Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Christina Christoffersen, Hideru Obinata, Sunil B Kumaraswamy, Sylvain Galvani, Josefin Ahnström, Madhumati Sevvana, Claudia Egerer-Sieber, Yves A Muller, Timothy Hla, Lars Bo Nielsen, Björn Dahlbäck

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.
OriginalsprogEngelsk
TidsskriftProceedings of the National Academy of Sciences USA (PNAS)
Vol/bind108
Udgave nummer23
Sider (fra-til)9613-8
Antal sider6
ISSN0027-8424
DOI
StatusUdgivet - 2011

ID: 38431877