title: High-Density Lipoprotein-Associated Apolipoprotein M Limits Endothelial Inflammation by Delivering Sphingosine-1-Phosphate to the Sphingosine-1-Phosphate Receptor 1.
abstract: Plasma high-density lipoproteins (HDL) are potent antiatherogenic and anti-inflammatory particles. However, HDL particles are highly heterogenic in composition, and different HDL-mediated functions can be ascribed to different subclasses of HDL. Only a small HDL population contains apolipoprotein M (ApoM), which is the main plasma carrier of the bioactive lipid mediator sphingosine-1-phosphate (S1P). Vascular inflammation is modulated by S1P, but both pro- and anti-inflammatory roles have been ascribed to S1P. The goal of this study is to elucidate the role of ApoM and S1P in endothelial anti-inflammatory events related to HDL.
  
  
  
  Aortic or brain human primary endothelial cells were challenged with tumor necrosis factor-α (TNF-α) as inflammatory stimuli. The presence of recombinant ApoM-bound S1P or ApoM-containing HDL reduced the abundance of adhesion molecules in the cell surface, whereas ApoM and ApoM-lacking HDL did not. Specifically, ApoM-bound S1P decreased vascular adhesion molecule-1 (VCAM-1) and E-selectin surface abundance but not intercellular adhesion molecule-1. Albumin, which is an alternative S1P carrier, was less efficient in inhibiting VCAM-1 than ApoM-bound S1P. The activation of the S1P receptor 1 was sufficient and required to promote anti-inflammation. Moreover, ApoM-bound S1P induced the rearrangement of the expression of S1P-related genes to counteract TNF-α. Functionally, HDL/ApoM/S1P limited monocyte adhesion to the endothelium and maintained endothelial barrier integrity under inflammatory conditions.
  
  
  
  ApoM-bound S1P is a key component of HDL and is responsible for several HDL-associated protective functions in the endothelium, including regulation of adhesion molecule abundance, leukocyte-endothelial adhesion, and endothelial barrier.
authors.affiliation: From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden. mario.ruiz_garcia@med.lu.se.
authors.forename: Mario
authors.initials: M
authors.lastname: Ruiz
authors.affiliation: From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Frej
authors.affiliation: From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Holmér
authors.affiliation: From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Li J
authors.initials: LJ
authors.lastname: Guo
authors.affiliation: From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Sinh
authors.initials: S
authors.lastname: Tran
authors.affiliation: From the Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Dahlbäck
mesh_terms: D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology*; D001053:Apolipoproteins / Q000378:metabolism / Q000494:pharmacology*; D000075243:Apolipoproteins M; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D054834:Lipocalins / Q000378:metabolism / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012709:Serum Albumin / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C400523:APOM protein, human; D000893:Anti-Inflammatory Agents; D001053:Apolipoproteins; D000075243:Apolipoproteins M; D019040:E-Selectin; D054834:Lipocalins; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D011994:Recombinant Proteins; C477362:S1PR1 protein, human; C546936:SELE protein, human; D012709:Serum Albumin; D000081025:Sphingosine-1-Phosphate Receptors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: atherosclerosis; brain; endothelial cells; inflammation; lipoproteins; sphingosine