Mahmoud, M. orcid.org/0000-0002-6812-4240, Souilhol, C., Serbanovic-Canic, J. orcid.org/0000-0002-8835-1491 et al. (1 more author) (2019) GATA4-Twist1 signalling in disturbed flow-induced atherosclerosis. Cardiovascular Drugs and Therapy, 33 (2). pp. 231-237. ISSN 0920-3206
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © Springer Science+Business Media, LLC, part of Springer Nature 2019. This is an author-produced version of a paper subsequently published in Cardiovascular Drugs and Therapy. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Atherosclerosis; Developmental signalling; EndoMT; Endothelial cell dysfunction |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) |
Funding Information: | Funder Grant number BRITISH HEART FOUNDATION RG/13/1/30042 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 23 Apr 2019 12:49 |
Last Modified: | 25 Nov 2021 12:16 |
Status: | Published |
Publisher: | Springer |
Refereed: | Yes |
Identification Number: | 10.1007/s10557-019-06863-3 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:145225 |