title: 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.
authors: Department of Clinical Biochemistry, Rigshospitalet, 2100 Copenhagen, Denmark.
authors: Christina
authors: C
authors: Christoffersen
authors: Hideru
authors: H
authors: Obinata
authors: Sunil B
authors: SB
authors: Kumaraswamy
authors: Sylvain
authors: S
authors: Galvani
authors: Josefin
authors: J
authors: Ahnström
authors: Madhumati
authors: M
authors: Sevvana
authors: Claudia
authors: C
authors: Egerer-Sieber
authors: Yves A
authors: YA
authors: Muller
authors: Timothy
authors: T
authors: Hla
authors: Lars B
authors: LB
authors: Nielsen
authors: Björn
authors: B
authors: Dahlbäck
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