Institute for Molecular Medicine III, University Hospital Düsseldorf, University of Düsseldorf, 40225 Düsseldorf, Germany.
Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Düsseldorf, 40225 Düsseldorf, Germany.
Int J Mol Sci. 2022 Aug 24;23(17):9606. doi: 10.3390/ijms23179606.
Altered plasma sphingosine-1-phosphate (S1P) concentrations are associated with clinical manifestations of atherosclerosis. However, whether long-term elevation of endogenous S1P is pro- or anti-atherogenic remains unclear. Here, we addressed the impact of permanently high S1P levels on atherosclerosis in cholesterol-fed apolipoprotein E-deficient () mice over 12 weeks. This was achieved by pharmacological inhibition of the S1P-degrading enzyme S1P lyase with 4-deoxypyridoxine (DOP). DOP treatment dramatically accelerated atherosclerosis development, propagated predominantly unstable plaque phenotypes, and resulted in frequent plaque rupture with atherothrombosis. Macrophages from S1P lyase-inhibited or genetically deficient mice had a defect in cholesterol efflux to apolipoprotein A-I that was accompanied by profoundly downregulated cholesterol transporters ATP-binding cassette transporters ABCA1 and ABCG1. This was dependent on S1P signaling through S1PR3 and resulted in dramatically enhanced atherosclerosis in mice, where DOP treatment had no additional effect. Thus, high endogenous S1P levels promote atherosclerosis, compromise cholesterol efflux, and cause genuine plaque rupture.
血浆鞘氨醇-1-磷酸（S1P）浓度的改变与动脉粥样硬化的临床表现有关。然而，内源性 S1P 的长期升高是促进还是抑制动脉粥样硬化仍不清楚。在这里，我们通过用 4-脱氧吡啶（DOP）抑制 S1P 降解酶 S1P 裂解酶的方法，在 12 周内研究了胆固醇喂养的载脂蛋白 E 缺陷（apoE-/-）小鼠中 S1P 水平长期升高对动脉粥样硬化的影响。DOP 治疗显著加速了动脉粥样硬化的发展，促进了主要不稳定斑块表型的发展，并导致经常发生动脉粥样血栓形成的斑块破裂。来自 S1P 裂解酶抑制剂或基因缺陷小鼠的巨噬细胞在胆固醇向载脂蛋白 A-I 的流出方面存在缺陷，这伴随着胆固醇转运体 ABCA1 和 ABCG1 的显著下调。这依赖于 S1PR3 介导的 S1P 信号转导，导致 小鼠的动脉粥样硬化显著增强，而 DOP 治疗没有额外的作用。因此，内源性 S1P 水平升高促进动脉粥样硬化，损害胆固醇流出，并导致真正的斑块破裂。
