Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form
As of April 1st VIVO Scientific Profiles will no longer updated for faculty, and the link to VIVO will be removed from the library website. Faculty profile pages will continue to be updated via Interfolio. VIVO will continue being used behind the scenes to update graduate student profiles. Please contact helplib@scripps.edu if you have questions.
How to download citations from VIVO | Alternative profile options

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

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Tolle, M.
  • Levkau, B.
  • Keul, P.
  • Brinkmann, V.
  • Giebing, G.
  • Schonfelder, G.
  • Schafers, M.
  • Lipinski, K. V.
  • Jankowski, J.
  • Jankowski, V.
  • Chun, Jerold
  • Zidek, W.
  • van der Giet, M.

publication date

  • 2005

journal

  • Circulation Research  Journal

abstract

  • 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 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.

subject areas

  • Cells, Cultured
  • Enzyme Activation
  • Fingolimod Hydrochloride
  • Humans
  • Immunosuppressive Agents
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Phosphorylation
  • Propylene Glycols
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Receptors, Lysosphingolipid
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Sphingosine
  • Vasodilation
scroll to property group menus

Identity

International Standard Serial Number (ISSN)

  • 0009-7330

Digital Object Identifier (DOI)

  • 10.1161/01.res.0000164321.91452.00

PubMed ID

  • 15802614
scroll to property group menus

Additional Document Info

start page

  • 913

end page

  • 920

volume

  • 96

issue

  • 8

©2022 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support