Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 23, Pages 9613-9618Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1103187108
Keywords
endothelial function; crystal structure; sphingolipids; vascular permeability; atherosclerosis
Categories
Funding
- Swedish Research Council [07143]
- Soderberg's Foundation
- Swedish Heart-Lung Foundation
- Danish National Research Council [09-06452/FSS, 09-073571/FSS]
- Rigshospitalet Research Council
- Sonderfonds of the University Erlangen-Nuremberg
- National Institutes of Health [HL-67330, HL-70694, HL89934]
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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.
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