Calcific Aortic Valve Disease: Molecular Mechanisms And Therapeutic Approaches

Lerman, Daniel Alejandro; Prasad, Sai; Alotti, Nasri

doi:10.15420/ecr.2015.10.2.108

Cited by 117 publications

(107 citation statements)

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“…Activation of VICs by shear stress induces inflammatory events and angiogenic activity. Once activated, VICs may then undergo osteoblastic differentiation with bone formation (Lerman et al 2015). Although insignificant, our results show that expression levels of certain Fzd receptors are higher in calcified BAV tissue.…”

Section: Discussionmentioning

confidence: 54%

Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves

Siddique

Khan

et al. 2018

Can. J. Physiol. Pharmacol.

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The cellular mechanisms that induce calcific aortic stenosis are yet to be unraveled. Wnt signaling is increasingly being considered as a major player in the disease process. However, the presence of Wnt Frizzled (Fzd) receptors and co-receptors LRP5 and 6 in normal and diseased human aortic valves remains to be elucidated. Immunohistochemistry and quantitative polymerase chain reaction were used to determine Fzd receptor expression in normal and calcified human aortic valve tissue, as well as human aortic valve interstitial cells (HAVICs) isolated from calcified and normal human aortic valves. There was significantly higher mRNA expression of 4 out of the 10 Fzd receptors in calcified aortic valve tissues and 8 out of the 10 in HAVICs, and both LRP5/6 co-receptors in calcified aortic valves (P < 0.05). These results were confirmed by immunohistochemistry, which revealed abundant increase in immunoreactivity for Fzd3, 7, and 8, mainly in areas of lipid core and calcified nodules of diseased aortic valves. The findings of abundant expression of Fzd and LRP5/6 receptors in diseased aortic valves suggests a potential role for both canonical and noncanonical Wnt signaling in the pathogenesis of human aortic valve calcification. Future investigations aimed at targeting these molecules may provide potential therapies for aortic valve stenosis.

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Section: Discussionmentioning

confidence: 54%

Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves

Siddique

Khan

et al. 2018

Can. J. Physiol. Pharmacol.

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“…The molecular mechanisms that contribute to AVS are not well understood and it is likely that multiple signaling pathways contribute to disease onset [1,6]. In this study, we examined ALP-dependent calcification in aortic valve interstitial cells from human and bovine models.…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…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].…”

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confidence: 99%

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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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“…The risk factors for development of this etiology of aortic stenosis are the same factors that contribute towards accelerating atherosclerotic disease: dyslipidemia, systemic arterial hypertension, diabetes mellitus and smoking. 1 The classic model showing a strong association between hypercholesterolemia and aortic stenosis is homozygous familial hypercholesterolemia. 2 In this disease, in which patients present very high levels of LDL-cholesterol, aortic stenosis or supravalvular stenosis progresses very fast and is an important cause of morbidity and mortality among these patients.…”

Section: Commentsmentioning

confidence: 99%