Title | Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Christoffersen C, Obinata H, Kumaraswamy SB, Galvani S, Ahnström J, Sevvana M, Egerer-Sieber C, Muller YA, Hla T, Nielsen LB, Dahlbäck B |
Journal | Proc Natl Acad Sci U S A |
Volume | 108 |
Issue | 23 |
Pagination | 9613-8 |
Date Published | 2011 Jun 07 |
ISSN | 1091-6490 |
Keywords | Animals, Apolipoproteins, Apolipoproteins M, 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 |
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. |
DOI | 10.1073/pnas.1103187108 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 21606363 |
PubMed Central ID | PMC3111292 |
Grant List | HL-70694 / HL / NHLBI NIH HHS / United States P01 HL070694 / HL / NHLBI NIH HHS / United States R37 HL067330 / HL / NHLBI NIH HHS / United States HL-67330 / HL / NHLBI NIH HHS / United States R01 HL067330 / HL / NHLBI NIH HHS / United States HL89934 / HL / NHLBI NIH HHS / United States R01 HL089934 / HL / NHLBI NIH HHS / United States |
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