title: Effect of sphingosine 1-phosphate (S1P) receptor agonists FTY720 and CYM5442 on atherosclerosis development in LDL receptor deficient (LDL-R⁻/⁻) mice.
abstract: OBJECTIVE
  Sphingosine 1-phosphate (S1P)--a lysosphingolipid present in HDL--exerts atheroprotective effects in vitro, while FTY720, a non-selective S1P mimetic inhibits atherosclerosis in LDL receptor-deficient (LDL-R⁻/⁻) mice under conditions of severe hypercholesterolemia. We here examined the effect of FTY720 and a selective S1P receptor type 1 agonist CYM5442 on atherosclerosis in moderately hypercholesterolemic LDL-R⁻/⁻ mice.
  
  
  RESULTS
  LDL-R⁻/⁻ mice fed Western diet (0.25% cholesterol) were given FTY720 (0.4 mg/kg/day) or CYM5442 (2.0 mg/kg/day) for 18 weeks. FTY720 but not CYM5422 persistently lowered blood lymphocytes, depleted CD4⁺ and CD8⁺ T cells in spleen and lymph nodes, and reduced splenocyte IL-2 secretion. However, both compounds reduced the activity of splenic and peritoneal macrophages as inferred from the down-regulated CD68 and MHC-II expression in CD11b⁺ cells and the reduced IL-6 secretion in response to LPS, respectively. CYM5442 and FTY720 reduced weight gain, white adipose tissue depots and fasting glucose suggesting improvement of metabolic control, but failed to influence atherosclerosis in LDL-R⁻/⁻ mice.
  
  
  CONCLUSIONS
  Despite down-regulating macrophage function and--in case of FTY720--altering lymphocyte distribution CYM5442 and FTY720 fail to affect atherosclerosis in moderately hypercholesterolemic LDL-R⁻/⁻ mice. We hypothesize that S1P mimetics exert atheroprotective effects only under conditions of increased cholesterol burden exacerbating vascular inflammation.
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: Sara
authors.initials: S
authors.lastname: Costa
authors.forename: Valeria
authors.initials: V
authors.lastname: Bergonzini
authors.forename: Margherita
authors.initials: M
authors.lastname: Galletti
authors.forename: Elisa
authors.initials: E
authors.lastname: Pignatti
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Manuela
authors.initials: M
authors.lastname: Simoni
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D001835:Body Weight / Q000276:immunology; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D000068876:Fingolimod Hydrochloride; D005802:Genes, MHC Class II / Q000276:immunology; D007189:Indans / Q000494:pharmacology*; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010069:Oxadiazoles / Q000494:pharmacology*; D043484:Proprotein Convertases / Q000276:immunology / Q000378:metabolism; D011409:Propylene Glycols / Q000276:immunology / Q000494:pharmacology*; D011973:Receptors, LDL / Q000276:immunology / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D039481:CD11b Antigen; D000068876:Fingolimod Hydrochloride; D007189:Indans; D007376:Interleukin-2; D015850:Interleukin-6; D010069:Oxadiazoles; D043484:Proprotein Convertases; D011409:Propylene Glycols; D011973:Receptors, LDL; D049349:Receptors, Lysosphingolipid; D012697:Serine Endopeptidases; D013110:Sphingosine; C532995:2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino)ethanol; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C115575:membrane-bound transcription factor peptidase, site 1