Abstract
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.
Highlights
Sphingosine 1-phosphate (S1P) is an important lipid mediator generated from phospholipids upon cell activation and is present in plasma and extracellular fluid in high nanomolar concentrations (200–1,000 nM) [1, 2]
S1P is produced by phosphorylation of sphingosine by sphingosine kinases (SphK) 1 and 2 in response to a variety of stimuli and is actively exported out of the cells, where it serves as a ligand for five G protein-coupled receptors termed S1PR1–5 [3,4,5]
We studied the development of atherosclerosis in low-density lipoprotein (LDL)-R-/mice exposed to ABC294640, a potent and specific SphK inhibitor [21, 22]
Summary
Sphingosine 1-phosphate (S1P) is an important lipid mediator generated from phospholipids upon cell activation and is present in plasma and extracellular fluid in high nanomolar concentrations (200–1,000 nM) [1, 2]. In addition to extracellular effects S1P assumes a role as an intracellular second messenger and promotes expression of cytokines and adhesion-mediating molecules such as VCAM-1 and ICAM-1 in macrophages and endothelial cells, respectively [1, 11, 12]. Due to these pleiotropic effects exerted both extra- and intracellulary, S1P is critical for the maintenance of vascular homeostasis, while its perturbations may be decisive for the emergence of inflammatory vascular diseases such as atherosclerosis
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