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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 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.
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.
| Original language | English |
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| Qualification | Doctor |
| Awarding Institution |
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| Supervisors/Advisors |
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| Award date | 2016 Dec 2 |
| Place of Publication | Lund |
| Publisher | |
| ISBN (Print) | 978-91-7619-368-6 |
| Publication status | Published - 2016 |
Bibliographical note
Defence detailsDate: 2016-12-02
Time: 13:00
Place: Jubileumsaulan, Skånes Universitetssjukhus i Malmö.
External reviewer(s)
Name: von Eckardstein, Arnold
Title: professor
Affiliation: University Hospital in Zürich
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ISSN: 1652-8220
Lund University, Faculty of Medicine Doctoral Dissertation Series 2016:141
Subject classification (UKÄ)
- Medical and Health Sciences
Free keywords
- lipoproteins
- Apolipoproteins
- Phospholipids
- sepsis
- Atherosclerosis
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- 2 Article
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Sphingosine 1-phosphate and its carrier apolipoprotein M in human sepsis and in Escherichia coli sepsis in baboons
Frej, C., Linder, A., Happonen, K. E., Taylor, F. B., Lupu, F. & Dahlbäck, B., 2016 Jun 1, In: Journal of Cellular and Molecular Medicine. 20, 6, p. 1170-1181 12 p.Research output: Contribution to journal › Article › peer-review
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Quantification of sphingosine 1-phosphate by validated LC-MS/MS method revealing strong correlation with apolipoprotein M in plasma but not in serum due to platelet activation during blood coagulation.
Frej, C., Andersson, A. S., Larsson, B., Guo, L. J., Norström, E., Happonen, K. & Dahlbäck, B., 2015, In: Analytical and Bioanalytical Chemistry. 407, 28, p. 8533-8542Research output: Contribution to journal › Article › peer-review
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