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Fingolimod does not prevent syndecan‑4 shedding from the endothelial glycocalyx in a cultured human umbilical vein endotheilial cell model of vascular injury1.34 MB
Published VersionCC BY V4.0, Open Access
Journal article
Fingolimod does not prevent syndecan‑4 shedding from the endothelial glycocalyx in a cultured human umbilical vein endothelial cell model of vascular injury
Intensive Care Medicine Experimental, Vol.10, pp.1-14
2022
Abstract
Background: Shedding of the endothelial glycocalyx (EG) is associated with poor outcomes in a range of conditions including sepsis. Fresh frozen plasma (FFP) restores the damaged EG to baseline thickness, however the mechanism for this effect is unknown, and some components of FFP have adverse effects unrelated to the EG. There is some limited evidence that sphingosine-1-phosphate (S1P) within FFP restores the EG by activating the endothelial cell S1P receptor 1 (S1PR 1). However, there are disadvantages to using S1P clinically as an EG restorative therapy. A potential alternative is the S1PR agonist fingolimod (FTY720). The aim of this study was to assess whether FTY720 prevents EG shedding in injured cultured human umbilical vein endothelial cells. Methods: Shedding of the EG was induced in cultured human umbilical vein endothelial cells (HUVECs) by exposure to adrenaline, TNF-α and H 2 O 2. The cells were then assigned to one of six conditions for 4 h: uninjured and untreated, injured and untreated, injured and treated with FTY720 with and without the S1PR 1 inhibitor W146, and injured and treated with 25% FFP with and without W146. Syndecan-4, a component of the EG, was measured in cell supernatants, and syndecan-4 and thrombomod-ulin mRNA expression was quantitated in cell lysates. Results: The injury resulted in a 2.1-fold increase in syndecan-4 (p < 0.001), consistent with EG shedding. Syndecan-4 and thrombomodulin mRNA expression was increased (p < 0.001) and decreased (p < 0.05), respectively, by the injury. Syndecan-4 shedding was not affected by treatment with FTY720, whereas FFP attenuated syndecan-4 shedding back to baseline levels in the injured cells and this was unaffected by W146. Neither treatment affected syndecan-4 or thrombomodulin mRNA expression. Conclusions: FTY720 did not prevent syndecan-4 shedding from the EG in the HUVEC model of endothelial injury, suggesting that activation of S1PR does not prevent EG damage. FFP prevented syndecan-4 shedding from the EG via a mechanism that was independent of S1PR 1 and upregulation of SDC-4 production. Further studies to examine whether FTY720 or another S1PR agonist might have EG-protective effects under different conditions are warranted, as are investigations seeking the mechanism of EG protection conferred by FFP in this experimental model.
Details
- Title
- Fingolimod does not prevent syndecan‑4 shedding from the endothelial glycocalyx in a cultured human umbilical vein endothelial cell model of vascular injury
- Authors
- Elissa M Milford (Corresponding Author) - The University of QueenslandLara Meital (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - LegacyAnna Kuballa (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - LegacyMichael C Reade (Author) - The University of QueenslandFraser Russell (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - Legacy
- Publication details
- Intensive Care Medicine Experimental, Vol.10, pp.1-14
- Publisher
- SpringerOpen
- Date published
- 2022
- DOI
- 10.1186/s40635-022-00462-7
- ISSN
- 2197-425X
- Copyright note
- (c) The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons.org/licenses/by/4.0/.
- Organisation Unit
- School of Health - Biomedicine; University of the Sunshine Coast, Queensland; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99665198202621
- Output Type
- Journal article
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