Journal Article

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

Ahnström, Josefin, Obinata, Hideru, Dahlbäck, Björn, Sevvana, Madhumati, Muller, Yves A, Christoffersen, Christina, Hla, Timothy, Galvani, Sylvain, Egerer-Sieber, Claudia, Nielsen, Lars B, Kumaraswamy, Sunil B

2011

Overview

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 S1P₁ 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 S1P₁ receptor on endothelial cells, is a vasculoprotective constituent of HDL.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: adherens junctions / Animals / Apolipoproteins / Apolipoproteins - chemistry / Apolipoproteins - genetics / Apolipoproteins - metabolism / Apolipoproteins M / Basic Medicine / Biological Sciences / Blotting, Western / Cell adhesion & migration / cell movement / Cells, Cultured / Cholesterols / Crystal structure / Crystallography, X-Ray / Endocytosis / Endothelial cells / Endothelial Cells - metabolism / Endothelium / Endothelium, Vascular - cytology / Endothelium, Vascular - metabolism / Enzyme Activation / gene overexpression / HDL lipoproteins / HEK293 Cells / high density lipoprotein / Humans / Lipids / Lipocalins - chemistry / Lipocalins - genetics / Lipocalins - metabolism / Lipoproteins / Lipoproteins, HDL - chemistry / Lipoproteins, HDL - metabolism / lung function / Lungs / Lysophospholipids - chemistry / Lysophospholipids - metabolism / Läkemedelskemi / Medical and Health Sciences / Medicin och hälsovetenskap / Medicinal Chemistry / Medicinska och farmaceutiska grundvetenskaper / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / mitogen-activated protein kinase / Mitogen-Activated Protein Kinases - metabolism / Models, Molecular / Protein Binding / Protein Conformation / Protein Structure, Tertiary / Proto-Oncogene Proteins c-akt - metabolism / Receptors / Receptors, Lysosphingolipid - metabolism / Rodents / Sphingosine - analogs & derivatives / Sphingosine - chemistry / Sphingosine - metabolism / Tissues / transgenic animals