Published online before print March 31, 2005, doi: 10.1161/01.RES.0000164321.91452.00
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Submitted on August 19, 2004
Revised on March 22, 2005
Accepted on March 22, 2005
Immunomodulator FTY720 Induces eNOS-Dependent Arterial Vasodilatation via the Lysophospholipid Receptor S1P3
Markus Tölle ;
From the Med. Klinik IV (M.T., G.G., J.J., V.J., W.Z., M.v.d.G.) and Institut für Klinische Pharmakologie und Toxikologie (G.S.), Charite-Campus Benjamin Franklin, Berlin, Germany; Institut für Pathophysiologie (B.L., P.K., K.v.W.L.), Zentrum für Innere Medizin, Universitätsklinikum Essen, Germany; Transplantation and Immunology (V.B.), Novartis Institutes for BioMedical Research, Basel, Switzerland; Department of Nuclear Medicine (M.S.), Hospital of the Westfälische Wilhelms-University, Münster; and the Department of Molecular Biology (J.C.), The Scripps Research Institute, La Jolla, Calif.
* To whom correspondence should be addressed. E-mail: markus.vandergiet{at}charite.de.
The novel immunomodulator FTY720 is effective in experimental models of transplantation and autoimmunity, and is currently undergoing Phase III clinical trials for prevention of kidney graft rejection. FTY720 is a structural analogue of sphingosine-1-phosphate (S1P) and activates several of the S1P receptors. We show that FTY720 induces endothelium-dependent arterial vasodilation in phenylephrine precontracted mouse aortae. Vasodilation did not occur in thoracic aortic rings from eNOS-deficient mice, implicating and effect dependent of activation of the eNOS/NO pathway. Accordingly, FTY720 induced NO release, Akt-dependent eNOS phosphorylation and activation in human endothelial cells. For biological efficacy, FTY720 required endogenous phosphorylation, since addition of the sphingosine kinase antagonist N',N-dimethylsphingosine (DMS) prevented activation of eNOS in vitro and inhibited vasodilation in isolated arteries. The endothelial phosphorylation of FTY720 was extremely rapid with also most complete conversion after 10 minutes as determined by mass spectrometry. Finally, we identified the lysophospholipid receptor S1P3 as the S1P receptor responsible for arterial vasodilation by FTY720, as the effect was completely abolished in arteries from S1P3-deficient mice. In summary, we have identified FTY720 as the first immunomodulator for prevention of organ graft rejection in clinical development that, in addition, positively affects the endothelium by stimulating NO production, and thus potentially displaying beneficial effects on transplant survival beyond classical T cell immunosuppression.
Key words: FTY720 • eNOS • S1P receptor
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