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

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.

scholarly journals Metformin alleviates the calcification of aortic valve interstitial cells through activating the PI3K/AKT pathway in an AMPK dependent way

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Qiao En ◽  
Huang Zeping ◽  
Wang Yuetang ◽  
Wang Xu ◽  
Wang Wei
Keyword(s):  
Aortic Valve ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Interstitial Cells ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Pathological Mechanism

Abstract Background Calcific aortic valve disease (CAVD) is the most prevalent valvular disease worldwide. However, no effective treatment could delay or prevent the progression of the disease due to the poor understanding of its pathological mechanism. Many studies showed that metformin exerted beneficial effects on multiple cardiovascular diseases by mediating multiple proteins such as AMPK, NF-κB, and AKT. This study aims to verify whether metformin can inhibit aortic calcification through the PI3K/AKT signaling pathway. Methods We first analyzed four microarray datasets to screen differentially expressed genes (DEGs) and signaling pathways related to CAVD. Then aortic valve samples were used to verify selected genes and pathways through immunohistochemistry (IHC) and western blot (WB) assays. Aortic valve interstitial cells (AVICs) were isolated from non-calcific aortic valves and then cultured with phosphate medium (PM) with or without metformin to verify whether metformin can inhibit the osteogenic differentiation and calcification of AVICs. Finally, we used inhibitors and siRNA targeting AMPK, NF-κB, and AKT to study the mechanism of metformin. Results We screened 227 DEGs; NF-κB and PI3K/AKT signaling pathways were implicated in the pathological mechanism of CAVD. IHC and WB experiments showed decreased AMPK and AKT and increased Bax in calcific aortic valves. PM treatment significantly reduced AMPK and PI3K/AKT signaling pathways, promoted Bax/Bcl2 ratio, and induced AVICs calcification. Metformin treatment ameliorated AVICs calcification and apoptosis by activating the PI3K/AKT signaling pathway. AMPK activation and NF-κB inhibition could inhibit AVICs calcification induced by PM treatment; however, AMPK and AKT inhibition reversed the protective effect of metformin. Conclusions This study, for the first time, demonstrates that metformin can inhibit AVICs in vitro calcification by activating the PI3K/AKT signaling pathway; this suggests that metformin may provide a potential target for the treatment of CAVD. And the PI3K/AKT signaling pathway emerges as an important regulatory axis in the pathological mechanism of CAVD.

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.

Primary culture and in vitro calcification model establishment of human aortic valve interstitial cells

2013 ◽  
Vol 33 (5) ◽  
pp. 488-492
Author(s):  
Mi ZHANG ◽  
Xiao-hong LIU ◽  
Bo-yao ZHANG ◽  
Lin HAN ◽  
Fang-lin LU ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Primary Culture ◽  
Interstitial Cells ◽  
Valve Interstitial Cells ◽  
Human Aortic Valve

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.

scholarly journals 182 Tissue factor expressed by aortic valve interstitial cells is able to generate thrombin in vitro

2012 ◽  
Vol 4 (1) ◽  
pp. 57
Author(s):  
Joke Breyne ◽  
Emmanuelle Jeanpierre ◽  
Delphine Corseaux ◽  
Alexia Jadot ◽  
Francis Juthier ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Tissue Factor ◽  
Interstitial Cells ◽  
Valve Interstitial Cells

scholarly journals Hypoxic Culture Maintains Cell Growth of the Primary Human Valve Interstitial Cells with Stemness

2021 ◽  
Vol 22 (19) ◽  
pp. 10534
Author(s):  
Kaho Kanno ◽  
Tomohisa Sakaue ◽  
Mika Hamaguchi ◽  
Kenji Namiguchi ◽  
Daisuke Nanba ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Aortic Valve ◽  
Molecular Mechanisms ◽  
Interstitial Cells ◽  
Oxidative Stress Marker ◽  
Marker Genes ◽  
Low Oxygen ◽  
Valve Interstitial Cells

The characterization of aortic valve interstitial cells (VICs) cultured under optimal conditions is essential for understanding the molecular mechanisms underlying aortic valve stenosis. Here, we propose 2% hypoxia as an optimum VIC culture condition. Leaflets harvested from patients with aortic valve regurgitation were digested using collagenase and VICs were cultured under the 2% hypoxic condition. A significant increase in VIC growth was observed in 2% hypoxia (hypo-VICs), compared to normoxia (normo-VICs). RNA-sequencing revealed that downregulation of oxidative stress-marker genes (such as superoxide dismutase) and upregulation of cell cycle accelerators (such as cyclins) occurred in hypo-VICs. Accumulation of reactive oxygen species was observed in normo-VICs, indicating that low oxygen tension can avoid oxidative stress with cell-cycle arrest. Further mRNA quantifications revealed significant upregulation of several mesenchymal and hematopoietic progenitor markers, including CD34, in hypo-VICs. The stemness of hypo-VICs was confirmed using osteoblast differentiation assays, indicating that hypoxic culture is beneficial for maintaining growth and stemness, as well as for avoiding senescence via oxidative stress. The availability of hypoxic culture was also demonstrated in the molecular screening using proteomics. Therefore, hypoxic culture can be helpful for the identification of therapeutic targets and the evaluation of VIC molecular functions in vitro.

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