Atheroprotective effects of sphingosine 1-phosphate (S1P) in macrophages and T-cells

动脉粥样硬化是一种导致冠心病和中风的炎症性疾病。高密度脂蛋白（HDL）是一种脂蛋白复合物，是人体血浆中最有效的抗动脉粥样硬化因子。越来越多的证据表明，HDL的动脉粥样硬化保护作用与其中断动脉壁中巨噬细胞和T细胞介导的炎症过程的能力有关。申请人的研究表明，HDL作为生物活性溶血鞘脂（如1-磷酸鞘氨醇（S1 P））的载体，并且S1 P是HDL体外抗动脉粥样硬化和抗炎作用的主要贡献者。然而，S1 P在体内抗动脉粥样硬化的潜在机制知之甚少。该项目的目的是研究S1 P对小鼠模型中动脉粥样硬化发展的影响，通过S1 P受体放大信号传导，并深入了解游离和HDL相关S1 P的抗炎作用的分子机制，以保护免受动脉粥样硬化。为此，将产生动脉粥样硬化倾向的鼠系，其在巨噬细胞或T细胞中选择性过表达1型和3型S1 P受体（S1 P1或S1 P3）。在每个鼠系中，动脉粥样硬化的发展将与炎症反应的检查一起沿着评估。此外，将在体外条件下对过表达S1 P1或S1 P3的巨噬细胞和T细胞进行与动脉粥样硬化发展相关的分子过程（胆固醇处理、细胞凋亡、细胞凋亡、炎症活化、极化）的功能表征。由此产生的见解，这里提出的项目可能形成的基础，为预防和治疗动脉粥样硬化性心血管疾病的新的诊断和治疗策略的发展。

Atherosclerosis is an inflammatory disease leading to coronary heart disease and stroke. High density lipoprotein (HDL) is a lipid-protein complex and the most potent plasma-born anti-atherogenic factor in humans. Increasing evidence suggests that atheroprotective effects of HDL are related to their capacity to interrupt macrophage- and T-cell-mediated inflammatory processes in the arterial wall. The investigations of the applicant revealed that HDL serves as a carrier of biologically active lysosphingolipids such as sphingosine 1-phosphate (S1P) and that S1P is a major contributor to anti-atherogenic and anti-inflammatory effects of HDL in vitro. However, mechanisms underlying the anti-atherogenic potential of S1P in vivo are poorly understood. The objective of the proposed project is to investigate the effects of S1P on the development of atherosclerosis in mouse models with amplified signalling through S1P receptors and to gain insights into molecular mechanisms underlying anti-inflammatory effects of free and HDL-associated S1P relevant for protection against atherosclerosis. For this purpose, atherosclerosis-prone murine lines will be generated, which selectively overexpress S1P receptors type 1 and 3 (S1P1 or S1P3) in macrophages or T-cells. In each murine line, the development of atherosclerosis will be assessed along with the examination of inflammatory responses. In addition, functional characterization of macrophages and T-cells overexpressing S1P1 or S1P3 with respect to molecular processes relevant to the development of atherosclerosis (cholesterol handling, apoptosis, efferocytosis, inflammatory activation, polarization) will be performed under in vitro conditions. The resulting insights of the project proposed here may form the fundament for the development of novel diagnostic and therapeutic strategies for the prevention and treatment of atherosclerotic cardiovascular disease.