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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2392.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Sphingosine-1-Phosphate Analogue FTY720 Causes Lymphocyte Redistribution and Hypercholesterolemia in ApoE-Deficient Mice

Roland Klingenberg; Jerzy-Roch Nofer; Mats Rudling; Florian Bea; Erwin Blessing; Michael Preusch; Hermann J. Grone; Hugo A. Katus; Göran K. Hansson; Thomas J. Dengler

From the Department of Cardiology (R.K., F.B., E.B., M.P., H.A.K., T.J.D.), University Hospital Heidelberg, Germany; Department of Medicine (R.K., G.K.H.), Karolinska Institutet, Stockholm, Sweden; the Leibniz-Institute for Arteriosclerosis Research (J.R.N.), University of Münster, Germany; the Center for Endocrinology, Metabolism, and Diabetes (M.R.), Karolinska Institutet, Stockholm, Sweden; and Deutsches Krebsforschungszentrum (DKFZ) (H.J.G.), Heidelberg, Germany.

Correspondence to Roland Klingenberg, MD, Center for Molecular Medicine, L8:03, Experimental Cardiovascular Research Unit, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail roland.klingenberg{at}ki.se

Objective— Resident immune cells are a hallmark of atherosclerotic lesions. The sphingolipid analogue drug FTY720 mediates retrafficking of immune cells and inhibits their homing to inflammatory sites. We have evaluated the effect of FTY720 on atherogenesis and lipid metabolism.

Methods and Results— ApoE^–/– mice on a normal laboratory diet received oral FTY720 for 12 weeks, which led to a 2.4-fold increase in serum cholesterol (largely VLDL fraction) and a 1.8-fold increase in hepatic HMGCoA reductase mRNA. FTY720 increased plasma sphingosine-1-phosphate and induced marked peripheral blood lymphopenia. A discoordinate modulation of B, T and monocyte cell numbers was found in peripheral lymphoid organs. Overall depletion of T cells was accompanied by a relative (2-fold) increase in regulatory T cell content paralleled by a similar increase in effector memory T cells (CD4+CD44hiCD62lo) as absolute numbers of both subpopulations remained essentially unchanged. Lymphocyte function was unaltered as indicated by anti-OxLDL antibodies and T cell proliferation. There were no changes in atherosclerotic lesions in early and established atherosclerosis.

Conclusions— FTY720 mediated peripheral lymphocyte depletion and retrafficking without altering function and overall balance of pro- and antiatherogenic lymphocyte populations. A net decrease in lymphocyte numbers occurred concomitantly with a more proatherogenic hypercholesterolemia resulting in unaltered atherogenesis.

Administration of the sphingolipid analogue FTY720 to ApoE^–/– mice on normal laboratory diet altered lipid metabolism yielding pronounced hypercholesterolemia. Despite lymphocyte depletion and retrafficking the overall balance of pro- and antiatherogenic lymphocyte populations was not changed. Hypercholesterolemia appears to have counteracted the otherwise beneficial effect on atherogenesis.

Key Words: atherosclerosis • immune system • immunosuppressive therapy • leukocytes • vascular biology

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