Advanced

The ApoM/S1P-complex: its role in vascular inflammatory disease and interaction with S1P-receptors

Frej, Cecilia LU (2016)
Abstract
HDL is believed to be protective against cardiovascular disease (CVD) via the reverse cholesterol transport and anti-inflammatory actions in the vessel. Apolipoprotein M (apoM) is an apolipoprotein mainly associated with HDL. Recently ApoM was proven to
be the main carrier of Sphingosine 1-phosphate (S1P) in circulation. SIP is a signaling phospholipid involved in the immune system, exerting most of its effects through signaling via 5-G-protein coupled receptors; SlPl-5.

The aim of this thesis is to investigate the role of the apoM/SlP-complex in vascular inflammatory diseases such as atherosclerosis and sepsis. We also want to study the interaction between the apoM/SlP-complex and the SlP-receptors.

We developed a... (More)
HDL is believed to be protective against cardiovascular disease (CVD) via the reverse cholesterol transport and anti-inflammatory actions in the vessel. Apolipoprotein M (apoM) is an apolipoprotein mainly associated with HDL. Recently ApoM was proven to
be the main carrier of Sphingosine 1-phosphate (S1P) in circulation. SIP is a signaling phospholipid involved in the immune system, exerting most of its effects through signaling via 5-G-protein coupled receptors; SlPl-5.

The aim of this thesis is to investigate the role of the apoM/SlP-complex in vascular inflammatory diseases such as atherosclerosis and sepsis. We also want to study the interaction between the apoM/SlP-complex and the SlP-receptors.

We developed a liquid chromatography-tandem mass spectrometry method for SlP-quantification in plasma and cell extracts. We found that plasma levels of SIP and apoM were decreased in sepsis, levels reflecting the severity of the disease. The apoM/SlP-complex contributes to the anti-inflammatory effects exerted by HDL as shown in vitro by its inhibiting potential of pro-inflammatory adhesion molecules on the endothelial surface and by its increment of the endothelial barrier function. Plasma levels of apoM and SIP in type-l-diabetes (TlD)- patients (who have increased risk of developing CVD) were not altered compared to healthy controls. However, HDL-particles from TlD showed decreased anti-inflammatory effects which were not related to reduced presence of apoM and S1P. The apoM/S1P-complex could interact with all SlP-receptors as shown by internalization of
fluorescently labelled S1P-receptors overexpressed in HEK293-cells. Interestingly, extracellular levels of apoM and SIP could detemine which receptor was available at the cellular surface.

ln conclusion, our data suggest apoM and SlP to have a role in acute and chronic inflammation. Future research could help us clarify how the apoM/SlP-complex signals through the different SlP-receptors in different inflammatory disorders and hence contribute in developing new therapies against diseases in the vasculature.
(Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor von Eckardstein, Arnold, University Hospital in Zürich
organization
publishing date
type
Thesis
publication status
published
subject
keywords
lipoproteins, Apolipoproteins, Phospholipids, sepsis, Atherosclerosis
pages
98 pages
publisher
Lund University, Faculty of Medicine
defense location
Jubileumsaulan, Skånes Universitetssjukhus i Malmö.
defense date
2016-12-02 13:00
ISBN
978-91-7619-368-6
language
English
LU publication?
yes
id
0703f211-06da-4600-863a-b17de3a8f0ca
date added to LUP
2016-11-14 10:48:07
date last changed
2017-01-12 16:07:44
@phdthesis{0703f211-06da-4600-863a-b17de3a8f0ca,
  abstract     = {HDL is believed to be protective against cardiovascular disease (CVD) via the reverse cholesterol transport and anti-inflammatory actions in the vessel. Apolipoprotein M (apoM) is an apolipoprotein mainly associated with HDL. Recently ApoM was proven to<br/>be the main carrier of Sphingosine 1-phosphate (S1P) in circulation. SIP is a signaling phospholipid involved in the immune system, exerting most of its effects through signaling via 5-G-protein coupled receptors; SlPl-5. <br/><br/>The aim of this thesis is to investigate the role of the apoM/SlP-complex in vascular inflammatory diseases such as atherosclerosis and sepsis. We also want to study the interaction between the apoM/SlP-complex and the SlP-receptors.<br/><br/>We developed a liquid chromatography-tandem mass spectrometry method for SlP-quantification in plasma and cell extracts. We found that plasma levels of SIP and apoM were decreased in sepsis, levels reflecting the severity of the disease. The apoM/SlP-complex contributes to the anti-inflammatory effects exerted by HDL as shown in vitro by its inhibiting potential of pro-inflammatory adhesion molecules on the endothelial surface and by its increment of the endothelial barrier function. Plasma levels of apoM and SIP in type-l-diabetes (TlD)- patients (who have increased risk of developing CVD) were not altered compared to healthy controls. However, HDL-particles from TlD showed decreased anti-inflammatory effects which were not related to reduced presence of apoM and S1P. The apoM/S1P-complex could interact with all SlP-receptors as shown by internalization of<br/>fluorescently labelled S1P-receptors overexpressed in HEK293-cells. Interestingly, extracellular levels of apoM and SIP could detemine which receptor was available at the cellular surface.<br/><br/>ln conclusion, our data suggest apoM and SlP to have a role in acute and chronic inflammation. Future research could help us clarify how the apoM/SlP-complex signals through the different SlP-receptors in different inflammatory disorders and hence contribute in developing new therapies against diseases in the vasculature.<br/>},
  author       = {Frej, Cecilia},
  isbn         = {978-91-7619-368-6},
  keyword      = {lipoproteins,Apolipoproteins,Phospholipids,sepsis,Atherosclerosis},
  language     = {eng},
  pages        = {98},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {The ApoM/S1P-complex: its role in vascular inflammatory disease and interaction with S1P-receptors},
  year         = {2016},
}