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

Research output: Contribution to journalArticle

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-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.

Details

Authors
  • Christina Christoffersen
  • Hideru Obinata
  • Sunil Kumaraswamy
  • Sylvain Galvani
  • Josefin Ahnström
  • Madhumati Sevvana
  • Claudia Egerer-Sieber
  • Yves A. Muller
  • Timothy Hla
  • Lars B. Nielsen
  • Björn Dahlbäck
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry

Keywords

  • endothelial function, crystal structure, sphingolipids, vascular, permeability, atherosclerosis
Original languageEnglish
Pages (from-to)9613-9618
JournalProceedings of the National Academy of Sciences
Volume108
Issue number23
Publication statusPublished - 2011
Publication categoryResearch
Peer-reviewedYes