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 IL-8 promotes the calcification of human aortic valve interstitial cells, which is prevented through antagonizing CXCR1 and CXCR2 receptors

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
K Dhayni ◽  
Y Chabry ◽  
L Henaut ◽  
H Ouled-Haddou ◽  
C Avondo ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Calcium Content ◽  
Interstitial Cells ◽  
Public Institution ◽  
Inflammatory Factor ◽  
Cellular Mechanisms ◽  
Aortic Valves ◽  
Alizarin Red ◽  
Valve Interstitial Cells ◽  
Human Aortic Valve

Abstract Background/Introduction Inflammation is a key feature of calcific aortic valve stenosis (CAVS) against which there is currently no pharmacological treatment. Purpose To verify the hypothesis that interleukin-8 (IL-8), a pro-inflammatory factor involved in arterial calcifications, also promotes the calcification of human aortic valve interstitial cells (hVICs). Methods Primary hVICs were isolated from healthy pieces of aortic valves harvested from patients undergoing surgical valve replacement. They were cultured in a pro-calcifying condition (Pi-3.8mM) with or without IL-8 (5 to 50 pg/ml) for up to 21 days. Calcification was analysed by alizarin red staining and calcium content was measured with the o-cresolphthalein complexone method. The viability of hVICs was verified by the MTT assay. The expression of osteogenic (BMP2, OPN, osterix and ALP) and myofibrotic (alpha-SMA, collagen-1, collagen-3 and elastin) markers as well as that of metalloproteases (MMP-2, -9 and -12) was analysed by RT-qPCR. The expression of IL-8 receptors, CXCR-1 and CXCR-2 was evaluated by Western blot and flow cytometry, and the effects of IL-8 were tested in the presence or absence of SCH527123, an antagonist of CXCR-1 and CXCR-2. Finally, the expression of CXCR-1 and -2 and elastin was analysed by immunohistochemistry in the calcified and non-calcified areas of human aortic valve samples. All of these experiments were carried out from valves of at least 5 different donors and a P&lt;0.05 was considered statistically significant. Results IL-8 (15 pg/mL) caused a significant ∼2-fold increase in the calcification of hVICs in the Pi condition, compared to the Pi-only condition, without modulation of cell viability. In the presence of Pi, IL-8 exposure significantly stimulated the expression of the transcripts of elastin and MMP-12, an elastase, and reduced that of OPN, a well-known inhibitor of calcification. The effects of IL-8 on hVICs calcification and on the expression of MMP-12, elastin and OPN transcripts were significantly prevented by the addition of SCH527123. In addition, the expression of CXCR-1 and -2 was confirmed in histological samples of human aortic valves. This expression was more pronounced in calcified areas compared to non-calcified areas and co-localized with degraded elastin. Conclusion IL-8 promoted the calcification of hVICs in culture. This effect was significantly prevented by antagonizing CXCR-1 and CXCR-2 IL-8 receptors, which we showed for the first time to be expressed by human VICs and aortic valves of patients with CAVS. Further studies are underway to clarify the cellular mechanisms involved. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Fédération Hospitalo-Universitaire REMOD-VHF

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 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.

Abstract 17341: Novel Lipid Markers of Calcific Aortic Valve Stenosis

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Pascal E Bogaert ◽  
Andrea L Edel ◽  
Arun Surendran ◽  
Michael Raabe ◽  
Shubhkarman Sandhawalia ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Pressure Gradient ◽  
Aortic Valve Stenosis ◽  
Internal Standard ◽  
Aortic Valves ◽  
Genetic Studies ◽  
High Incidence ◽  
Oxidized Phosphatidylcholine ◽  
Human Aortic Valve ◽  
Severe Calcification

Introduction: Calcific aortic valve stenosis (CAVS) is the most prevalent cardiac valvular pathology, leading to a high incidence of morbidity and mortality if left untreated. The exact pathophysiology of CAVS is largely undefined. Genetic studies have shown a strong correlation of the Lp(a) gene to developing CAVS. Lp(a) is known to be the carrier of plasma Oxidized Phosphatidylcholine and results in Lysophosphatidic acid (LPA) accumulation. The focus of the present study was to determine if OxPC and LPA in calcific human aortic valves relate with echocardiographic markers of CAVS. Methods: Aortic valves (n=98) were obtained from patients undergoing AVR. OxPC and LPA were extracted from pulverized aortic valves and analyzed using a targeted mass spectrometry approach. Lipid values are represented relative to an internal standard and normalized by homogenate and leaflet weights. The severity of calcification and aortic stenosis were measured anatomically by Echocardiographic calcification (ECC) score and hemodynamically by mean AV pressure gradient. Results: One-palmitoyl-2-(9-oxo)-nonanoyl- sn- glycero-3-phosphocholine (PONPC) was the most abundant OxPC among 58 OxPC molecules detected (49.3±3.8ng), in AV tissue. When valves were graded by ECC score, scores of 1 (no calcification) had observably attenuated amounts of mean total OxPC’s (135.3±39.3ng) compared to those with a score of 4 (severe calcification) (310.1±34.8 ng). Total valvular OxPC increased linearly with increased ECC score. Total non-fragmented OxPC’s were also significantly lower in valves with ECC scores of 1 and 2 compared to a score of 4 ( P =0.03). Six LPA species were also identified with 16:0 and 18:1 being the most prevalent. Mean AV pressure gradient had a significant, positive correlation with Total LPA amounts (r 2 =0.580, p <0.001), suggesting that elevated LPA concentrations in CAVS tissue is associated with disease severity. Conclusions: Our study is the largest lipidomics study of human aortic valve tissue demonstrating that OxPC and LPA molecules play a significant role in the etiology of CAVS and provides a novel therapeutic target for mitigating disease progression.

scholarly journals Role of Noncanonical Wnt Signaling Pathway in Human Aortic Valve Calcification

2017 ◽  
Vol 37 (3) ◽  
pp. 543-552 ◽  
Author(s):  
Isabella Albanese ◽  
Bin Yu ◽  
Hamood Al-Kindi ◽  
Bianca Barratt ◽  
Leah Ott ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Aortic Valve Calcification ◽  
Valve Calcification ◽  
Human Aortic Valve

Wnt Signaling Mediates Pro-Fibrogenic Activity in Human Aortic Valve Interstitial Cells

2020 ◽  
Author(s):  
Michael J. Jarrett ◽  
Anna K. Houk ◽  
Peyton E. McCuistion ◽  
Michael J. Weyant ◽  
T. Brett Reece ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Wnt Signaling ◽  
Interstitial Cells ◽  
Valve Interstitial Cells ◽  
Human Aortic Valve

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.

scholarly journals Neurotrophin 3 upregulates proliferation and collagen production in human aortic valve interstitial cells: a potential role in aortic valve sclerosis

2017 ◽  
Vol 312 (6) ◽  
pp. C697-C706 ◽  
Author(s):  
Qingzhou Yao ◽  
Rui Song ◽  
Lihua Ao ◽  
Joseph C. Cleveland ◽  
David A. Fullerton ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Cyclin D1 ◽  
Cellular Proliferation ◽  
D1 Protein ◽  
Collagen Deposition ◽  
Aortic Valves ◽  
Aortic Valve Sclerosis ◽  
Collagen Production ◽  
Neurotrophin 3 ◽  
Human Aortic Valve

Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. Diseased aortic valves are characterized by sclerosis (fibrosis) and nodular calcification. Sclerosis, an early pathological change, is caused by aortic valve interstitial cell (AVIC) proliferation and overproduction of extracellular matrix (ECM) proteins. However, the mechanism of aortic valve sclerosis remains unclear. Recently, we observed that diseased human aortic valves overexpress growth factor neurotrophin 3 (NT3). In the present study, we tested the hypothesis that NT3 is a profibrogenic factor to human AVICs. AVICs isolated from normal human aortic valves were cultured in M199 growth medium and treated with recombinant human NT3 (0.10 µg/ml). An exposure to NT3 induced AVIC proliferation, upregulated the production of collagen and matrix metalloproteinase (MMP), and augmented collagen deposition. These changes were abolished by inhibition of the Trk receptors. NT3 induced Akt phosphorylation and increased cyclin D1 protein levels in a Trk receptor-dependent fashion. Inhibition of Akt abrogated the effect of NT3 on cyclin D1 production. Furthermore, inhibition of either Akt or cyclin D1 suppressed NT3-induced cellular proliferation and MMP-9 and collagen production, as well as collagen deposition. Thus, NT3 upregulates cellular proliferation, ECM protein production, and collagen deposition in human AVICs. It exerts these effects through the Trk-Akt-cyclin D1 cascade. NT3 is a profibrogenic mediator in human aortic valve, and overproduction of NT3 by aortic valve tissue may contribute to the mechanism of valvular sclerosis.

scholarly journals Matrix Gla protein negatively regulates calcification of human aortic valve interstitial cells isolated from calcified aortic valves

2018 ◽  
Vol 136 (4) ◽  
pp. 257-265 ◽  
Author(s):  
Mari Chiyoya ◽  
Kazuhiko Seya ◽  
Zaiqiang Yu ◽  
Kazuyuki Daitoku ◽  
Shigeru Motomura ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Interstitial Cells ◽  
Matrix Gla Protein ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Human Aortic Valve
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