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

最有效的动脉粥样硬化保护因子是高密度脂蛋白（HDL）。我们已经确定鞘氨醇-1-磷酸（S1P）是人类高密度脂蛋白的一个组成部分，并将其多种功能归因于它们的S1P含量。具体来说，我们已经描述了S1P及其受体S1P3在实验性动脉粥样硬化中巨噬细胞驱动炎症中的重要作用。在临床环境中，我们已经确定HDL结合和非HDL结合的S1P是冠状动脉疾病（CAD）心血管风险的新生物标志物，并提供了冠心病患者因S1P摄取HDL缺陷的证据。在这个项目中，我们将描述S1P如何影响单核细胞/巨噬细胞向动脉粥样硬化病变和其他炎症部位募集的机制。我们将通过S1P裂解酶抑制和S1P中和抗体调节内源性S1P水平，并将探索其对炎症和动脉粥样硬化的影响。关注HDL和S1P之间的相互作用，我们将确定HDL内的S1P分子受体及其所谓的导致CAD中HDL摄取S1P缺陷的改变，并将探索补偿方法。最后，我们将对CAD患者进行前瞻性研究，以检验hdl结合和非结合S1P作为心肌梗死后心血管风险和心功能预测指标的适用性。我们的研究将阐明S1P在CAD中的诊断和治疗意义，并评估基于S1P的临床治疗方法的潜力。

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.