Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M
Författare
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.
Avdelning/ar
Publiceringsår
2011
Språk
Engelska
Sidor
9613-9618
Publikation/Tidskrift/Serie
Proceedings of the National Academy of Sciences
Volym
108
Issue
23
Dokumenttyp
Artikel i tidskrift
Förlag
National Academy of Sciences
Ämne
- Medicinal Chemistry
Nyckelord
- endothelial function
- crystal structure
- sphingolipids
- vascular
- permeability
- atherosclerosis
Status
Published
Forskningsgrupp
- Clinical Chemistry, Malmö
ISBN/ISSN/Övrigt
- ISSN: 1091-6490