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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.
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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 13:00:00
ISBN
978-91-7619-368-6
language
English
LU publication?
yes
additional info
ISSN: 1652-8220 Lund University, Faculty of Medicine Doctoral Dissertation Series 2016:141
id
0703f211-06da-4600-863a-b17de3a8f0ca
date added to LUP
2016-11-14 10:48:07
date last changed
2019-11-19 13:49:16
@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}},
  keywords     = {{lipoproteins; Apolipoproteins; Phospholipids; sepsis; Atherosclerosis}},
  language     = {{eng}},
  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}},
  url          = {{https://lup.lub.lu.se/search/files/18171482/161031_Cecilia_F_kappa.pdf}},
  year         = {{2016}},
}