Transthyretin binds soluble endoglin and increases its uptake by hepatocytes: A possible role for transthyretin in preeclampsia?
Description
Background: Preeclampsia is a common but life-threatening condition of pregnancy. It is caused by poor placentation resulting in release of trophoblast material (including soluble endoglin (sEng)) into the maternal circulation leading to maternal vascular dysfunction and to the life-threatening condition of eclampsia. The only cure is early delivery, which can have lifelong consequences for the premature child. The thyroid hormone binding protein transthyretin is dysregulated in preeclampsia, however it is not known if this plays a role in disease pathology. We hypothesised that transthyretin may bind sEng and abrogate its negative effects by removing it from the maternal serum. Methods: The effect of transthyretin on hepatocyte uptake of Alexa-labelled sEng was measured using live cell imaging. Interactions between transthyretin, and sEng were investigated using molecular modelling, direct binding on CnBr Sepharose columns, confocal imaging, and measurement of fluorescence resonance energy transfer. Results: Transthyretin directly bound to sEng and increased its uptake by hepatocytes. This uptake was altered in the presence of transforming growth factor-β1 (TGF-β1). Molecular modelling predicted that transthyretin and TGF-β1 bind at the same site in sEng and may compete for binding. Endocytosed transthyretin and endoglin entered cells together and co-localised inside hepatocyte cells. Conclusion: Transthyretin can bind sEng and increase its uptake from the extracellular medium. This suggests that increasing transthyretin levels or developing drugs that normalise or mimic transthyretin, may provide treatment options to reduce sEng induced vascular dysfunction.
Impact and interest:
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ID Code: | 248354 | ||
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Item Type: | Contribution to Journal (Journal Article) | ||
Refereed: | Yes | ||
ORCID iD: |
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Measurements or Duration: | 10 pages | ||
Keywords: | Hepatocyte, Preeclampsia, Soluble endoglin, Transthyretin, Trophoblast | ||
DOI: | 10.1016/j.mce.2023.111851 | ||
ISSN: | 0303-7207 | ||
Pure ID: | 167649665 | ||
Divisions: | Current > Research Centres > Centre for Genomics and Personalised Health Current > QUT Faculties and Divisions > Faculty of Health Current > Schools > School of Biomedical Sciences |
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Funding Information: | This project was funded by the Science and Education Research Committee, Pathology Queensland, Queensland Health . | ||
Copyright Owner: | 2023 Elsevier B.V. | ||
Copyright Statement: | This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au | ||
Deposited On: | 09 May 2024 02:45 | ||
Last Modified: | 09 May 2024 22:01 |
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