Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy.
Thromb Haemost. 2012 Mar;107(3):552-61. doi: 10.1160/TH11-08-0583. Epub 2012 Jan 11.
Sphingosine 1-phosphate (S1P), a lysosphingolipid associated with high-density lipoprotein (HDL), contributes to the anti-atherogenic potential attributed to this lipoprotein. This study examined whether a reduction of S1P plasma levels affects atherosclerosis in a murine model of disease. LDL-R(-/-)mice on Western diet were given ABC294640, an inhibitor of sphingosine kinase (SphK) for 16 weeks. ABC294640 decreased plasma S1P by approximately 30%. However, ABC294640 failed to affect atherosclerotic lesion formation. Plasma triglycerides were reduced whereas total and HDL-cholesterol remained unchanged in course of ABC294640 treatment. ABC294640 increased plasma interleukin (IL)-12p70 and RANTES concentration as well as IL-12p70, RANTES and interferon (IFN)-γ production by peritoneal cells and this was paralleled by enhanced activity of peritoneal and spleen dendritic cells as evidenced by up-regulation of CD86 and MHC-II on CD11c(+) cells. As a consequence, increased T-cell activation was noted in ABC294640-treated mice as indicated by enhanced CD4(+) splenocyte proliferation, IFN-γ and IL-2 production, and CD69 expression. Concomitantly, however, ABC294640 treatment redistributed CD4(+) and CD8(+) cells from blood to lymphatic organs and reduced T-cell number within atherosclerotic lesions. In addition, plasma sVCAM-1, sICAM-1, and MCP-1 levels as well as in vivo leukocyte adhesion and CCL19-induced T-cell penetration into peritoneum were lower in ABC294640-treated animals. In vitro experiments demonstrated reduced VCAM-1 and ICAM-1 expression and lymphocyte adhesion to endothelial cells exposed to ABC294640. In conclusion, treatment with SphK inhibitor leads to both pro- and anti-atherogenic effects in LDL-R(-/-) mice. As a consequence, SphK inhibition fails to affect atherosclerosis despite significant S1P reduction in plasma.
鞘氨醇 1-磷酸（S1P）是一种与高密度脂蛋白（HDL）相关的溶血神经鞘脂，有助于赋予这种脂蛋白抗动脉粥样硬化的潜力。本研究探讨了降低 S1P 血浆水平是否会影响疾病的小鼠模型中的动脉粥样硬化形成。给予 Western 饮食的 LDL-R（-/-）小鼠 SphK 抑制剂 ABC294640 治疗 16 周。ABC294640 使血浆 S1P 降低约 30%。然而，ABC294640 并未影响动脉粥样硬化病变的形成。在 ABC294640 治疗过程中，血浆甘油三酯降低，而总胆固醇和 HDL-胆固醇保持不变。ABC294640 增加了血浆白细胞介素（IL）-12p70 和 RANTES 浓度以及腹腔细胞产生的 IL-12p70、RANTES 和干扰素（IFN）-γ，这与腹腔和脾脏树突状细胞活性增强相平行，表现为 CD11c（+）细胞上 CD86 和 MHC-II 的上调。因此，在 ABC294640 治疗的小鼠中观察到 T 细胞激活增加，如 CD4（+）脾细胞增殖、IFN-γ 和 IL-2 产生以及 CD69 表达增强所示。然而，同时，ABC294640 治疗将 CD4（+）和 CD8（+）细胞从血液重新分布到淋巴器官，并减少动脉粥样硬化病变内的 T 细胞数量。此外，ABC294640 治疗动物的血浆 sVCAM-1、sICAM-1 和 MCP-1 水平以及体内白细胞黏附和 CCL19 诱导的 T 细胞渗透到腹膜中降低。体外实验表明，暴露于 ABC294640 的 VCAM-1 和 ICAM-1 表达和淋巴细胞黏附减少。总之，SphK 抑制剂的治疗在 LDL-R（-/-）小鼠中既导致动脉粥样硬化形成，也导致抗动脉粥样硬化作用。因此，尽管血浆 S1P 显著降低，但 SphK 抑制仍未影响动脉粥样硬化。
