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

HDL 结合和未结合的 S1P 在人和小鼠动脉粥样硬化中的作用

• 批准号: 39297953
• 负责人: Professor Dr. Bodo Levkau
• 金额: --
• 依托单位: Institut für Molekulare Medizin III
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/39297953?language=en
• 关键词: role; HDL; bound; unbound; S1P

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.

最强有力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（S1 P）作为人类HDL的组成部分，并已归因于其S1 P含量的几个多效性功能。具体来说，我们已经确定了S1 P及其受体S1 P3在实验性动脉粥样硬化中巨噬细胞驱动的炎症中的重要作用。在临床环境中，我们已经确定HDL结合和非HDL结合的S1 P作为冠状动脉疾病（CAD）心血管风险的新生物标志物，并提供了CAD患者HDL摄取缺陷的证据。在这个项目中，我们将描述S1 P如何影响单核细胞/巨噬细胞募集到动脉粥样硬化病变和其他炎症部位的机制。我们将通过S1 P裂解酶抑制和S1 P中和抗体调节内源性S1 P水平，并将探索对炎症和动脉粥样硬化的影响。重点是HDL和S1 P之间的相互作用，我们将确定HDL内的分子S1 P受体和他们声称的改变，导致有缺陷的S1 P摄取的HDL在CAD中，并将探讨如何补偿it. Finally，我们将进行前瞻性研究与CAD患者，以测试HDL结合和未结合的S1 P作为预测心血管风险和心肌梗死后的心功能的适用性。我们的研究将阐明S1 P在CAD中的诊断和治疗分支，并评估基于S1 P的治疗在其临床治疗中的潜力。