Human interstitial cellular model in therapeutics of heart valve calcification

He, Caimei; Tang, Hai Ling; Mei, Zijian; Li, Nichujie; Zeng, Zhi; Darko, Kwame Oteng; Yin, Yulong; Hu, Chien‐An Andy; Yang, Xiao‐Ping

doi:10.1007/s00726-017-2432-3

Cited by 8 publications

(7 citation statements)

References 140 publications

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“…The expression of BMP2 has been shown to be mediated through NF‐κB signaling in order to induce valve calcification 75,76 . Since Selumetinib causes complete reversal of calcification, further investigation of the role of ERK signaling within the NF‐κB pathway to promote VIC calcification is warranted 62,77,78 . However, reduced RUNX2 gene expression suggests the potential involvement of the MAPK/ERK pathway in TNF‐α induced exacerbated calcification.…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor‐α promotes and exacerbates calcification in heart valve myofibroblast populations

et al. 2021

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Pro‐inflammatory cytokines play critical roles in regulating valvular interstitial cell (VIC) phenotypic changes that can cause heart valve fibrosis and calcification. Tumor necrosis factor alpha (TNF‐α) is a cytokine known to influence VIC behavior and has been reported at high levels in calcified valves ex vivo. We sought to understand the specific effects of TNF‐α on VIC phenotypes (eg, fibroblast, profibrotic activated myofibroblasts) and its link with heart valve disorders. We characterize human aortic valve tissue from patients with valve disorders and identify a high variability of fibrotic and calcific markers between tissues. These results motivated in vitro studies to explore the effects of TNF‐α on defined VIC fibroblasts and profibrotic activated myofibroblasts, induced via FGF‐2 and TGF‐β1 treatment. Using 3D hydrogels to culture VICs, we measure the effect of TNF‐α (0.1‐10 ng/mL) on key markers of fibrosis (eg, αSMA, COL1A1) and calcification (eg, RUNX2, BMP2, and calcium deposits). We observe calcification in TNF‐α‐treated VIC activated myofibroblasts and identify the MAPK/ERK signaling cascade as a potential pathway for TNF‐α mediated calcification. Conversely, VIC fibroblasts respond to TNF‐α with decreased calcification. Treatment of VIC profibrotic activated myofibroblast populations with TNF‐α leads to increased calcification. Our in vitro findings correlate with findings in diseased human valves and highlight the importance of understanding the effect of cytokines and signaling pathways on specific VIC phenotypes. Finally, we reveal MAPK/ERK as a potential pathway involved in VIC‐mediated matrix calcification with TNF‐α treatment, suggesting this pathway as a potential pharmaceutical target for aortic valve disease.

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Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor‐α promotes and exacerbates calcification in heart valve myofibroblast populations

et al. 2021

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“…In the past, different animals were used to study disease pathologies due to the limitations of acquiring human samples. However, we now have the means to study calcification in AVS using human tissues [14,15,29], which according to our results, may be the only effective way to study the disease. Our study is limited, however, in that it only explores ALP-dependent calcification and does not address other molecular contributors including Runx2 [30], Wnts [4], UII [15], BMPs [31], and TGF-β [32].…”

Section: Discussionmentioning

confidence: 82%

Assessing Calcification Onset in Aortic Valve Interstitial Cells

Khan¹,

B²,

Al‐Kindi³

et al. 2017

Cardiovasc Pharm Open Access

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IntroductionAortic valve stenosis (AVS) is a complex disease, characterized by the thickening of the aortic valve with significant fibrosis and/or calcification [1]. Short-term symptoms include shortness of breath and fainting, while more long-term symptoms include heart failure and inevitably, death [2]. Treatment for AVS remains non-existent, with surgical intervention being the only viable option for at-risk patients. Thus, there has been interest in finding innovative approaches to treating this perilous disease [3,4].The pathogenesis of AVS is an active process involving multiple cell types and complexed underlying mechanisms [5,6]. Upon differentiation of mesenchymal-like cells to chondrogenic cells, matrix vesicles are released, containing enzymes and other factors that lead to the onset of calcification [7]. One of these enzymes, alkaline phosphatase (ALP), is a metalloenzyme that has been shown to play a profound role in calcification onset by concentrating calcium [8], mineralizing hydroxyapatite crystals [8], and inactivating inhibitory polyphosphates [9]. In humans, there are four ALP isozymes: alkaline phosphatase, tissue-nonspecific isozyme (TNALP), intestinal-type alkaline phosphatase, placental-type alkaline phosphatase, and placental-like alkaline phosphatase [10]. Two isoforms of TNALP exist: bone-specific TNALP and liver-specific TNALP, both of which are abundantly found in the serum [10]. Within the context of vascular calcification, bone TNALP is highly expressed in calcifying vascular smooth muscle cells and is likely to be responsible for calcium deposition and AVS pathogenesis [10].A multitude of studies draw conclusions regarding the pathogenesis of AVS in humans by utilizing aortic valve interstitial cells from bovine [11][12][13]. The ultimate goal of these studies is to identify mechanisms that will help us better understand calcification onset in humans. However, there is a need to directly compare these animal models to humans and assess whether or not it is plausible to make such a AbstractAortic valve stenosis (AVS) is one of the most common heart valve diseases, and surgical intervention remains the only viable treatment option. Thus, there is a need for novel and innovative treatments. One approach is to study the biological pathogenesis of this disease in hopes of finding new targets for drug therapy. Although this may be a viable option, it faces some methodological concerns. Many studies attempted to address the underlying mechanisms of this disease using aortic valves from bovine models. Although these may be viable models in certain diseased conditions, this may not be the case when studying calcification in AVS. Thus, the aim of our study was to assess the significance of drawing conclusions from bovine models to humans in the context of AVS, and investigate the role of alkaline phosphatase (ALP), an enzyme that increases calcium mineralization and deposition in aortic valve calcification. We also wanted to identify any differences in calcification when using different os...

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“…We and others have shown that altered biomechanics can also promote calcific nodule formation when VICs are cultured on stiff matrices such as glass [ 24 , 88 , 89 ], or tissue culture polystyrene pre-coated with fibrin, laminin, and heparin also leads to an increase in the number of calcific nodules [ 90 ] or the addition of TGF-β [ 91 ]. In most assays, investigators utilize VICs isolated from human, porcine, and ovine models as these have been previously reported to have potential to undergo calcification in vitro (reviewed in [ 92 ]). Similar protocols for murine VICs have been more technically challenging, although intact, whole aortic valve explants can undergo osteogenic changes upon stimulation [ 93 , 94 ].…”

Section: Calcific Aortic Valve Diseasementioning

confidence: 99%

Calcific Aortic Valve Disease: a Developmental Biology Perspective

Dutta

Lincoln

2018

Curr Cardiol Rep

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Purpose of ReviewThis review aims to highlight the past and more current literature related to the multifaceted pathogenic programs that contribute to calcific aortic valve disease (CAVD) with a focus on the contribution of developmental programs.Recent FindingsCalcification of the aortic valve is an active process characterized by calcific nodule formation on the aortic surface leading to a less supple and more stiffened cusp, thereby limiting movement and causing clinical stenosis. The mechanisms underlying these pathogenic changes are largely unknown, but emerging studies have suggested that signaling pathways common to valvulogenesis and bone development play significant roles and include Transforming Growth Factor-β (TGF-β), bone morphogenetic protein (BMP), Wnt, Notch, and Sox9.SummaryThis comprehensive review of the literature highlights the complex nature of CAVD but concurrently identifies key regulators that can be targeted in the development of mechanistic-based therapies beyond surgical intervention to improve patient outcome.

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Human interstitial cellular model in therapeutics of heart valve calcification

Cited by 8 publications

References 140 publications

Tumor necrosis factor‐α promotes and exacerbates calcification in heart valve myofibroblast populations

Tumor necrosis factor‐α promotes and exacerbates calcification in heart valve myofibroblast populations

Assessing Calcification Onset in Aortic Valve Interstitial Cells

Calcific Aortic Valve Disease: a Developmental Biology Perspective

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