Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve.
Hanna M BjörckLei DuSilvia PulignaniValentina PaloschiKarin LundströmerAlexandra S KostinaCecilia ÖsterholmAnna MalashichevaAnna KostarevaArturo EvangelistaGisela TeixidóShohreh MalekiAnders Franco-CerecedaPer Erikssonnull nullPublished in: Scientific reports (2018)
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.
Keyphrases
- aortic valve
- dna methylation
- aortic stenosis
- transcatheter aortic valve replacement
- transcatheter aortic valve implantation
- epithelial mesenchymal transition
- aortic valve replacement
- gene expression
- genome wide
- end stage renal disease
- ejection fraction
- endothelial cells
- high frequency
- coronary artery
- newly diagnosed
- stem cells
- cell proliferation
- chronic kidney disease
- left ventricular
- type diabetes
- cardiovascular disease
- poor prognosis
- peritoneal dialysis
- transforming growth factor
- signaling pathway
- climate change
- long non coding rna
- metabolic syndrome
- aortic dissection
- bioinformatics analysis