Calcific Aortic Stenosis—A Review on Acquired Mechanisms of the Disease and Treatments

Zebhi, Banafsheh; Lazkani, Mohamad; Bark, David

doi:10.3389/fcvm.2021.734175

Cited by 24 publications

(20 citation statements)

References 160 publications

(191 reference statements)

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“…Estimates have predicted that the disease burden in developed countries will double from 2000 to 2030 (14). For years, the progression of valve calcification had been considered a kind of irreversible degeneration during which calcium nodules are deposited on leaflets (15). With the improved understanding of disease mechanisms, valve calcification has been widely accepted to involve mixed pathophysiological progression, including endothelial dysfunction, lipid deposition, inflammation response, myofibroblastic and osteoblastic differentiation, calcific pathways activation, immune infiltration, and so on (15,16).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Sequencing Data Reveal LncRNA-miRNA-mRNA Regulatory Network in Calcified Aortic Valve Disease

Huang

Gao

et al. 2022

Front. Cardiovasc. Med.

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BackgroundCalcified aortic valve disease (CAVD) is one of the most common valvular heart diseases in the elderly population. However, no effective medical treatments have been found to interfere with the progression of CAVD, and specific molecular mechanisms of CAVD remain unclear.Materials and MethodsTranscriptome sequencing data of GSE55492 and GSE148219 were downloaded from the European Nucleotide Archive, and the microarray dataset, GSE12644 was acquired from the Gene Expression Omnibus database. Software, including FastQC, HISAT2, samtools, and featureCounts was applied to generate the read count matrix. The “Limma” package in R was utilized to analyze differentially expressed genes (DEGs). Thereafter, weighted gene co-expression network analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the protein-protein interaction (PPI) network were used to identify hub genes associated with CAVD, which were further validated by receiver operating characteristic curve (ROC) analysis using GSE12644. The long non-coding RNA (LncRNA)-mediated regulatory network was established based on the differentially expressed LncRNAs and hub genes, which were detected using quantitative real-time PCR (qRT-PCR) in clinical samples and valve interstitial cells. Moreover, CIBERSORT was used to calculate the expression distribution of immune cell infiltration in CAVD.ResultsA total of 126 DEGs were included in the PPI network. PI3K-Akt signaling pathway, ECM-receptor interaction, hematopoietic cell lineage, cell adhesion molecules, and focal adhesion were the most enriched pathways revealed by KEGG. Four LncRNAs, including TRHDE-AS1, LINC00092, LINC01094, and LINC00702 were considered the differentially expressed LncRNA. SPP1, TREM1, GPM6A, CCL19, CR1, NCAM1, CNTN1, TLR8, SDC1, and COL6A6 were the 10 hub genes identified to be associated with CAVD. Moreover, the calcified aortic valve samples had a greater level of Tregs, naïve B cells, and M0 macrophages than the noncalcified ones, whereas CAVD samples had a lower M2 macrophage expression compared to the noncalcified valve tissues.ConclusionThe current study identified SPP1, TREM1, TLR8, SDC1, GPM6A, and CNTN1 as hub genes that could potentially be associated with CAVD. The LINC00702–miR-181b-5p–SPP1 axis might participate in the development of CAVD. Additionally, M2 macrophages, Tregs, naïve B cells, and M0 macrophages might possibly play a role in the initiation of CAVD.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Sequencing Data Reveal LncRNA-miRNA-mRNA Regulatory Network in Calcified Aortic Valve Disease

Huang

Gao

et al. 2022

Front. Cardiovasc. Med.

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“…The role of VCL has previously been reported in both valvular and vascular endothelial morphological alignment ( 54 ). Endothelial cells sense the hemodynamics in their environment and contribute to calcification by responding to the shear stress experienced on the cells’ apical side ( 55 ). To test the expression of these integrin pathway genes, we combined our data with previously published scRNAseq data of mouse adult aortic valves at P30 as described previously ( 7 , 39 ).…”

Section: Resultsmentioning

confidence: 99%

Single-cell RNA-sequencing analysis of aortic valve interstitial cells demonstrates the regulation of integrin signaling by nitric oxide

Majumdar

Choudhury

Manivannan

et al. 2022

Front. Cardiovasc. Med.

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Calcific aortic valve disease (CAVD) is an increasingly prevalent condition among the elderly population that is associated with significant morbidity and mortality. Insufficient understanding of the underlying disease mechanisms has hindered the development of pharmacologic therapies for CAVD. Recently, we described nitric oxide (NO) mediated S-nitrosylation as a novel mechanism for preventing the calcific process. We demonstrated that NO donor or an S-nitrosylating agent, S-nitrosoglutathione (GSNO), inhibits spontaneous calcification in porcine aortic valve interstitial cells (pAVICs) and this was supported by single-cell RNA sequencing (scRNAseq) that demonstrated NO donor and GSNO inhibited myofibroblast activation of pAVICs. Here, we investigated novel signaling pathways that are critical for the calcification of pAVICs that are altered by NO and GSNO by performing an in-depth analysis of the scRNA-seq dataset. Transcriptomic analysis revealed 1,247 differentially expressed genes in pAVICs after NO donor or GSNO treatment compared to untreated cells. Pathway-based analysis of the differentially expressed genes revealed an overrepresentation of the integrin signaling pathway, along with the Rho GTPase, Wnt, TGF-β, and p53 signaling pathways. We demonstrate that ITGA8 and VCL, two of the identified genes from the integrin signaling pathway, which are known to regulate cell-extracellular matrix (ECM) communication and focal adhesion, were upregulated in both in vitro and in vivo calcific conditions. Reduced expression of these genes after treatment with NO donor suggests that NO inhibits calcification by targeting myofibroblast adhesion and ECM remodeling. In addition, withdrawal of NO donor after 3 days of exposure revealed that NO-mediated transcriptional and translational regulation is a transient event and requires continuous NO exposure to inhibit calcification. Overall, our data suggest that NO and S-nitrosylation regulate the integrin signaling pathway to maintain healthy cell-ECM interaction and prevent CAVD.

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“…In the CFD analysis, the NCC cusp was the most diseased compared to LCC and RCC. This correlates to a lower shear stress and high flow oscillation on NCC compared to other cusps, resulting in calcific lesions [ 22 , 23 ]. The images of the explanted severely calcified valves ( Figure 3 ) on the fibrosa layer concur with previous studies that show the valve fibrosa layer being most critically involved in aortic valve calcification, specifically near the annulus, or base regions [ 8 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

Valve Endothelial Cell Exposure to High Levels of Flow Oscillations Exacerbates Valve Interstitial Cell Calcification

et al. 2022

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The aortic valve facilitates unidirectional blood flow to the systemic circulation between the left cardiac ventricle and the aorta. The valve’s biomechanical function relies on thin leaflets to adequately open and close over the cardiac cycle. A monolayer of valve endothelial cells (VECs) resides on the outer surface of the aortic valve leaflet. Deeper within the leaflet are sublayers of valve interstitial cells (VICs). Valve tissue remodeling involves paracrine signaling between VECs and VICs. Aortic valve calcification can result from abnormal paracrine communication between these two cell types. VECs are known to respond to hemodynamic stimuli, and, specifically, flow abnormalities can induce VEC dysfunction. This dysfunction can subsequently change the phenotype of VICs, leading to aortic valve calcification. However, the relation between VEC-exposed flow oscillations under pulsatile flow to the progression of aortic valve calcification by VICs remains unknown. In this study, we quantified the level of flow oscillations that VECs were exposed to under dynamic culture and then immersed VICs in VEC-conditioned media. We found that VIC-induced calcification was augmented under maximum flow oscillations, wherein the flow was fully forward for half the cardiac cycle period and fully reversed for the other half. We were able to computationally correlate this finding to specific regions of the aortic valve that experience relatively high flow oscillations and that have been shown to be associated with severe calcified deposits. These findings establish a basis for future investigations on engineering calcified human valve tissues and its potential for therapeutic discovery of aortic valve calcification.

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Calcific Aortic Stenosis—A Review on Acquired Mechanisms of the Disease and Treatments

Cited by 24 publications

References 160 publications

Transcriptome Sequencing Data Reveal LncRNA-miRNA-mRNA Regulatory Network in Calcified Aortic Valve Disease

Transcriptome Sequencing Data Reveal LncRNA-miRNA-mRNA Regulatory Network in Calcified Aortic Valve Disease

Single-cell RNA-sequencing analysis of aortic valve interstitial cells demonstrates the regulation of integrin signaling by nitric oxide

Valve Endothelial Cell Exposure to High Levels of Flow Oscillations Exacerbates Valve Interstitial Cell Calcification

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