The role of HDL-bound and unbound S1P in human and mouse atherosclerosis

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The most powerful atheroprotective factor are high-density lipoproteins (HDL). We have identified sphingosine-1-phosphate (S1P) as a constituent of human HDL and have attributed several of their pleiotropic functions to their S1P content. Specifically, we have characterized an important role for S1P and its receptor S1P3 in macrophage-driven inflammation in experimental atherosclerosis. In a clinical setting, we have identified HDL-bound and non-HDL-bound S1P as novel biomarkers for cardiovascular risk in coronary artery disease (CAD) and have provided evidence of an uptake defect of HDL from CAD patients for S1P. In this project, we will characterize how S1P impacts on the mechanisms governing monocyte/macrophage recruitment to atherosclerotic lesions and other inflammation sites. We will modulate endogenous S1P levels by S1P lyase inhibition and S1P-neutralizing antibodies and will explore the effects on inflammation and atherosclerosis. Focussing on the interplay between HDL and S1P, we will identify the molecular S1P acceptors inside HDL and their alleged alterations that cause the defective S1P uptake by HDL in CAD, and will explore ways to compensate it. Finally, we will perform prospective studies with CAD patients to test the applicability of HDL-bound and unbound S1P as predictors of cardiovascular risk and cardiac function after myocardial infarction. Our studies will elucidate the diagnostic and therapeutic ramifications of S1P in CAD and assess the potential of S1Pbased therapies for its clinical treatment.