Abstract 1515: FTY720, a Synthetic Sphingosine 1-Phosphate (S1P) Analogue, Inhibits Development of Atherosclerosis in LDL Receptor-Deficient Mice
Background: Numerous in vitro studies suggest that sphingosine 1-phosphate (S1P), a bioactive lysosphingolipid associated with high density lipoproteins (HDL), at least partly accounts for the potent anti-inflammatory properties of HDL and thereby contributes to the anti-atherogenic potential attributed to HDL. The present study was undertaken to investigate whether modulation of S1P signaling will affect atherosclerosis in a murine model of disease.
Methods and Results: LDL receptor-deficient (LDL-R−/ −) mice on a cholesterol-rich diet were given FTY720, a synthetic S1P analog, at a low (0.04 mg/kg/day) or high (0.4 mg/kg/day) dose for 16 weeks. FTY720 dose-dependently reduced atherosclerotic lesion formation both in the aortic root and brachiocephalic artery and almost completely blunted necrotic core formation. Plasma lipids remained unchanged in the course of FTY720 treatment. However, FTY720 lowered blood lymphocyte count (at high dose) and potently interfered with lymphocyte function, as evidenced by reduced splenocyte proliferation and IFN-γ levels in plasma. Plasma concentrations of pro-inflammatory cytokines such as TNF-α, IL-6, IL-12 and RANTES were reduced by FTY720 administration. Moreover, LPS elicited generation of nitrite/nitrate and IL-6 - two markers of classical (M1) macrophage activation - was inhibited, whereas IL-4-induced production of IL-1 receptor antagonist, a marker of alternative (M2) macrophage activation, was augmented in peritoneal macrophages from FTY720-treated LDL-R−/ − mice.
Conclusions: The present results demonstrate that an S1P analogue inhibits atherosclerosis by modulating lymphocyte and macrophage function and are consistent with the notion that S1P contributes to the anti-atherogenic potential of HDL.