Bicuspid Aortic Valves Experience Increased Strain as Compared to Tricuspid Aortic Valves

Szeto, Kai; Pastuszko, Peter; Álamo, Juan C. del; Lasheras, Juan C.; Nigam, Vishal

doi:10.1177/2150135113501901

Cited by 17 publications

(18 citation statements)

References 16 publications

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“…Given this disorganization, isotropic strain is a starting point to examine the stretch responsive molecular pathways in BAV AVICs. Anisotropic strains are an interesting topic to study because we have found that BAVs experience anisotropic strains in ex vivo experiments (13). In addition, there are interesting data that porcine AVICs have differential responses to anisotropic strain (53).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, there are interesting data that porcine AVICs have differential responses to anisotropic strain (53). Although we have found BAV leaflets can experience as high as 25% increase in strain (13), a 14% strain for our experiments was used because that was the maximum strain that the Flexcell system could deliver at 1 Hz. Exposing human AVICs to anisotropic strains and different magnitudes of strain has potential to further the understanding of the role that stretch plays in the pathogenesis of BAV calcification.…”

Section: Discussionmentioning

confidence: 99%

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The stretch responsive microRNA miR‐148a‐3p is a novel repressor of IKBKB , NF‐κB signaling, and inflammatory gene expression in human aortic valve cells

et al. 2015

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Bicuspid aortic valves calcify at a significantly higher rate than normal aortic valves, a process that involves increased inflammation. Because we have previously found that bicuspid aortic valve experience greater stretch, we investigated the potential connection between stretch and inflammation in human aortic valve interstitial cells (AVICs). Microarray, quantitative PCR (qPCR), and protein assays performed on AVICs exposed to cyclic stretch showed that stretch was sufficient to increase expression of interleukin and metalloproteinase family members by more than 1.5-fold. Conditioned medium from stretched AVICs was sufficient to activate leukocytes. microRNA sequencing and qPCR experiments demonstrated that miR-148a-3p was repressed in both stretched AVICs (43% repression) and, as a clinical correlate, human bicuspid aortic valves (63% reduction). miR-148a-3p was found to be a novel repressor of IKBKB based on data from qPCR, luciferase, and Western blot experiments. Furthermore, increasing miR-148a-3p levels in AVICs was sufficient to decrease NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling and NF-κB target gene expression. Our data demonstrate that stretch-mediated activation of inflammatory pathways is at least partly the result of stretch-repression of miR-148a-3p and a consequent failure to repress IKBKB. To our knowledge, we are the first to report that cyclic stretch of human AVICs activates inflammatory genes in a tissue-autonomous manner via a microRNA that regulates a central inflammatory pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The stretch responsive microRNA miR‐148a‐3p is a novel repressor of IKBKB , NF‐κB signaling, and inflammatory gene expression in human aortic valve cells

et al. 2015

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“…One is the susceptibility of the bicuspid aortic valve (BAV) to valve calcification (Michelena et al 2014); BAV is a congenital valve defect in which the patient has only two aortic valves, while a normal person has three. BAVs experience more hemodynamic stress, which can increase the risk of developing CAVD (Szeto et al 2013). The other example is the side-dependent pathological characteristics of CAVD.…”

Section: Introductionmentioning

confidence: 99%

Integrated Bioinformatics Analysis Predicts the Key Genes Involved in Aortic Valve Calcification: From Hemodynamic Changes to Extracellular Remodeling

Liu

Luo

Sun

et al. 2017

Tohoku J. Exp. Med.

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In our aging world, increasing numbers of people are suffering from calcific aortic valve disease (CAVD). In this study, we used integrated bioinformatics analysis to predict several key genes that are involved in the initiation and progression of CAVD. Expression profiles of 15 calcific and 14 normal human aortic valve samples were generated from two gene expression datasets (GSE12644 and GSE51472). Dataset GSE26953 from the human aortic valve fibrosa-derived endothelial cells cultured under laminar or oscillatory shear stress was also evaluated. Related R packages were used to process the data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for functional annotation. Hub genes were identified based on the protein-protein interaction network. CAVD-related gene modules were identified by Weighted Gene Co-expression Network Analysis (WGCNA). The predicted key genes were manually reviewed. In our present work, complex connections among mechano-response, oxidative stress, inflammation and extracellular remodeling pathways in the etiology of CAVD were revealed. The key genes, thus identified, encode a transcription factor KLF2 and phospholipid phosphatase 3 (PLPP3) that are involved in mechanoresponses; eNOS involved in oxidative stress; IL-8 involved in inflammation; and collagen triple helix repeat containing 1 (CTHRC1) and secretogranin II (SCG2) involved in extracellular remodeling. These gene products are predicted to play critical roles in CAVD development and progression. The present study provides valuable information for future research and drug development.

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“…BAVs are under a significantly higher amount strain compared to tricuspid aortic valves, and increased mechanical stress on VICs contributes to cell injury in AVC (Merryman and Schoen 2013;Szeto et al 2013). Activation of VICs by shear stress induces inflammatory events and angiogenic activity.…”

Section: Discussionmentioning

confidence: 99%

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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Bicuspid Aortic Valves Experience Increased Strain as Compared to Tricuspid Aortic Valves

Cited by 17 publications

References 16 publications

The stretch responsive microRNA miR‐148a‐3p is a novel repressor of IKBKB , NF‐κB signaling, and inflammatory gene expression in human aortic valve cells

The stretch responsive microRNA miR‐148a‐3p is a novel repressor of IKBKB , NF‐κB signaling, and inflammatory gene expression in human aortic valve cells

Integrated Bioinformatics Analysis Predicts the Key Genes Involved in Aortic Valve Calcification: From Hemodynamic Changes to Extracellular Remodeling

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

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