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


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.

SUBMITTER: Christoffersen C 

PROVIDER: S-EPMC3111292 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Christoffersen Christina C   Obinata Hideru H   Kumaraswamy Sunil B SB   Galvani Sylvain S   Ahnström Josefin J   Sevvana Madhumati M   Egerer-Sieber Claudia C   Muller Yves A YA   Hla Timothy T   Nielsen Lars B LB   Dahlbäck Björn B  

Proceedings of the National Academy of Sciences of the United States of America 20110523 23


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 t  ...[more]

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