Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M
Research output: Contribution to journal › Journal article › Research › peer-review
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.
|Journal||Proceedings of the National Academy of Sciences USA (PNAS)|
|Number of pages||6|
|Publication status||Published - 2011|
- 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