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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:607.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

The Sphingosine-1-Phosphate Analogue FTY720 Reduces Atherosclerosis in Apolipoprotein E–Deficient Mice

Petra Keul; Markus Tölle; Susann Lucke; Karin von Wnuck Lipinski; Gerd Heusch; Mirjam Schuchardt; Markus van der Giet; Bodo Levkau

From the Institute of Pathophysiology (P.K., S.L., K.v.W.L., G.H., B.L.), University Hospital Essen, and the Med. Klinik IV (M.T., M.S., M.v.d.G.), Charite – Campus Benjamin Franklin, Berlin, Germany.

Correspondence to Bodo Levkau, Institute of Pathophysiology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany. E-mail levkau{at}uni-essen.de

Objective— The sphingosine-1-phosphate (S1P) analogue FTY720 is a potent immunosuppressive agent currently in Phase III clinical trials for kidney transplantation. FTY720 traps lymphocytes in secondary lymphoid organs thereby preventing their migration to inflammatory sites. Previously, we have identified FTY720 as a potent activator of eNOS. As both inhibition of immune responses and stimulation of eNOS may attenuate atherosclerosis, we administered FTY720 to apolipoprotein E^–/– mice fed a high-cholesterol diet.

Methods and Results— FTY720 dramatically reduced atherosclerotic lesion volume (62.5%), macrophage (41.8%), and collagen content (63.5%) after 20 weeks of high-cholesterol diet. In isolated aortic segments and cultured vascular smooth muscle cell, FTY720 potently inhibited thrombin-induced release of monocyte chemoattractant protein-1. This effect was mediated by the S1P₃ sphingolipid receptor as FTY720 had no effect on thrombin-induced monocyte chemoattractant protein-1 release in S1P₃^–/– mice. In contrast to S1P receptors on lymphocytes, FTY720 did not desensitize vascular S1P receptors as arteries from FTY720-treated mice retained their vasodilator response to FTY720-phosphate.

Conclusions— We suggest that FTY720 inhibits atherosclerosis by suppressing the machinery involved in monocyte/macrophage emigration to atherosclerotic lesions. As vascular S1P receptors remained functional under FTY720 treatment, S1P agonists that selectively target the vasculature and not the immune system may be promising new drugs against atherosclerosis.

The S1P analogue FTY720 potently induces immunosuppression and activates eNOS. Therefore, we tested its effect on atherosclerosis in ApoE^–/– mice. FTY720 dramatically reduced lesion volume, macrophage and collagen content and potently inhibited thrombin-induced release of MCP-1 via S1P₃. Thus FTY720 may suppress the machinery regulating monocyte/macrophage emigration to atherosclerotic lesions.

Key Words: sphingosine-1-phosphate • atherosclerosis • MCP-1 • FTY720 • ApoE^–/–

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