title: KRP-203, sphingosine 1-phosphate receptor type 1 agonist, ameliorates atherosclerosis in LDL-R-/- mice.
abstract: OBJECTIVE
  Sphingosine 1-phosphate (S1P) partly accounts for antiatherogenic properties of high-density lipoproteins. We previously demonstrated that FTY720, a synthetic S1P analog targeting all S1P receptors but S1P receptor type 2, inhibits murine atherosclerosis. Here, we addressed the identity of S1P receptor mediating atheroprotective effects of S1P.
  
  
  RESULTS
  Low-density lipoprotein receptor-deficient mice on cholesterol-rich diet were given selective S1P receptor type 1 agonist KRP-203 (3.0 mg/kg per day; 6 and 16 weeks). KRP-203 substantially reduced atherosclerotic lesion formation without affecting plasma lipid concentrations. However, KRP-203 induced lymphopenia, reduced total (CD4(+), CD8(+)) and activated (CD69(+)/CD8(+), CD69(+)/CD4(+)) T cells in peripheral lymphoid organs, and interfered with lymphocyte function, as evidenced by decreased T-cell proliferation and interleukin-2 and interferon-γ production in activated splenocytes. Cyto- and chemokine (tumor necrosis factor-α, regulated and normal T cell expressed and secreted) levels in plasma and aortas were reduced by KRP-203 administration. Moreover, macrophages from KRP-203-treated mice showed reduced expression of activation marker MCH-II and poly(I:C)-elicited production of tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6. In vitro studies demonstrated that KRP-203 reduced tumor necrosis factor-α, interleukin-6, and interferon-γ-induced protein-10 production; IκB and signal transducer and activator of transcription-1 phosphorylation; and nuclear factor κB and signal transducer and activator of transcription-1 activation in poly(I:C)-, lipopolysaccharide-, or interferon-γ-stimulated bone marrow macrophages, respectively.
  
  
  CONCLUSIONS
  Present results demonstrate that activation of S1P signaling pathways inhibit atherosclerosis by modulating lymphocyte and macrophage function and suggest that S1P receptor type 1 at least partially mediates antiatherogenic effects of S1P.
authors: Department of Biomedical Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Francesco
authors: F
authors: Potì
authors: Fabio
authors: F
authors: Gualtieri
authors: Sandro
authors: S
authors: Sacchi
authors: Gabriele
authors: G
authors: Weißen-Plenz
authors: Georg
authors: G
authors: Varga
authors: Martin
authors: M
authors: Brodde
authors: Christian
authors: C
authors: Weber
authors: Manuela
authors: M
authors: Simoni
authors: Jerzy-Roch
authors: JR
authors: Nofer
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008213:Lymphocyte Activation / Q000187:drug effects; D008231:Lymphopenia / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D015415:Biomarkers; D002317:Cardiovascular Agents; D018836:Inflammation Mediators; C501899:KRP-203; D008055:Lipids; D011973:Receptors, LDL; D049349:Receptors, Lysosphingolipid; D013438:Sulfhydryl Compounds
keywords: T cells; high-density lipoproteins; inflammation; macrophage; murine models of disease; sphingosine 1-phosphate