FTY720, a synthetic sphingosine 1 phosphate analogue, inhibits development of atherosclerosis in low-density lipoprotein receptor-deficient mice.
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.


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-gamma levels in plasma. Plasma concentrations of proinflammatory cytokines such as tumor necrosis factor-alpha, 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.
Nofer
Jerzy-Roch
JR
Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität Münster, Albert Schweizer Str 33, D-48129 Münster, Germany. nofer@uni-muenster.de
Bot
Martine
M
Brodde
Martin
M
Taylor
Paul J
PJ
Salm
Paul
P
Brinkmann
Volker
V
van Berkel
Theo
T
Assmann
Gerd
G
Biessen
Erik A L
EA
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D008076:Cholesterol, HDL / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011409:Propylene Glycols / Q000494:pharmacology*; D011973:Receptors, LDL / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
D008076:Cholesterol, HDL; D016207:Cytokines; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D011409:Propylene Glycols; D011973:Receptors, LDL; D014280:Triglycerides; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine