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

Objectives: Sphingosine 1-phosphate (S1P) – a lysosphingolipid present in HDL – exerts atheroprotective ef- fects 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 (0.4 mg/kg/day) or CYM5442 (2.0 mg/kg/day) for 18 weeks. FTY720 but not CYM5422 persistently lowered blood lympho- cytes, 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 glu- cose 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 dis- tribution 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.