Cardamonin inhibits osteogenic differentiation of human valve interstitial cells and ameliorates aortic valve calcification via interfering NF-κB/NLRP3 inflammasome pathway

2021 ◽  
Author(s):  
Chunli wang ◽  
Yi Xia ◽  
Linghang Qu ◽  
Yanju Liu ◽  
Xianqiong Liu ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Osteogenic Differentiation ◽  
Nlrp3 Inflammasome ◽  
Aortic Valve Disease ◽  
Interstitial Cells ◽  
Valve Disease ◽  
Aortic Valve Calcification ◽  
Calcific Aortic Valve Disease ◽  
Valve Calcification ◽  
Valve Interstitial Cells

Cardamonin (CDM) is a natural chalcone with strong anti-inflammatory properties. Inflammation-induced osteogenic changes in valve interstitial cells (VICs) play crucial roles in the development of calcific aortic valve disease (CAVD),...

Abstract P098: Inhibitory Role of Notch1 in Calcific Aortic Valve Disease Is Mediated by Sox9

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Chetan P Hans ◽  
Asha Acharya ◽  
Sara N Koenig ◽  
Haley A Nichols ◽  
Cristi L Galindo ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Aortic Valve Disease ◽  
Notch Signaling Pathway ◽  
Valve Disease ◽  
Calcium Deposition ◽  
Aortic Valve Calcification ◽  
Calcific Aortic Valve Disease ◽  
Valve Calcification

Introduction: Aortic valve calcification is the most common form of valvular heart disease; however the mechanism(s) underlying calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. Objective: To investigate the molecular changes associated with the calcification of aortic valve that occurs with inhibition of Notch signaling. Methods and Results: The expression of Notch signaling pathway members was validated in the aortic valve cusps from adult mice, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1 signaling, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of many cartilage-specific genes that constitute the valve extracellular matrix (ECM). Analysis of these cartilage-specific genes demonstrated that several were transcriptional targets of Sox9, a master regulator of chondrogenesis, which has been previously shown to be essential for proper valve development and maintenance. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, utilizing transfection studies, addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. Conclusions: Loss of Notch signaling contributes to aortic valve calcification by a Sox9-dependent mechanism. Further elucidation of the Notch1-Sox9 molecular pathway and its role in the maintenance of the ECM will lead to an improved mechanistic understanding of aortic valve calcification and development of novel therapeutic strategies for CAVD.

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 Decreased Glucagon-Like Peptide-1 Is Associated With Calcific Aortic Valve Disease: GLP-1 Suppresses the Calcification of Aortic Valve Interstitial Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Fan Xiao ◽  
Qing Zha ◽  
Qianru Zhang ◽  
Qihong Wu ◽  
Zhongli Chen ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Interstitial Cells ◽  
Valve Disease ◽  
Dependent Manner ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Objectives: This study explores the concentration and role of glucagon-like peptide-1 (GLP-1) in calcific aortic valve disease (CAVD).Background: Calcific aortic valve disease is a chronic disease presenting with aortic valve degeneration and mineralization. We hypothesized that the level of GLP-1 is associated with CAVD and that it participates in the calcification of aortic valve interstitial cells (AVICs).Methods: We compared the concentration of GLP-1 between 11 calcific and 12 normal aortic valve tissues by immunohistochemical (IHC) analysis. ELISA was used to measure GLP-1 in serum of the Control (n = 197) and CAVD groups (n = 200). The effect of GLP-1 on the calcification of AVICs and the regulation of calcific gene expression were also characterized.Results: The GLP-1 concentration in the calcific aortic valves was 39% less than that in the control non-calcified aortic valves. Its concentration in serum was 19.3% lower in CAVD patients. Multivariable regression analysis demonstrated that GLP-1 level was independently associated with CAVD risk. In vitro, GLP-1 antagonized AVIC calcification in a dose- and time-dependent manner and it down-regulated RUNX2, MSX2, BMP2, and BMP4 expression but up-regulated SOX9 expression.Conclusions: A reduction in GLP-1 was associated with CAVD, and GLP-1 participated in the mineralization of AVICs by regulating specific calcific genes. GLP-1 warrants consideration as a novel treatment target for CAVD.

scholarly journals Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

2017 ◽  
Vol 114 (7) ◽  
pp. 1631-1636 ◽  
Author(s):  
Qingchun Zeng ◽  
Rui Song ◽  
David A. Fullerton ◽  
Lihua Ao ◽  
Yufeng Zhai ◽  
...  
Keyword(s):  
Aortic Valve ◽  
High Fat Diet ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
High Fat ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Valve Lesions ◽  
Osteogenic Factors

Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.

Abstract 27: Role of Sirtuin 6 in the Initiation and Progression of Calcific Aortic Valve Disease

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Carolyn M Roos ◽  
Bin Zhang ◽  
Grace Verzosa ◽  
Elise A Oehler ◽  
Michael A Hagler ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
Left Ventricular Ejection ◽  
Calcific Aortic Valve Disease ◽  
Valve Calcification ◽  
Age Related ◽  
Valve Function ◽  
Osteogenic Signaling

Increasing age is a major risk factor for calcific aortic valve disease (CAVD). Interestingly, SIRT6 knockout mice have a marked progeroid phenotype, and we recently reported that sirtuin enzyme expression is dramatically reduced with aging and that SIRT6 expression is reduced further in valves from patients with end-stage CAVD. It is unknown, however, whether experimentally reducing SIRT6 promotes osteogenic signaling in the valve and ultimately accelerates progression of CAVD. Thus, we used cultured mouse aortic valve interstitial cells and ldlr-deficient, apolipoprotein B100-only mice (LA) that were SIRT6 wild-type (LA-SIRT6 +/+ ) or heterozygous (LA-SIRT6 +/- ) and fed a Western diet for 3 or 12 months to determine the role of SIRT6 in valve calcification. In vitro , reduction of SIRT6 increased histone acetylation and significantly increased mRNA and protein levels of the osteogenic genes Runx2 and Sp7 in response to bone morphogenetic protein 2 (100ng/ml BMP2 for 18 hours), and siRNA knockdown of SIRT6 increased mRNA levels of Sp7 even in the absence of exogenous bone morphogens. Using high-resolution ultrasound to evaluate aortic valve function in vivo, we found that 3 month old LA-SIRT6 +/- mice did not have significant impairments in valve function compared to LA-SIRT6 +/+ mice. In contrast, 12 month old LA-SIRT6 +/- had dramatically worsened aortic valve dysfunction and stenosis compared to LA-SIRT6 +/+ mice, which was also associated with reductions in left ventricular ejection fraction. Collectively, our data strongly suggest SIRT6 plays a critical role in the tonic repression of osteogenic signaling in the aortic valve, and that age-related reductions in SIRT6 are likely to increase susceptibility to valve calcification in response to risk factors for CAVD such as hypercholesterolemia. Collectively, increasing activity of SIRT6 or reducing acetylation of its targets may serve as viable therapeutic strategies to slow progression of age-related valvular calcification and stenosis.

Abstract 201: BMP-pSmad1/5/8 Pathway Activation in a Novel Mouse Model of Calcific Aortic Valve Disease

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Maria V Gomez ◽  
Jonathan D Cheek ◽  
Elaine E Wirrig ◽  
Katherine E Yutzey
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Gene Induction ◽  
Signaling Cascade ◽  
Nodule Formation ◽  
Aortic Valve Calcification ◽  
Calcific Aortic Valve Disease ◽  
Valve Calcification ◽  
Deficient Mice ◽  
Osteogenic Gene

Calcific Aortic Valve Disease (CAVD) affects >2% of the population over the age of 65, for whom the current standard of care is valve replacement surgery. To date, there are no pharmacologic-based therapies that prevent the progression or inhibit the development of CAVD, thus highlighting the necessity for new therapeutic approaches. Despite its clinical significance, the pathogenic mechanisms that drive the development of CAVD, and that could serve as potential therapeutic targets, remain unknown. We have recently identified Klotho-deficient mice, an established model of premature aging, as a novel model of CAVD that exhibit aortic valve calcification on the fibrosa side of the hinge region, closely mimicking human CAVD pathology. Unlike previous models, calcification occurs independent of inflammation and valve thickening in these mice, supporting a distinct mechanism of age-related calcification common in elderly patients. In bone, BMP-mediated osteogenic gene induction is essential for the process of calcification. Notably, pSmad1/5/8 activation, indicative of active BMP signaling, is observed prior to the onset of calcification and later is localized with calcific nodule formation in klotho-deficient mice with CAVD. Our hypothesis is that activation of BMP-pSmad1/5/8 signaling pathway promotes osteogenic gene induction and aortic valve mineralization in CAVD. Osteogenic factors, Runx2 and Osteopontin, are significantly increased in the aortic valves of klotho-deficient mice, suggesting an osteogenic-like mechanism of disease. Likewise, pSmad1/5/8 activation precedes osteogenic gene induction in these mice. Moreover, increased BMP2/4 ligand expression is detected prior to the onset of disease, as well as during calcific nodule formation, thus supporting an active role for the BMP-pSmad1/5/8 signaling cascade during aortic valve calcification. Our ongoing work includes BMP pathway inhibition studies to determine if this is an effective therapeutic strategy for the treatment of CAVD in the klotho-deficient mice. Altogether our data support a role for the BMP-pSmad1/5/8 signaling cascade as a critical mechanism in the initial onset and progression of aortic valve calcification in a novel mouse model of CAVD.

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