Objectives: 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. Methods and results: LDL-R-/- mice fed Western diet (0.25% cholesterol) were given FTY720 (0.4mg/kg/day) or CYM5442 (2.0mg/kg/day) for 18weeks. 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. Conclusion: 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. © 2012 Elsevier Inc.

Effect of sphingosine 1-phosphate (S1P) receptor agonists FTY720 and CYM5442 on atherosclerosis development in LDL receptor deficient (LDL-R-/-) mice / Poti', Francesco; Costa, Sara; Bergonzini, Valeria; Galletti, Margherita; Pignatti, Elisa; Weber, Christian; Simoni, Manuela; Nofer, Jerzy Roch. - In: VASCULAR PHARMACOLOGY. - ISSN 1537-1891. - 57:1(2012), pp. 56-64. [10.1016/j.vph.2012.03.003]

Effect of sphingosine 1-phosphate (S1P) receptor agonists FTY720 and CYM5442 on atherosclerosis development in LDL receptor deficient (LDL-R-/-) mice

POTI', Francesco;COSTA, Sara;
2012-01-01

Abstract

Objectives: 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. Methods and results: LDL-R-/- mice fed Western diet (0.25% cholesterol) were given FTY720 (0.4mg/kg/day) or CYM5442 (2.0mg/kg/day) for 18weeks. 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. Conclusion: 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. © 2012 Elsevier Inc.
Effect of sphingosine 1-phosphate (S1P) receptor agonists FTY720 and CYM5442 on atherosclerosis development in LDL receptor deficient (LDL-R-/-) mice / Poti', Francesco; Costa, Sara; Bergonzini, Valeria; Galletti, Margherita; Pignatti, Elisa; Weber, Christian; Simoni, Manuela; Nofer, Jerzy Roch. - In: VASCULAR PHARMACOLOGY. - ISSN 1537-1891. - 57:1(2012), pp. 56-64. [10.1016/j.vph.2012.03.003]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2815706
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 32
  • ???jsp.display-item.citation.isi??? 30
social impact