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

鞘脂与炎症性心血管疾病的相关性：S1P1 和 S1P3 受体的信号传导

• 批准号: 39297764
• 负责人: Professor Dr. Markus van der Giet
• 金额: --
• 依托单位: Lehrstuhl für Ernährungstoxikologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/39297764?language=en
• 关键词: relevance; sphingolipids; inflammatory; cardiovascular; disease

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.

最近几年，越来越多的证据表明，S1P受体信号在心血管系统的控制中发挥着重要作用。研究表明，血管系统中S1P受体的激活减少了促炎信号，特别是保护内皮细胞，内皮细胞被认为是控制适当的血管内稳态的最重要的细胞之一。首先，我们想要获得更多关于S1P及其类似物潜在的血管保护作用、涉及的受体和分子机制的信息。我们发现，S1P3受体的激活通过抑制早期动脉粥样硬化细胞因子如单核细胞趋化蛋白1(MCP1)或晚期动脉粥样硬化酶基质金属蛋白酶9(MMP9)来减少血管细胞的促炎反应。在一个典型的动脉粥样硬化模型中，我们可以证明FTY720激活S1P受体确实可以减少动脉粥样硬化。我们首次发现S1P信号通过抑制血管平滑肌细胞向成骨样细胞的转化，在血管平滑肌细胞的钙化(动脉硬化)中发挥核心作用。此外，我们有证据表明，S1P受体信号是一种生理相关系统，可以保护内皮细胞，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中的S1P水平降低，高密度脂蛋白是高密度脂蛋白的主要载体。随着S1P水平的降低，高密度脂蛋白失去了血管保护作用。最后，我们发现了S1P受体相互作用的良好证据，尤其是与转化生长因子受体系统的相互作用。现在我们必须确定S1P在动脉硬化中的作用，找出心血管高危患者中S1P降低的原因，并定义S1P受体及其相互作用，这些受体主要与心血管系统相关。我们希望这些信息使我们有可能将S1P受体系统定义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S1P受体激动剂。