ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells

Li, Fēi; Song, Rui; Ao, Lihua; Reece, T. Brett; Cleveland, Joseph C.; Dong, Nianguo; Fullerton, David A.; Meng, Xianzhong

doi:10.1161/atvbaha.117.309021

Cited by 33 publications

(33 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we observed that NF-κB signaling is activated in human AVICs by soluble matrilin-2, which is consistent with our previous findings [33]. In addition, we found that NF-κB activation is associated with PKR phosphorylation.…”

Section: Discussionsupporting

confidence: 93%

“…Human AVICs were stimulated with recombinant matrilin-2 (2.0 µg/mL) for different time periods to determine the impact of soluble matrilin-2 on cellular inflammatory activity. We have found in a previous study that this concentration of matrilin-2 is capable of activating NF-κB [33]. To evaluate the roles of NF-κB and PKR in mediating the effect of matrilin-2, cells were treated with NF-κB inhibitor Bay11-7082 (10 µM) and PKR inhibitors 2-AP (1.0 mM) or C 13 H 8 N 4 OS (0.5 µM) one hour before matrilin-2 treatment.…”

Section: Isolation and Culture Of Human Avicsmentioning

confidence: 77%

“…Accumulating evidence suggests that soluble ECM proteins can function as DAMPs to induce the inflammatory responses [22], and DAMPs have attracted attention for their potential role in CAVD progression [21]. In this regard, our previous studies demonstrated that soluble matrilin-2 promotes the pro-osteogenic activity in human AVICs by a TLR-dependent mechanism [33]. However, the impact of soluble matrilin-2 on AVIC inflammatory responses is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…To evaluate the roles of NF-κB and PKR in mediating the effect of matrilin-2, cells were treated with NF-κB inhibitor Bay11-7082 (10 µM) and PKR inhibitors 2-AP (1.0 mM) or C 13 H 8 N 4 OS (0.5 µM) one hour before matrilin-2 treatment. The concentrations of these pharmacological reagents were determined in reference of published studies [33,40]. To assess the effect of Klotho on AVIC inflammatory activity, recombinant Klotho was applied as a pretreatment in a concentration (0.5 µg/mL) used in our previous study [39].…”

Section: Isolation and Culture Of Human Avicsmentioning

confidence: 99%

See 3 more Smart Citations

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

Yao

Zhang

Zhai

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease. Soluble extracellular matrix (ECM) proteins can act as damage-associated molecular patterns and may induce valvular inflammation. Matrilin-2 is an ECM protein and has been found to elevate the pro-osteogenic activity in human aortic valve interstitial cells (AVICs). Klotho, an anti-aging protein, appears to have anti-inflammatory properties. The effect of matrilin-2 and Klotho on AVIC inflammatory responses remains unclear. Methods and Results: Isolated human AVICs were exposed to matrilin-2. Soluble matrilin-2 induced the production of ICAM-1, MCP-1, and IL-6. It also induced protein kinase R (PKR) activation via Toll-like receptor (TLR) 2 and 4. Pretreatment with PKR inhibitors inhibited NF-κB activation and inflammatory mediator production induced by matrilin-2. Further, recombinant Klotho suppressed PKR and NF-κB activation and markedly reduced the production of inflammatory mediators in human AVICs exposed to matrilin-2. Conclusions: This study revealed that soluble matrilin-2 upregulates AVIC inflammatory activity via activation of the TLR-PKR-NF-κB pathway and that Klotho is potent to suppress AVIC inflammatory responses to a soluble ECM protein through inhibiting PKR. These novel findings indicate that soluble matrilin-2 may accelerate the progression of CAVD by inducing valvular inflammation and that Klotho has the potential to suppress valvular inflammation.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Isolation and Culture Of Human Avicsmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Isolation and Culture Of Human Avicsmentioning

confidence: 99%

See 2 more Smart Citations

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

Yao

Zhang

Zhai

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…The process of aortic valve cell calcification is thought to involve multiple mechanisms and pathways, one of which is through ALP [17][18][19]. ALPs are membrane-bound metalloenzymes suggested to play an active role in calcium deposition by decreasing levels of pyrophosphate, a calcification inhibitor 8 , and increasing levels of inorganic phosphate, which promotes mineralization [20].…”

Section: Discussionmentioning

confidence: 99%

Assessing Calcification Onset in Aortic Valve Interstitial Cells

Khan¹,

B²,

Al‐Kindi³

et al. 2017

Cardiovasc Pharm Open Access

View full text Add to dashboard Cite

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...

show abstract

Decreased expression of RPL15 and RPL18 exacerbated the calcification of valve interstitial cells during aortic valve calcification

Wang

Qin

Zhang

et al. 2023

Cell Biology International

View full text Add to dashboard Cite

Calcific aortic valve disease (CAVD) is the most common valvular heart disease, with an increasing prevalence due to an aging population. The pathobiology of CAVD is a multifaceted and actively regulated process, but the detailed mechanisms have not been elucidated. The present study aims to identify the differentially expressed genes (DEGs) in calcified aortic valve tissues, and to analyze the correlation between DEGs and clinical features in CAVD patients. The DEGs were screened by microarray in normal and CAVD groups (n = 2 for each group), and confirmed by quantitative real‐time polymerase chain reaction in normal (n = 12) and calcified aortic valve tissues (n = 34). A total of 1048 DEGs were identified in calcified aortic valve tissues, including 227 upregulated mRNAs and 821 downregulated mRNAs. Based on multiple bioinformatic analyses, three 60S ribosomal subunit components (RPL15, RPL18, and RPL18A), and two 40S ribosomal subunit components (RPS15 and RPS21) were identified as the top 5 hub genes in the protein–protein interaction network of DEGs. The expression of RPL15 and RPL18 was also found significantly decreased in calcified aortic valve tissues (both p < .01), and negatively correlated with the osteogenic differentiation marker OPN in CAVD patients (both p < .01). Moreover, inhibition of RPL15 or RPL18 exacerbated the calcification of valve interstitial cells under osteogenic induction conditions. The present study proved that decreased expression of RPL15 and RPL18 was closely associated with aortic valve calcification, which provided valuable clues to find therapeutic targets for CAVD.

show abstract

ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells

Cited by 33 publications

References 43 publications

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

Assessing Calcification Onset in Aortic Valve Interstitial Cells

Decreased expression of RPL15 and RPL18 exacerbated the calcification of valve interstitial cells during aortic valve calcification

Contact Info

Product

Resources

About