Sphingosine-1-phosphate promotes barrier-stabilizing effects in human microvascular endothelial cells via AMPK-dependent mechanisms.

Dennhardt, Sophie; Finke, Karl R; Huwiler, Andrea; Coldewey, Sina M (2019). Sphingosine-1-phosphate promotes barrier-stabilizing effects in human microvascular endothelial cells via AMPK-dependent mechanisms. Biochimica et biophysica acta - molecular basis of disease, 1865(4), pp. 774-781. Elsevier 10.1016/j.bbadis.2018.12.022

[img]
Preview
Text
Huwiler_Sphingosine-1-phosphate...pdf - Published Version
Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND).

Download (1MB) | Preview

Breakdown of the endothelial barrier is a critical step in the development of organ failure in severe inflammatory conditions such as sepsis. Endothelial cells from different tissues show phenotypic variations which are often neglected in endothelial research. Sphingosine-1-phosphate (S1P) and AMP-dependent kinase (AMPK) have been shown to protect the endothelium and phosphorylation of AMPK by S1P was shown in several cell types. However, the role of the S1P-AMPK interrelationship for endothelial barrier stabilization has not been investigated. To assess the role of the S1P-AMPK signalling axis in this context, we established an in vitro model allowing real-time monitoring of endothelial barrier function in human microvascular endothelial cells (HMEC-1) and murine glomerular endothelial cells (GENCs) with the electric cell-substrate impedance sensing (ECIS™) system. Following the disruption of the cell barrier by co-administration of LPS, TNF-α, IL-1ß, IFN-γ, and IL-6, we demonstrated self-recovery of the disrupted barrier in HMEC-1, while the barrier remained compromised in GENCs. Under physiological conditions we observed a rapid phosphorylation of AMPK in HMEC-1 stimulated with S1P, but not in GENCs. Consistently, S1P enhanced the basal endothelial barrier in HMEC-1 exclusively. siRNA-mediated knockdown of AMPK in HMEC-1 led to a less pronounced barrier enhancement. Thus we present evidence for a functional role of AMPK in S1P-mediated barrier stabilization in HMEC-1 and we provide insight into cell-type specific differences of the S1P-AMPK-interrelationship, which might influence the development of interventional strategies targeting endothelial barrier dysfunction.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Huwiler, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0925-4439

Publisher:

Elsevier

Language:

English

Submitter:

Sabrina Cookman

Date Deposited:

15 May 2019 13:53

Last Modified:

22 Oct 2019 21:53

Publisher DOI:

10.1016/j.bbadis.2018.12.022

PubMed ID:

30660683

Uncontrolled Keywords:

AMP-dependent kinase Barrier breakdown ECIS Endothelial barrier Inflammation Sphingosine-1-phosphate

BORIS DOI:

10.7892/boris.125014

URI:

https://boris.unibe.ch/id/eprint/125014

Actions (login required)

Edit item Edit item
Provide Feedback