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.

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.

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.

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

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.

scholarly journals miRNA Expression Profiling Uncovers a Role of miR-139-5p in Regulating the Calcification of Human Aortic Valve Interstitial Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Fan Zhang ◽  
Naixuan Cheng ◽  
Yingchun Han ◽  
Congcong Zhang ◽  
Haibo Zhang
Keyword(s):  
Aortic Valve ◽  
Osteogenic Differentiation ◽  
Mirna Expression ◽  
Structural Heart Disease ◽  
Interstitial Cells ◽  
Calcific Aortic Valve Disease ◽  
Valve Interstitial Cells ◽  
Functional Studies ◽  
Human Aortic Valve ◽  
Osteogenic Gene

Calcific aortic valve disease (CAVD) is the most common structural heart disease, and the morbidity is increased with elderly population. Several microRNAs (miRNAs) have been identified to play crucial roles in CAVD, and numerous miRNAs are still waiting to be explored. In this study, the miRNA expression signature in CAVD was analyzed unbiasedly by miRNA-sequencing, and we found that, compared with the normal control valves, 152 miRNAs were upregulated and 186 miRNAs were downregulated in calcified aortic valves. The functions of these differentially expressed miRNAs were associated with cell differentiation, apoptosis, adhesion and immune response processes. Among downregulated miRNAs, the expression level of miR-139-5p was negatively correlated with the osteogenic gene RUNX2, and miR-139-5p was also downregulated during the osteogenic differentiation of primary human aortic valve interstitial cells (VICs). Subsequent functional studies revealed that miR-139-5p overexpression inhibited the osteogenic differentiation of VICs by negatively modulating the expression of pro-osteogenic gene FZD4 and CTNNB1. In conclusion, these results suggest that miR-139-5p plays an important role in osteogenic differentiation of VICs via the Wnt/β-Catenin pathway, which may further provide a new therapeutic target for CAVD.

Abstract 18216: Epigenetic Up-regulation of α-smooth Muscle Actin Expression and Cell Aggregation in Human Aortic Valve Interstitial Cells Promotes Calcific Nodule Formation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Rui Song ◽  
David A. Fullerton ◽  
Lihua Ao ◽  
Kesen Zhao ◽  
Xianzhong Meng
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Smooth Muscle Actin ◽  
Cell Aggregation ◽  
Interstitial Cells ◽  
Nodule Formation ◽  
Muscle Actin ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Tgf Β1

Older people are at risk of calcific aortic valve disease. Aortic valve interstitial cells (AVICs) play an important role in nodular calcification in aortic valve leaflets. AVICs in human aortic valves consist of fibroblasts and myofibroblasts that express α-smooth muscle actin (α-SMA). We have observed that AVICs of diseased aortic valves have greater osteogenic activities. However, molecular mechanism underlying AVIC formation of calcification nodules is not well understood. We hypothesized that an epigenetic mechanism promotes AVIC calcification nodule formation through induction of α-SMA expression and cell aggregation. Methods and Results: MiRNA profiles in AVICs from normal and diseased human aortic valves were analyzed by miRNA array and real-time qPCR. Diseased AVICs displayed higher levels of miR-486. Immunoblotting and immunofluorescence staining revealed that diseased AVICs had higher levels of α-SMA and α-SMA fibers. Inhibition of miR-486 by lentiviral-delivered miR-486 antagomir in diseased AVICs suppressed α-SMA expression and cell aggregation, resulting in reduced calcification nodule formation. Conversely, lentiviral-delivered miR-486 mimic in normal AVICs induced α-SMA expression and cell aggregation, leading to exacerbated calcification nodule formation. Stimulation of normal AVICs with pro-osteogenic mediators TGF-β1 and BMP-2 up-regulated miR-486 levels. MiR-486 antagomir reduced α-SMA expression, cell aggregation and calcification nodule formation in cells exposed to TGF-β1 or BMP-2. Further, miR-486 mimic induced AKT phosphorylation. Inhibition of AKT decreased α-SMA expression and cell aggregation induced by miR-486 mimic in normal AVICs. Knockdown of α-SMA suppressed cell aggregation and calcification nodule formation. Conclusions: The pro-osteogenic phenotype of AVICs of diseased aortic valves is associated with up-regulated levels of miR-486 and α-SMA. MiR-486 modulates the AKT pathway to up-regulate α-SMA expression and cell aggregation that are required for calcification nodule formation. These novel findings indicate that miR-486 contributes to the mechanism underlying aortic valve calcification and appears to be a therapeutic target for suppression of valvular osteogenic activity.

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.

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