Altered DNA Methylation Indicates an Oscillatory Flow Mediated Epithelial-to-mesenchymal Transition Signature in Ascending Aorta of Patients with Bicuspid Aortic Valve

Overview

Journal Sci Rep

Specialty Science

Date 2018 Feb 11

PMID 29426841

Citations 15

Authors

Hanna M Bjorck

Lei Du

Silvia Pulignani

Valentina Paloschi

Karin Lundstromer

Alexandra S Kostina

Cecilia Osterholm

Anna Malashicheva

Anna Kostareva

Arturo Evangelista

Gisela Teixido-Tura

Shohreh Maleki

Anders Franco-Cereceda

Per Eriksson

Affiliations

Soon will be listed here.

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/cm) or laminar (12 dynes/cm) 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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