Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M
Author
Summary, in English
Protection of the endothelium is provided by circulating sphingosine-1-phosphate(S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM(+) HDL contained S1P, whereas ApoM(-) HDL did not. Moreover, HDL in Apom(-/-) mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-angstrom structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM(+) HDL induced S1P(1) receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM(-) HDL did not. Importantly, lack of S1P in the HDL fraction of Apom(-/-) mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P(1) receptor on endothelial cells, is a vasculoprotective constituent of HDL.
Department/s
Publishing year
2011
Language
English
Pages
9613-9618
Publication/Series
Proceedings of the National Academy of Sciences
Volume
108
Issue
23
Document type
Journal article
Publisher
National Academy of Sciences
Topic
- Medicinal Chemistry
Keywords
- endothelial function
- crystal structure
- sphingolipids
- vascular
- permeability
- atherosclerosis
Status
Published
Research group
- Clinical Chemistry, Malmö
ISBN/ISSN/Other
- ISSN: 1091-6490