Defects of High-Density Lipoproteins in Coronary Artery Disease Caused by Low Sphingosine-1-Phosphate Content: Correction by Sphingosine-1-Phosphate-Loading

Abstract

Background: Sphingosine-1-phosphate (S1P) is a constituent of high-density lipoproteins (HDL) that contributes to their beneficial effects. We have shown decreased HDL-S1P in coronary artery disease (CAD) but its functional relevance remains unclear.

Objectives: This study investigated the functional consequences of reduced HDL-S1P content in CAD and tested if increasing it may improve or restore HDL function.

Methods: Human HDL from healthy and CAD subjects, as well as mouse HDL, were isolated by ultracentrifugation. HDL-S1P-dependent activation of cell-signaling pathways and induction of vasodilation were examined in vitro and in isolated arteries using native and S1P-loaded HDL, S1P receptor antagonists, and S1P-blocking antibodies.

Results: HDL-S1P-dependent signaling was clearly impaired and S1P content reduced in CAD-HDL as compared to healthy HDL. Both healthy and CAD-HDL could be efficiently and equally well loaded with S1P from cellular donors and plasma. S1P-loading greatly improved HDL signaling and vasodilatory potential in pre-contracted arteries and completely corrected the defects inherent to CAD-HDL. HDL-S1P content and uptake was reduced by oxidation and was lower in HDL3 than HDL2. Loading with S1P in vitro and in vivo fully replenished the virtually absent S1P content of apolipoprotein M-deficient HDL and restored their defective signaling. Infusion of erythrocyte-associated C17-S1P in mice led to its rapid and complete uptake by HDL providing a means to directly S1P-load HDL in vivo.

Conclusions: Reduced HDL-S1P content contributes to HDL dysfunction in CAD. It can be efficiently increased by S1P-loading in vitro and in vivo, providing a novel approach to correcting HDL dysfunction in CAD.

Keywords: apolipoprotein M; dysfunction; lipids; lipoproteins; signaling; sphingolipids; vasodilation.