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(高密度脂蛋白)是一种脂-蛋白复合体，是人类体内最有效的血浆源性抗动脉粥样硬化因子。越来越多的证据表明，高密度脂蛋白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，高密度脂蛋白是生物活性溶鞘磷脂的载体，如鞘氨醇1-磷酸(S1P)，而S1P是高密度脂蛋白体外抗动脉粥样硬化和抗炎作用的主要贡献者。然而，S1P在体内抗动脉粥样硬化的潜在机制还知之甚少。该项目的目的是在通过S1P受体放大信号的小鼠模型中研究S1P在动脉粥样硬化发展中的作用，并深入了解游离和高密度脂蛋白相关的S1P抗炎作用的分子机制，这些作用与保护动脉粥样硬化相关。为此，将产生易患动脉粥样硬化的小鼠系，它们选择性地在巨噬细胞或T细胞中过表达S1P受体1和3(S1P1或S1P3)。在每个小鼠品系中，动脉粥样硬化的发展将与炎症反应的检查一起评估。此外，巨噬细胞和过度表达S1P1或S1P3的T细胞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、胞吐作用、炎症激活、极化)的功能特征将在体外条件下进行。在此提出的项目所产生的见解可能为开发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.