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

动脉粥样硬化是一种炎症性疾病，可导致冠心病和中风。高密度脂蛋白（HDL）是一种脂蛋白复合物，是人类最有效的血浆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阻断巨噬细胞和t细胞介导的动脉壁炎症过程的能力有关。申请人的研究表明，HDL作为生物活性溶鞘脂的载体，如鞘磷脂1-磷酸（S1P），而S1P是HDL抗动脉粥样硬化和抗炎作用的主要贡献者。然而，体内S1P抗动脉粥样硬化潜能的机制尚不清楚。该项目的目的是研究S1P对通过S1P受体扩增信号的小鼠模型中动脉粥样硬化发展的影响，并深入了解与保护动脉粥样硬化相关的游离和高密度脂蛋白相关S1P的抗炎作用的分子机制。为此，将产生动脉粥样硬化易感小鼠系，其在巨噬细胞或t细胞中选择性地过表达S1P受体1型和3型（S1P1或S1P3）。在每个小鼠系中，将评估动脉粥样硬化的发展以及检查炎症反应。此外，将在体外条件下对巨噬细胞和过表达S1P1或S1P3的t细胞在动脉粥样硬化发生相关的分子过程（胆固醇处理、细胞凋亡、efferocytosis、炎症激活、极化）中的功能进行表征。本文提出的该项目的结果见解可能为预防和治疗动脉粥样硬化性心血管疾病的新诊断和治疗策略的发展奠定基础。

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.