The sphingosine-1-phosphate analogue FTY720 reduces atherosclerosis in apolipoprotein E-deficient mice.
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.


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.
Keul
Petra
P
Institute of Pathophysiology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.
Tölle
Markus
M
Lucke
Susann
S
von Wnuck Lipinski
Karin
K
Heusch
Gerd
G
Schuchardt
Mirjam
M
van der Giet
Markus
M
Levkau
Bodo
B
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000503:physiopathology / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D008246:Lysophospholipids; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D011336:Probability; D011409:Propylene Glycols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018709:Statistics, Nonparametric
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D016207:Cytokines; D008246:Lysophospholipids; D011409:Propylene Glycols; D012333:RNA, Messenger; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine