The relevance of sphingolipids in inflammatory cardiovascular disease: Signaling of S1P1 and S1P3 receptors

近年来，越来越多的证据表明S1 P受体信号在心血管系统的控制中起着重要作用。可以表明，血管系统中的S1 P受体活化减少促炎信号传导，特别是保护内皮，内皮被认为是控制适当血管稳态的最突出的细胞之一。首先，我们希望获得更多的信息，潜在的血管保护作用的S1 P，其类似物，参与的受体和分子机制。我们发现，特别是S1 P3受体激活减少促炎反应的血管细胞抑制早期动脉粥样硬化细胞因子，如单核细胞趋化蛋白1（MCP 1）或晚期动脉粥样硬化酶基质金属蛋白酶9（MMP 9）。在典型的动脉粥样硬化模型中，我们可以证明FTY 720激活S1 P受体确实可以减少动脉粥样硬化。我们有第一个证据表明，S1 P信号在血管平滑肌细胞的钙化（动脉硬化）中起着核心作用，抑制细胞从血管平滑肌细胞转化成骨细胞样细胞。此外，我们有证据表明，S1 P受体信号是一个生理相关的系统，以保护内皮细胞，特别是在女性。在心血管死亡率高的患者中，例如终末期肾病患者，我们可以证明高密度脂蛋白（HDL的主要载体）中的S1 P水平降低。S1 P水平降低的HDL失去其血管保护作用。最后，我们已经发现了很好的证据表明，S1 P受体之间的相互作用，特别是与TGF-β受体系统。现在，我们必须定义S1 P在动脉硬化中的作用，确定心血管高危患者HDL中S1 P降低的原因，并定义主要与心血管系统相关的精确S1 P受体及其相互作用。我们希望这些信息给我们的可能性，以确定S1 P受体系统作为一个高度相关的系统，以建立新的药物治疗。作为第一种方法，我们将在动脉硬化模型中测试新的S1 P受体激动剂。

In the last years there is an increasing body of evidence that S1P receptor signalling plays a prominent role in the control of the cardiovascular system. It could be shown that S1P receptor activation in the vascular system reduces proinflammatory signalling and especially protects the endothelium which is believed to be one of the most prominent cells to control proper vascular homeostasis. At first we wanted to get more information on the potentially vasculoprotective actions of S1P, its analogues, the involved receptors and the molecular mechanism. We showed that especially S1P3 receptor activation reduced proinflammatory response in vascular cells by inhibition of early atherosclerotic cytocines like monocyte-chemoattractant protein 1 (MCP1) or late atherosclerotic enzymes matrix-metalloproteinase 9 (MMP9). In a typical atherosclerosis model, we could show that S1P receptor activation by FTY720 indeed reduces atherosclerosis. We have first evidence that S1P signaling plays a central role in the calcification of vascular smooth muscle cells (arteriosclerosis) by inhibition of cell transformation from vascular smooth muscle cells to osteoblast like cells. In addition we have evidence that S1P receptor signalling is a physiological relevant system to protect endothelial cells especially in females. In patients with high cardiovascular mortality, e.g. patients with end-stage renal disease, we can demonstrate that S1P levels are reduced in high-density lipoproteins, which are the main carrier for HDL. HDL with reduced S1P levels loses its vasoprotective actions. Finally we have found good evidence that S1P receptors interact among each and especially with the TGF-ß receptor system. Now we have to define the role of S1P in arteriosclerosis, to identify the reasons why S1P is reduced in HDL from patients with high cardiovascular risks and to define the precise S1P receptors their interactions which are mainly relevant for the cardiovascular system. We hope that these informations give us the possibility to define the S1P receptor system as a highly relevant system to establish new pharmacological therapies. As a first approach we will test new S1P receptor agonists in arteriosclerosis models.