title: Sphingosine kinase inhibition exerts both pro- and anti-atherogenic effects in low-density lipoprotein receptor-deficient (LDL-R(-/-)) mice.
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.
authors.affiliation: Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Poti
authors.forename: Martine
authors.initials: M
authors.lastname: Bot
authors.forename: Sara
authors.initials: S
authors.lastname: Costa
authors.forename: Valeria
authors.initials: V
authors.lastname: Bergonzini
authors.forename: Lynn
authors.initials: L
authors.lastname: Maines
authors.forename: Georg
authors.initials: G
authors.lastname: Varga
authors.forename: Hendrik
authors.initials: H
authors.lastname: Freise
authors.forename: Horst
authors.initials: H
authors.lastname: Robenek
authors.forename: Manuela
authors.initials: M
authors.lastname: Simoni
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D043484:Proprotein Convertases / Q000097:blood; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D011973:Receptors, LDL / Q000235:genetics; D012697:Serine Endopeptidases / Q000097:blood; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000099157:Sphingosine Kinase
chemical_list: D000218:Adamantane; D015815:Cell Adhesion Molecules; D016207:Cytokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D017853:Phosphotransferases (Alcohol Group Acceptor); D043484:Proprotein Convertases; D011725:Pyridines; D011973:Receptors, LDL; D012697:Serine Endopeptidases; D000099157:Sphingosine Kinase; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide; C115575:membrane-bound transcription factor peptidase, site 1