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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins / chemistry
  • Apolipoproteins / genetics
  • Apolipoproteins / metabolism*
  • Apolipoproteins M
  • Blotting, Western
  • Cells, Cultured
  • Crystallography, X-Ray
  • Endocytosis
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Enzyme Activation
  • HEK293 Cells
  • Humans
  • Lipocalins / chemistry
  • Lipocalins / genetics
  • Lipocalins / metabolism
  • Lipoproteins, HDL / chemistry
  • Lipoproteins, HDL / metabolism*
  • Lysophospholipids / chemistry
  • Lysophospholipids / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Lysosphingolipid / metabolism
  • Sphingosine / analogs & derivatives*
  • Sphingosine / chemistry
  • Sphingosine / metabolism

Substances

  • APOM protein, human
  • ApoM protein, mouse
  • Apolipoproteins
  • Apolipoproteins M
  • Lipocalins
  • Lipoproteins, HDL
  • Lysophospholipids
  • Receptors, Lysosphingolipid
  • sphingosine 1-phosphate
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Sphingosine

Associated data

  • PDB/2YG2