Sphingosine kinase inhibition exerts both pro- and anti-atherogenic effects in low-density lipoprotein receptor-deficient (LDL-R(-/-)) mice

Thromb Haemost. 2012 Mar;107(3):552-61. doi: 10.1160/TH11-08-0583. Epub 2012 Jan 11.


Sphingosine 1-phosphate (S1P), a lysosphingolipid associated with high-density lipoprotein (HDL), contributes to the anti-atherogenic potential attributed to this lipoprotein. This study examined whether a reduction of S1P plasma levels affects atherosclerosis in a murine model of disease. LDL-R(-/-)mice on Western diet were given ABC294640, an inhibitor of sphingosine kinase (SphK) for 16 weeks. ABC294640 decreased plasma S1P by approximately 30%. However, ABC294640 failed to affect atherosclerotic lesion formation. Plasma triglycerides were reduced whereas total and HDL-cholesterol remained unchanged in course of ABC294640 treatment. ABC294640 increased plasma interleukin (IL)-12p70 and RANTES concentration as well as IL-12p70, RANTES and interferon (IFN)-γ production by peritoneal cells and this was paralleled by enhanced activity of peritoneal and spleen dendritic cells as evidenced by up-regulation of CD86 and MHC-II on CD11c(+) cells. As a consequence, increased T-cell activation was noted in ABC294640-treated mice as indicated by enhanced CD4(+) splenocyte proliferation, IFN-γ and IL-2 production, and CD69 expression. Concomitantly, however, ABC294640 treatment redistributed CD4(+) and CD8(+) cells from blood to lymphatic organs and reduced T-cell number within atherosclerotic lesions. In addition, plasma sVCAM-1, sICAM-1, and MCP-1 levels as well as in vivo leukocyte adhesion and CCL19-induced T-cell penetration into peritoneum were lower in ABC294640-treated animals. In vitro experiments demonstrated reduced VCAM-1 and ICAM-1 expression and lymphocyte adhesion to endothelial cells exposed to ABC294640. In conclusion, treatment with SphK inhibitor leads to both pro- and anti-atherogenic effects in LDL-R(-/-) mice. As a consequence, SphK inhibition fails to affect atherosclerosis despite significant S1P reduction in plasma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / administration & dosage
  • Adamantane / adverse effects
  • Adamantane / analogs & derivatives*
  • Animals
  • Atherosclerosis / blood
  • Atherosclerosis / drug therapy*
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Differentiation / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Disease Models, Animal
  • Disease Progression
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / adverse effects
  • Humans
  • Inflammation Mediators / metabolism
  • Mice
  • Mice, Knockout
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Proprotein Convertases / blood
  • Pyridines / administration & dosage*
  • Pyridines / adverse effects
  • Receptors, LDL / genetics
  • Serine Endopeptidases / blood
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology


  • Cell Adhesion Molecules
  • Cytokines
  • Enzyme Inhibitors
  • Inflammation Mediators
  • Pyridines
  • Receptors, LDL
  • 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Proprotein Convertases
  • Serine Endopeptidases
  • membrane-bound transcription factor peptidase, site 1
  • Adamantane