Fingolimod does not prevent syndecan‑4 shedding from the endothelial glycocalyx in a cultured human umbilical vein endothelial cell model of vascular injury

Elissa M Milford; Lara Meital; Anna Kuballa; Michael C Reade; Fraser Russell

doi:10.1186/s40635-022-00462-7

Back

Fingolimod does not prevent syndecan‑4 shedding from the endothelial glycocalyx in a cultured human umbilical vein endothelial cell model of vascular injury

Journal article

Open access

Peer reviewed

Fingolimod does not prevent syndecan‑4 shedding from the endothelial glycocalyx in a cultured human umbilical vein endothelial cell model of vascular injury

Elissa M Milford, Lara Meital, Anna Kuballa, Michael C Reade and Fraser Russell

Intensive Care Medicine Experimental, Vol.10, pp.1-14

2022

DOI: https://doi.org/10.1186/s40635-022-00462-7

PMCID: PMC9388705

PMID: 35980492

Files and links (2)

pdf

Fingolimod does not prevent syndecan‑4 shedding from the endothelial glycocalyx in a cultured human umbilical vein endotheilial cell model of vascular injury1.34 MBDownload View

Published Version Open Access CC BY V4.0

url

https://doi.org/10.1186/s40635-022-00462-7View

Published Version

Abstract

Fingolimod

FTY720

Glycocalyx

Endothelium

Cell culture

Syndecan-1

Syndecan-4

Fresh frozen plasma

Sphingosine 1-phosphate

Human umbilical vein endothelial cells

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 Queensland
Lara Meital (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - Legacy
Anna Kuballa (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - Legacy
Michael C Reade (Author) - The University of Queensland
Fraser 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
PMID: 35980492; PMC9388705
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

Metrics

1 File views/ downloads

53 Record Views

3 Times Cited - Web of Science

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration
Web Of Science research areas: Critical Care Medicine

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: SDGs from InCites