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(Circulation. 2007;115:501-508.)
© 2007 American Heart Association, Inc.

Vascular Medicine

FTY720, a Synthetic Sphingosine 1 Phosphate Analogue, Inhibits Development of Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice

Jerzy-Roch Nofer, MD, MBA^*; Martine Bot, MS^*; Martin Brodde, PhD; Paul J. Taylor, PhD; Paul Salm, PhD; Volker Brinkmann, PhD; Theo van Berkel, PhD; Gerd Assmann, MD, FRCP; Erik A.L. Biessen, PhD

From the Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster, Germany (J.-R.N., G.A.), Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany (J.-R.N., G.A.), Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, the Netherlands (M. Bot, T.v.B., E.A.L.B.), Klinik und Poliklinik für Anästhesiologie und Operative Intensivmedizin, Experimentelle und Klinische Hämostaseologie, Universitätsklinik, Münster, Germany (M. Brodde), Australian Bioanalytical Services Pty Ltd, Princess Alexandra, Hospital, Brisbane, Australia (P.J.T., P.S.), Department of Clinical Pharmacology, Princess Alexandra Hospital, Brisbane, Australia (P.J.T.), and Transplantation and Immunology, Novartis Institutes for BioMedical Research, Basel, Switzerland (V.B.).

Correspondence to Jerzy-Roch Nofer, MD, MBA, Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität Münster, Albert Schweizer Str 33, D-48129 Münster, Germany. E-mail nofer{at}uni-muenster.de

Received May 22, 2006; accepted November 15, 2006.

Background— Numerous in vitro studies suggest that sphingosine 1-phosphate (S1P), a bioactive lysosphingolipid associated with high-density lipoproteins, accounts at least partly for the potent antiinflammatory properties of high-density lipoprotein and, thereby, contributes to the antiatherogenic potential attributed to high-density lipoproteins. The present study was undertaken to investigate whether modulation of S1P signaling would affect atherosclerosis in a murine model of disease.

Methods and Results— Low-density lipoprotein receptor–deficient mice on a cholesterol-rich diet were given FTY720, a synthetic S1P analogue, at low (0.04 mg/kg per day) or high (0.4 mg/kg per day) doses for 16 weeks. FTY720 dose-dependently reduced atherosclerotic lesion formation, both in the aortic root and brachiocephalic artery, and almost completely blunted necrotic core formation. Plasma lipids remained unchanged during the course of FTY720 treatment. However, FTY720 lowered blood lymphocyte count (at a high dose) and significantly interfered with lymphocyte function, as evidenced by reduced splenocyte proliferation and interferon- levels in plasma. Plasma concentrations of proinflammatory cytokines such as tumor necrosis factor-, interleukin (IL)-6, IL-12, and regulated on activation normal T cell expressed and secreted were reduced by FTY720 administration. Moreover, lipopolysaccharide-elicited generation of nitrite/nitrate and IL-6—two markers of classical (M1) macrophage activation—was inhibited, whereas IL-4–induced production of IL-1–receptor antagonist, a marker of alternative (M2) macrophage activation, was augmented in peritoneal macrophages from FTY720-treated low-density lipoprotein receptor–deficient mice.

Conclusions— The present results demonstrate that an S1P analogue inhibits atherosclerosis by modulating lymphocyte and macrophage function, and these results are consistent with the notion that S1P contributes to the antiatherogenic potential of high-density lipoprotein.

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