Altered plasma sphingosine-1-phosphate (S1P) concentrations are associated with clinical manifestations of atherosclerosis but whether long-term elevation of endogenous S1P is pro- or anti-atherogenic remains unclear. Most importantly, S1P loading of CAD-HDL fully restored HDL function. Therefore, we have defined reduced HDL-S1P are responsible for several aspects of the HDL dysfunction associated witch CAD and atherosclerosis. Recently, we have identified endogenous S1P production to be involved in cholesterol efflux to apolipoprotein A1, the initial event in reverse cholesterol transport. Here we address the impact of high endogenous S1P levels on cholesterol homeostasis and atherosclerosis.

Pharmacological inhibition of the S1P-degrading enzyme S1P lyase with 4-deoxypyridoxine dramatically accelerated atherosclerosis and caused genuine plaque rupture with appositional athero­thrombosis in cholesterol-fed ApoE^-/- mice. Macrophages from S1P lyase-inhibited or -deficient mice featured profoundly downregulated ATP-binding cassette transporters A1 and G1 (ABCA1  and ABCG1), compromised cholesterol efflux to apolipoprotein A-I (ApoA-I) and increased intracellular cholesterol content.

The aim of the current study was to investigate the effect of long-term S1P elevation in all tissues in combination with a Western type diet in ApoE^-/-  mice on the development of atherosclerosis. Using pharmacological S1P lyase inhibition we show dramatic effects on plaque size, composition and stability leading to plaque rupture and atherothrombosis, an event observed virtually never in regular ApoE^-/- mice. By suppressing ABCA1-mediated cholesterol efflux, S1P is a novel regulator of reverse cholesterol transport. Elevated endogenous S1P levels promote athero­sclerosis, hyper­cholesterolemia and plaque rupture.