Cadherin-11 Regulates Calcific Nodule Formation by Aortic Valve Interstitial Cells

2013 ◽  
Author(s):  
Joseph Chen ◽  
Joshua D. Hutcheson ◽  
M. K. Sewell-Loftin ◽  
Larisa M. Ryzhova ◽  
Charles I. Fisher ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β1 ◽  
Interstitial Cells ◽  
In Vitro Models ◽  
Nodule Formation ◽  
Calcific Aortic Valve Disease ◽  
Valve Interstitial Cells

Calcific aortic valve disease (CAVD) is characterized by the stiffening and calcification of the aortic valve leaflets which result in impaired valve function and increased load on the myocardium. In vitro models of CAVD involve the formation the calcific nodules via aortic valve interstitial cells (AVICs). Transforming growth factor β1 (TGF-β1) induced myofibroblast differentiation of AVICs, which is evidenced by increased αSMA expression, has been shown to be a key mediator of dystrophic calcific nodule formation. Benton et al. demonstrated the critical role of αSMA in nodule formation in that when αSMA was suppressed, calcific nodules did not form [1]. Confoundingly, preventing phosphorylation of Erk1/2 with a MEK1/2 inhibitor leads to increased αSMA expression yet prevents calcific nodule formation [2], suggesting the requirement of another essential component of nodule formation that has yet to be revealed.

Calcific Nodule Morphogenesis by Aortic Valve Interstitial Cells: Synergism of Applied Strain and TGF-β1

2011 ◽  
Author(s):  
Joseph Chen ◽  
Charles I. Fisher ◽  
M. K. Sewell-Loftin ◽  
W. David Merryman
Keyword(s):  
Aortic Valve ◽  
The United States ◽  
Interstitial Cells ◽  
Nodule Formation ◽  
Matrix Stiffness ◽  
Calcific Aortic Valve Disease ◽  
Valve Interstitial Cells ◽  
Compliant Substrates ◽  
Tgf Β1

Calcific Aortic Valve Disease (CAVD) is the third most common cause of cardiovascular disease, affecting nearly 5 million people in the United States alone. It is now the most common form of acquired valvular disease in industrialized countries and will likely affect more individuals in the coming years as the prevalence increases with life expectancy. It is known that the progression of CAVD is closely related to the behavior of aortic valve interstitial cells (AVICs); however the cellular mechanobiological mechanisms leading to dysfunction remain unclear. Generally, CAVD is characterized by the formation of calcified AVIC aggregates with an apoptotic core. These aggregates increase the leaflet stiffness and impede normal valve function. Multiple studies have investigated the effects of various biochemical cues on this process, such as transformation growth factor β1 (TGF-β1), on the regulation of nodule formation [1]. Additionally, Yip et al revealed that matrix stiffness controls nodule formation in vitro, with stiffer substrates promoting apoptotic nodule formation, while compliant substrates generated nodules containing cells with osteoblast markers [2]. This suggests that matrix stiffness is involved in the regulatory mechanisms of nodule formation and may initiate different types of nodule formation (i.e. osteogenic vs. dystrophic). In the current study, we examined the synergistic role of strain and TGF-β1 in the generation of calcified nodules AVICs.

scholarly journals KPT-330 Prevents Aortic Valve Calcification via a Novel C/EBPβ Signaling Pathway

2021 ◽  
Vol 128 (9) ◽  
pp. 1300-1316
Author(s):  
Punashi Dutta ◽  
Karthik M. Kodigepalli ◽  
Stephanie LaHaye ◽  
J. Will Thompson ◽  
Sarah Rains ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Nuclear Export ◽  
The United States ◽  
Interstitial Cells ◽  
Nodule Formation ◽  
Calcific Aortic Valve Disease ◽  
Valve Interstitial Cells ◽  
Subsequent Decrease ◽  
Inhibitor Drug

Rationale: Calcific aortic valve disease (CAVD) affects >5.2 million people in the United States. The only effective treatment is surgery, and this comes with complications and no guarantee of long-term success. Objective: Outcomes from pharmacological initiatives remain unsubstantiated and, therefore, the aim of this study is to determine if repurposing a selective XPO1 (exportin-1) inhibitor drug (KPT-330) is beneficial in the treatment of CAVD. Methods and Results: We show that KPT-330 prevents, attenuates, and mitigates calcific nodule formation in heart valve interstitial cells in vitro and prevents CAVD in Klotho −/− mice. Using RNA-sequencing and mass spectrometry, we show that KPT-330’s beneficial effect is mediated by inhibiting nuclear export of the C/EBPβ (transcription factor CCAAT/enhancing-binding protein) in valve interstitial cells, leading to repression of canonical Wnt signaling, in part, through activation of the Wnt antagonist Axin1 , and a subsequent decrease in proosteogenic markers and cell viability. Conclusions: Our findings have met a critical need to discover alternative, pharmacological-based therapies in the treatment of CAVD.

scholarly journals Cadherin-11 as a regulator of valve myofibroblast mechanobiology

2018 ◽  
Vol 315 (6) ◽  
pp. H1614-H1626 ◽  
Author(s):  
Meghan A. Bowler ◽  
Matthew R. Bersi ◽  
Larisa M. Ryzhova ◽  
Rachel J. Jerrell ◽  
Aron Parekh ◽  
...  
Keyword(s):  
Growth Factor ◽  
Aortic Valve ◽  
Interstitial Cell ◽  
Transforming Growth Factor ◽  
Focal Adhesions ◽  
Transforming Growth Factor Β ◽  
Interstitial Cells ◽  
Calcific Aortic Valve Disease ◽  
Valve Interstitial Cells ◽  
Myofibroblast Phenotype

Cadherin-11 (CDH11) is upregulated in a variety of fibrotic diseases, including arthritis and calcific aortic valve disease. Our recent work has identified CDH11 as a potential therapeutic target and shown that treatment with a CDH11 functional blocking antibody can prevent hallmarks of calcific aortic valve disease in mice. The present study investigated the role of CDH11 in regulating the mechanobiological behavior of valvular interstitial cells believed to cause calcification. Aortic valve interstitial cells were harvested from Cdh11+/+, Cdh11+/−, and Cdh11−/− immortomice. Cells were subjected to inflammatory cytokines transforming growth factor (TGF)-β1 and IL-6 to characterize the molecular mechanisms by which CDH11 regulates their mechanobiological changes. Histology was performed on aortic valves from Cdh11+/+, Cdh11+/−, and Cdh11−/− mice to identify key responses to CDH11 deletion in vivo. We showed that CDH11 influences cell behavior through its regulation of contractility and its ability to bind substrates via focal adhesions. We also show that transforming growth factor-β1 overrides the normal relationship between CDH11 and smooth muscle α-actin to exacerbate the myofibroblast disease phenotype. This phenotypic switch is potentiated through the IL-6 signaling axis and could act as a paracrine mechanism of myofibroblast activation in neighboring aortic valve interstitial cells in a positive feedback loop. These data suggest CDH11 is an important mediator of the myofibroblast phenotype and identify several mechanisms by which it modulates cell behavior. NEW & NOTEWORTHY Cadherin-11 influences valvular interstitial cell contractility by regulating focal adhesions and inflammatory cytokine secretion. Transforming growth factor-β1 overrides the normal balance between cadherin-11 and smooth muscle α-actin expression to promote a myofibroblast phenotype. Cadherin-11 is necessary for IL-6 and chitinase-3-like protein 1 secretion, and IL-6 promotes contractility. Targeting cadherin-11 could therapeutically influence valvular interstitial cell phenotypes in a multifaceted manner.

scholarly journals In vitro 3D model and miRNA drug delivery to target calcific aortic valve disease

2017 ◽  
Vol 131 (3) ◽  
pp. 181-195 ◽  
Author(s):  
Casper F.T. van der Ven ◽  
Pin-Jou Wu ◽  
Mark W. Tibbitt ◽  
Alain van Mil ◽  
Joost P.G. Sluijter ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
3D Model ◽  
In Vitro Models ◽  
Valve Disease ◽  
Calcific Aortic Valve Disease ◽  
Valve Interstitial Cells ◽  
Delivery Strategies

Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease. Valve interstitial cells (VICs) mediate calcification in the aortic valve (AV) leaflets, leading to aortic stenosis (AS) and eventually heart failure. Aortic valve replacement (AVR) surgery is the only available treatment. Drug-based therapies and the in vitro models to study CAVD are inadequate or lacking. Here, we present a forward-looking review of 3D CAVD models, miRNA-based therapeutics and controlled drug-delivery strategies.

Ultrastructural and Spectrophotometric Study on the Effects of Putative Triggers on Aortic Valve Interstitial Cells in In Vitro Models Simulating Metastatic Calcification

2012 ◽  
Vol 295 (7) ◽  
pp. 1117-1127 ◽  
Author(s):  
Antonella Bonetti ◽  
Alberto Della Mora ◽  
Magali Contin ◽  
Franco Tubaro ◽  
Maurizio Marchini ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Spectrophotometric Study ◽  
Interstitial Cells ◽  
In Vitro Models ◽  
Metastatic Calcification ◽  
Valve Interstitial Cells

P2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt: Implication for calcific aortic valve disease

2014 ◽  
Vol 72 ◽  
pp. 146-156 ◽  
Author(s):  
Diala El Husseini ◽  
Marie-Chloé Boulanger ◽  
Ablajan Mahmut ◽  
Rihab Bouchareb ◽  
Marie-Hélène Laflamme ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Interstitial Cells ◽  
Valve Disease ◽  
P2y2 Receptor ◽  
Calcific Aortic Valve Disease ◽  
Valve Interstitial Cells
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