose ◽  
Antje Schomakers ◽  
Lena S Kiene ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Interstitial Cells ◽  
Valve Disease ◽  
Enzyme Linked Immunosorbent Assay ◽  
Aortic Valves ◽  
Potential Link ◽  
Human Aortic Valve

Degenerative aortic valve disease in combination with diabetes is an increasing burden worldwide. There is growing evidence that particularly small leucine-rich proteoglycans are involved in the development of degenerative aortic valve disease. Nevertheless, the role of these molecules in this disease in the course of diabetes has not been elucidated in detail and previous studies remain controversial. Therefore, the aim of this study is to broaden the knowledge about small leucine-rich proteoglycans in degenerative aortic valve disease and the influence of diabetes and hyperglycaemia on aortic valves and valvular interstitial cells is examined. Analyses were performed using reverse-transcription polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, (immuno)histology and colorimetric assays. We could show that biglycan, but not decorin and lumican, is upregulated in degenerated human aortic valve cusps. Subgroup analysis reveals that upregulation of biglycan is stage-dependent. In vivo, loss of biglycan leads to stage-dependent calcification and also to migratory effects on interstitial cells within the extracellular matrix. In late stages of degenerative aortic valve disease, diabetes increases the expression of biglycan in aortic valves. In vitro, the combinations of hyperglycaemic with pro-degenerative conditions lead to an upregulation of biglycan. In conclusion, biglycan represents a potential link between degenerative aortic valve disease and diabetes.

Platelet membrane-coated nanoparticles target sclerotic aortic valves in ApoE−/− mice by multiple binding mechanisms under pathological shear stress

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Yang ◽  
Y Song ◽  
Z Huang ◽  
J Qian ◽  
Z Pang ◽  
...  
Keyword(s):  
Shear Stress ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Binding Capacity ◽  
Platelet Membrane ◽  
Valve Disease ◽  
Funding Source ◽  
Aortic Valves ◽  
Coated Nanoparticles

Abstract Background Aortic valve disease is the most common valvular heart disease leading to valve replacement. The efficacy of pharmacological therapy for aortic valve disease is limited by the high mechanical stress at the aortic valves impairing the binding rate. We aimed to identify nanoparticle coating with entire platelet membranes to fully mimic their inherent multiple adhesion mechanisms and target the sclerotic aortic valve of apolipoprotein E-deficient (ApoE−/−) mice based on their multiple sites binding capacity under high shear stress. Methods Considering the potent interaction of platelet membrane glycoproteins with components present in sclerotic aortic valves, platelet membrane-coated nanoparticles (PNPs) were synthetized and the binding capacity under high shear stress was evaluated in vitro and in vivo. Results Compared with PNPs bound intensity in the static station, 161%, 59%, and 39% of attached PNPs remained adherent on VWF-, collagen-, and fibrin-coated surfaces under shear stress of 25dyn/cm2 respectively. PNPs demonstrated effectively adhering to von Willebrand factor, collagen and fibrin under shear stresses in vitro. In an aortic valve disease model established in ApoE−/− mice, PNPs group exhibited significant increase of accumulation in the aortic valves compared with PBS and control NP group. PNPs displayed high degrees of proximity or co-localization with vWF, collagen and fibrin, which exhibited good targeting to sclerotic aortic valves by mimicking platelet multiple adhesive mechanisms. Conclusion PNPs could provide a promising platform for the molecular diagnosis and targeting treatment of aortic valve disease. Targeting combination Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China

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.

scholarly journals Iron promotes Slc7a11-deficient valvular interstitial cell osteogenic differentiation: A possible mechanism by which ferroptosis participates in intraleaflet hemorrhage-induced calcification.

2021 ◽  
Author(s):  
Ran Xu ◽  
Dan Zhu ◽  
Jianghong Guo ◽  
Ying Huang
Keyword(s):  
Lipid Peroxidation ◽  
Aortic Valve ◽  
Osteogenic Differentiation ◽  
Developed Countries ◽  
Mitochondrial Morphology ◽  
Metabolic Dysfunction ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Alizarin Red

Background: Calcific aortic valve disease (CAVD) is the most frequent pathogeny of aortic valve replacement in developed countries. Iron deposits are found in the intraleaflet hemorrhage (IH) areas of calcific aortic valves. Ferroptosis is a form of regulated cell death that involves metabolic dysfunction resulting from iron overload-dependent excessive lipid peroxidation. In this research, we attempted to clarify the role of ferroptosis in CAVD. Methods: The level of ferroptosis in tissue and valvular interstitial cells (VICs) was assessed by the contents of 4-HNE, NADPH, ROS, and GSH, lipid peroxidation and mitochondrial morphology. The levels of calcification, iron accumulation and Slc7a11 expression in surgical aortic valve specimens were detected by Alizarin red or Von Kossa, Perl's blue and immunohistochemical staining. The osteogenic differentiation of VICs was assessed by PCR and western blot analyses. Furthermore, RNA sequencing was used to detect potential differentially expressed genes between normal and osteogenic medium-treated (OM-treated) VICs. Results: Our experiments demonstrated that ferroptosis occurred in the IH areas of calcific aortic valves. We also found that Slc7a11 was expressed at low levels in OM-treated VICs and IH areas. Finally, we demonstrated that iron promoted Slc7a11-deficient VICs osteogenic differentiation by aggravating ferroptosis in vitro. Conclusion: In conclusion, iron promotes Slc7a11-deficient VIC osteogenic differentiation by aggravating ferroptosis in vitro, thereby accelerating the progression of aortic valve calcification.

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 Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

2017 ◽  
Vol 114 (7) ◽  
pp. 1631-1636 ◽  
Author(s):  
Qingchun Zeng ◽  
Rui Song ◽  
David A. Fullerton ◽  
Lihua Ao ◽  
Yufeng Zhai ◽  
...  
Keyword(s):  
Aortic Valve ◽  
High Fat Diet ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
High Fat ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Valve Lesions ◽  
Osteogenic Factors

Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.

scholarly journals COX-2 Is Downregulated in Human Stenotic Aortic Valves and Its Inhibition Promotes Dystrophic Calcification

2020 ◽  
Vol 21 (23) ◽  
pp. 8917
Author(s):  
Francesco Vieceli Dalla Sega ◽  
Francesca Fortini ◽  
Paolo Cimaglia ◽  
Luisa Marracino ◽  
Elisabetta Tonet ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Clinical Analysis ◽  
Dystrophic Calcification ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Induced Apoptosis ◽  
Human Aortic Valve

Calcific aortic valve disease (CAVD) is the result of maladaptive fibrocalcific processes leading to a progressive thickening and stiffening of aortic valve (AV) leaflets. CAVD is the most common cause of aortic stenosis (AS). At present, there is no effective pharmacotherapy in reducing CAVD progression; when CAVD becomes symptomatic it can only be treated with valve replacement. Inflammation has a key role in AV pathological remodeling; hence, anti-inflammatory therapy has been proposed as a strategy to prevent CAVD. Cyclooxygenase 2 (COX-2) is a key mediator of the inflammation and it is the target of widely used anti-inflammatory drugs. COX-2-inhibitor celecoxib was initially shown to reduce AV calcification in a murine model. However, in contrast to these findings, a recent retrospective clinical analysis found an association between AS and celecoxib use. In the present study, we investigated whether variations in COX-2 expression levels in human AVs may be linked to CAVD. We extracted total RNA from surgically explanted AVs from patients without CAVD or with CAVD. We found that COX-2 mRNA was higher in non-calcific AVs compared to calcific AVs (0.013 ± 0.002 vs. 0.006 ± 0.0004; p < 0.0001). Moreover, we isolated human aortic valve interstitial cells (AVICs) from AVs and found that COX-2 expression is decreased in AVICs from calcific valves compared to AVICs from non-calcific AVs. Furthermore, we observed that COX-2 inhibition with celecoxib induces AVICs trans-differentiation towards a myofibroblast phenotype, and increases the levels of TGF-β-induced apoptosis, both processes able to promote the formation of calcific nodules. We conclude that reduced COX-2 expression is a characteristic of human AVICs prone to calcification and that COX-2 inhibition may promote aortic valve calcification. Our findings support the notion that celecoxib may facilitate CAVD progression.

scholarly journals FP608SNF472 INHIBITS HUMAN AORTIC VALVE CALCIFICATION IN VITRO

2018 ◽  
Vol 33 (suppl_1) ◽  
pp. i247-i247
Author(s):  
Arseny Zabirnyk ◽  
Maria Bogdanova ◽  
Miguel D Ferrer ◽  
Maria Pérez ◽  
Mari-Liis Kaljusto ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Calcification ◽  
Valve Calcification ◽  
Human Aortic Valve

scholarly journals Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves

2018 ◽  
Vol 96 (2) ◽  
pp. 208-214 ◽  
Author(s):  
Ateeque Siddique ◽  
Bin Yu ◽  
Kashif Khan ◽  
Ryan Buyting ◽  
Hamood Al-Kindi ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Wnt Signaling ◽  
Quantitative Polymerase Chain Reaction ◽  
Disease Process ◽  
Receptor Expression ◽  
Cellular Mechanisms ◽  
Aortic Valves ◽  
Major Player ◽  
Frizzled Receptors ◽  
Human Aortic Valve

The cellular mechanisms that induce calcific aortic stenosis are yet to be unraveled. Wnt signaling is increasingly being considered as a major player in the disease process. However, the presence of Wnt Frizzled (Fzd) receptors and co-receptors LRP5 and 6 in normal and diseased human aortic valves remains to be elucidated. Immunohistochemistry and quantitative polymerase chain reaction were used to determine Fzd receptor expression in normal and calcified human aortic valve tissue, as well as human aortic valve interstitial cells (HAVICs) isolated from calcified and normal human aortic valves. There was significantly higher mRNA expression of 4 out of the 10 Fzd receptors in calcified aortic valve tissues and 8 out of the 10 in HAVICs, and both LRP5/6 co-receptors in calcified aortic valves (P < 0.05). These results were confirmed by immunohistochemistry, which revealed abundant increase in immunoreactivity for Fzd3, 7, and 8, mainly in areas of lipid core and calcified nodules of diseased aortic valves. The findings of abundant expression of Fzd and LRP5/6 receptors in diseased aortic valves suggests a potential role for both canonical and noncanonical Wnt signaling in the pathogenesis of human aortic valve calcification. Future investigations aimed at targeting these molecules may provide potential therapies for aortic valve stenosis.

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
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