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Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 2/2019

01-04-2019 | Arterial Occlusive Disease | ORIGINAL ARTICLE

GATA4-Twist1 Signalling in Disturbed Flow-Induced Atherosclerosis

Authors: Marwa Mahmoud, Celine Souilhol, Jovana Serbanovic-Canic, Paul Evans

Published in: Cardiovascular Drugs and Therapy | Issue 2/2019

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Abstract

Background

Endothelial cell (EC) dysfunction (enhanced inflammation, proliferation and permeability) is the initial trigger for atherosclerosis. Atherosclerosis shows preferential development near branches and bends exposed to disturbed blood flow. By contrast, sites that are exposed to non-disturbed blood flow are atheroprotected. Disturbed flow promotes atherosclerosis by promoting EC dysfunction. Blood flow controls EC function through transcriptional and post-transcriptional mechanisms that are incompletely understood.

Methods and Results

We identified the developmental transcription factors Twist1 and GATA4 as being enriched in EC at disturbed flow, atheroprone regions of the porcine aorta in a microarray study. Further work using the porcine and murine aortae demonstrated that Twist1 and GATA4 expression was enhanced at the atheroprone, disturbed flow sites in vivo. Using controlled in vitro flow systems, the expression of Twist1 and GATA4 was enhanced under disturbed compared to non-disturbed flow in cultured cells. Disturbed flow promoted Twist1 expression through a GATA4-mediated transcriptional mechanism as revealed by a series of in vivo and in vitro studies. GATA4-Twist1 signalling promoted EC proliferation, inflammation, permeability and endothelial-to-mesenchymal transition (EndoMT) under disturbed flow, leading to atherosclerosis development, as shown in a combination of in vitro and in vivo studies using GATA4 and Twist1-specific siRNA and EC-specific GATA4 and Twist1 Knock out (KO) mice.

Conclusions

We revealed that GATA4-Twist1-Snail signalling triggers EC dysfunction and atherosclerosis; this work could lead to the development of novel anti-atherosclerosis therapeutics.
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Metadata
Title
GATA4-Twist1 Signalling in Disturbed Flow-Induced Atherosclerosis
Authors
Marwa Mahmoud
Celine Souilhol
Jovana Serbanovic-Canic
Paul Evans
Publication date
01-04-2019
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 2/2019
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-019-06863-3

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