Tölle M, Levkau B, Kleuser B, van der Giet M
Charite - Universitätsmedizin Berlin, Campus Benjamin Franklin, Med. Klinik mit Schwerpunkt Nephrologie, Berlin, Germany.
Eur J Clin Invest. 2007 Mar;37(3):171-9. doi: 10.1111/j.1365-2362.2007.01776.x.
All stages of atherosclerosis have been identified as a chronic vascular inflammatory disease. In the last few years there is increasing evidence that endogenous lysophospholipids such as sphingosine-1-phosphate (S1P) have potent anti-inflammatory properties. The S1P analogue FTY720 that has been developed as a potent, orally active, immunosuppressant in the field of transplantation and autoimmune disease has interesting effects on inflammatory processes in the arterial vessel wall. S1P targets five specific S1P receptors (S1P(1-5)), which are ubiquitously expressed. S1P(1-3) receptor expression is identified in arterial vessels. S1P and FTY720 show potent silencing effects on some vascular proinflammatory mechanisms in endothelial and vascular smooth muscle cells. In addition, the interaction of monocytes with the vessel wall is inhibited. As shown recently, FTY720 can effectively reduce the progression of atherosclerosis in apolipoprotein E-deficient mice having a high-cholesterol diet. It is not entirely clear which S1P receptor subtype is mainly involved in this process. However, it is currently speculated that the S1P(3) and probably the S1P(1) is involved in the anti-atherosclerotic effects of FTY720. This review summarizes the current knowledge about S1P- and FTY720-effects on mechanisms of vascular inflammatory disease. In addition S1P receptor subtypes are identified which might be interesting for molecular drug targeting.
动脉粥样硬化的各个阶段均已被确认为一种慢性血管炎症性疾病。在过去几年中，越来越多的证据表明，内源性溶血磷脂，如1-磷酸鞘氨醇（S1P），具有强大的抗炎特性。已被开发为移植和自身免疫疾病领域中一种强效、口服活性免疫抑制剂的S1P类似物FTY720，对动脉血管壁的炎症过程具有有趣的作用。S1P作用于五种特异性S1P受体（S1P(1 - 5)），这些受体广泛表达。在动脉血管中可检测到S1P(1 - 3)受体的表达。S1P和FTY720对内皮细胞和血管平滑肌细胞中的一些血管促炎机制具有强大的抑制作用。此外，单核细胞与血管壁的相互作用也受到抑制。最近的研究表明，FTY720能够有效减缓喂食高胆固醇饮食的载脂蛋白E缺陷小鼠的动脉粥样硬化进程。目前尚不完全清楚在此过程中主要涉及哪种S1P受体亚型。然而，目前推测S1P(3)，可能还有S1P(1)，参与了FTY720的抗动脉粥样硬化作用。本综述总结了目前关于S1P和FTY720对血管炎症性疾病机制影响的相关知识。此外，还确定了可能对分子药物靶向治疗有意义的S1P受体亚型。
