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

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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.