Immunomodulator FTY720 induces eNOS-dependent arterial vasodilatation via the lysophospholipid receptor S1P3

被引:105
作者
Tölle, M
Levkau, B
Keul, P
Brinkmann, V
Giebing, G
Schönfelder, G
Schäfers, M
Lipinski, KV
Jankowski, J
Jankowski, V
Chun, J
Zidek, W
van der Giet, M
机构
[1] Charite, Med Klin 4, D-12200 Berlin, Germany
[2] Charite, Inst Klin Pharmakol & Toxikol, D-12200 Berlin, Germany
[3] Univ Essen Gesamthsch Klinikum, Inst Pathophysiol, Zentrum Innere Med, D-4300 Essen, Germany
[4] Novartis Inst BioMed Res, Basel, Switzerland
[5] Hosp Westfal Wilhelms Univ, Dept Nucl Med, Munster, Germany
[6] Scripps Res Inst, Dept Mol Biol, La Jolla, CA USA
关键词
FTY720; eNOS; S1P receptor;
D O I
10.1161/01.RES.0000164321.91452.00
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 almost complete conversion after 10 minutes as determined by mass spectrometry. Finally, we identified the lysophospholipid receptor S1P(3) as the S1P receptor responsible for arterial vasodilation by FTY720, as the effect was completely abolished in arteries from S1P(3)-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.
引用
收藏
页码:913 / 920
页数:8
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