Abstract
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-Å 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.
| Original language | English |
|---|---|
| Journal | Proceedings of the National Academy of Sciences USA (PNAS) |
| Volume | 108 |
| Issue number | 23 |
| Pages (from-to) | 9613-8 |
| Number of pages | 6 |
| ISSN | 0027-8424 |
| DOIs | |
| Publication status | Published - 7 Jun 2011 |
Keywords
- Animals
- Apolipoproteins
- Blotting, Western
- Cells, Cultured
- Crystallography, X-Ray
- Endocytosis
- Endothelial Cells
- Endothelium, Vascular
- Enzyme Activation
- HEK293 Cells
- Humans
- Lipocalins
- Lipoproteins, HDL
- Lysophospholipids
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Mitogen-Activated Protein Kinases
- Models, Molecular
- Protein Binding
- Protein Conformation
- Protein Structure, Tertiary
- Proto-Oncogene Proteins c-akt
- Receptors, Lysosphingolipid
- Sphingosine