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GATA4-Twist1 Signalling in Disturbed Flow-Induced Atherosclerosis

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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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Acknowledgements

I wish to thank members of the Evans lab and the Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, for the help and support with this work. This work was funded by the British Heart Foundation. I wish to also thank the BSCR committee and The Bernard and Joan Marshall Early Career Investigator Prize Judging panel for the award and for the opportunity to present my work.

Funding

This study was funded by the British Heart Foundation (RG/13/1/30042).

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Authors and Affiliations

  1. Department of Biomedical Engineering, The City College of New York, New York, NY, 10031, USA

    Marwa Mahmoud

  2. Department of Infection, Immunity and Cardiovascular Disease, INSIGNEO Institute for In Silico Medicine, and the Bateson Centre, University of Sheffield, Sheffield, UK

    Celine Souilhol, Jovana Serbanovic-Canic & Paul Evans

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  1. Marwa Mahmoud
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  2. Celine Souilhol
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  3. Jovana Serbanovic-Canic
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Contributions

Contributions: (1) Conception and design: M. Mahmoud and P. Evans. (2) Administrative support: None. (3) Provision of study material or patients: None. (4) Collection and assembly of data: M. Mahmoud. (5) Data analysis and interpretation: M. Mahmoud and P. Evans. (6) Manuscript writing: All authors. (7) Final approval of manuscript: All authors.

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Correspondence to Marwa Mahmoud.

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Mahmoud, M., Souilhol, C., Serbanovic-Canic, J. et al. GATA4-Twist1 Signalling in Disturbed Flow-Induced Atherosclerosis. Cardiovasc Drugs Ther 33, 231–237 (2019). https://doi.org/10.1007/s10557-019-06863-3

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