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- Bjorck, HM, et al.
(author)
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Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve
- 2018
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 2777-
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Journal article (peer-reviewed)abstract
- Disturbed flow has been suggested to contribute to aneurysm susceptibility in bicuspid aortic valve (BAV) patients. Lately, flow has emerged as an important modulator of DNA methylation. Hear we combined global methylation analysis with in vitro studies of flow-sensitive methylation to identify biological processes associated with BAV-aortopathy and the potential contribution of flow. Biopsies from non-dilated and dilated ascending aortas were collected from BAV (n = 21) and tricuspid aortic valve (TAV) patients (n = 23). DNA methylation and gene expression was measured in aortic intima-media tissue samples, and in EA.hy926 and primary aortic endothelial cells (ECs) isolated from BAV and TAV exposed to oscillatory (±12 dynes/cm2) or laminar (12 dynes/cm2) flow. We show methylation changes related to epithelial-mesenchymal-transition (EMT) in the non-dilated BAV aorta, associated with oscillatory flow related to endocytosis. The results indicate that the flow-response in BAV ECs involves hypomethylation and increased expression of WNT/β-catenin genes, as opposed to an angiogenic profile in TAV ECs. The EMT-signature was exasperated in dilated BAV aortas. Aberrant EMT in BAV aortic walls could contribute to increased aneurysm susceptibility, and may be due to disturbed flow-exposure. Perturbations during the spatiotemporally related embryonic development of ascending aorta and semilunar valves can however not be excluded.
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- Maleki, S, et al.
(author)
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Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves
- 2016
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 35712-
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Journal article (peer-reviewed)abstract
- Individuals with a bicuspid aortic valve (BAV) are at significantly higher risk of developing aortic complications than individuals with tricuspid aortic valves (TAV) and defective signaling during the embryonic development and/or life time exposure to abnormal hemodynamic have been proposed as underlying factors. However, an explanation for the molecular mechanisms of aortopathy in BAV has not yet been provided. We combined proteomics, RNA analyses, immunohistochemistry, and electron microscopy to identify molecular differences in samples of non-dilated ascending aortas from BAV (N = 62) and TAV (N = 54) patients. Proteomic analysis was also performed for dilated aortas (N = 6 BAV and N = 5 TAV) to gain further insight into the aortopathy of BAV. Our results collectively showed the molecular signature of an endothelial/epithelial-mesenchymal (EndMT/EMT) transition-like process, associated with instability of intimal cell junctions and activation of RHOA pathway in the intima and media layers of ascending aorta in BAV patients. We propose that an improper regulation of EndMT/EMT during the spatiotemporally related embryogenesis of semilunar valves and ascending aorta in BAV individuals may result in aortic immaturity and instability prior to dilation. Exasperation of EndMT/EMT state in post embryonic life and/or exposure to non-physiological hemodynamic could lead to the aneurysm of ascending aorta in BAV individuals.
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- Paloschi, V., et al.
(author)
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Impaired splicing of fibronectin is associated with thoracic aortic aneurysm formation in patients with bicuspid aortic valve
- 2011
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In: Arteriosclerosis, Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 31:3, s. 691-7
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Thoracic aortic aneurysm is a common complication in patients with bicuspid aortic valve (BAV). Alternatively spliced extra domain A (EDA) of fibronectin (FN) has an essential role in tissue repair. Here we analyze the expression of FN spliceforms in dilated and nondilated ascending aorta of tricuspid aortic valve (TAV) and BAV patients. METHODS AND RESULTS: The mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=40) and BAV (n=69). EDA and extra domain B (EDB) expression was increased in dilated aorta from TAV patients compared with nondilated aorta (P<0.001 and P<0.05, respectively). In contrast, EDA expression was not increased in dilated aorta from BAV patients (P=0.25), whereas EDB expression was upregulated (P<0.01). The expression of EDA correlated with maximum aortic diameter in TAV (rho=0.58) but not in BAV (rho=0.15) patients. Protein analyses of EDA-FN showed concordant results. Transforming growth factor-beta treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in cultured medial cells from TAV patients but not in cells derived from BAV patients. Gene set enrichment analysis together with multivariate and univariate data analyses of mRNA expression suggested that differences in the transforming growth factor-beta signaling pathway may explain the impaired EDA inclusion in BAV patients. CONCLUSIONS: Decreased EDA expression may contribute to increased aneurysm susceptibility of BAV patients.
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- Paloschi, V, et al.
(author)
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Mechanistic Links between Non-Coding RNAs and Myeloid Cell Inflammation in Atherosclerosis
- 2019
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In: Thrombosis and haemostasis. - : Georg Thieme Verlag KG. - 2567-689X .- 0340-6245. ; 119:8, s. 1205-1211
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Journal article (peer-reviewed)abstract
- Inflammation plays a pivotal role in the chronicity of atherosclerotic lesion development and progression. Myeloid cells are involved in all stages of atherosclerosis development: they contribute in early phases to endothelial dysfunction and create a pro-inflammatory environment responsible for disease progression. Numerous studies over the last decade have repeatedly provided evidence for the crucial importance for different classes of non-coding ribonucleic acids (RNAs) in regulating gene expression, as well as messenger RNA and protein stability. Functional studies using tools to either over-express or inhibit these non-coding RNAs showcased strong effects on tempering vascular inflammation and atherosclerosis progression. With this current review article, we want to discuss prominent examples of non-coding RNAs, being either produced by myeloid cells or affecting their recruitment and activity in the context of vascular inflammation, atherosclerosis and consequential diseases (such as myocardial infarction and stroke). All of the discussed transcripts were thoroughly studied in mechanistic explorations, indicating that they have the capability to modulate inflammatory cascades in the vasculature during disease exacerbation.
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