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Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9613-8. doi: 10.1073/pnas.1103187108. Epub 2011 May 23.

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

Author information

1
Department of Clinical Biochemistry, Rigshospitalet, 2100 Copenhagen, Denmark.

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.

PMID:
21606363
PMCID:
PMC3111292
DOI:
10.1073/pnas.1103187108
[Indexed for MEDLINE]
Free PMC Article

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