IP receptor-dependent activation of PPARgamma by stable prostacyclin analogues

Biochem Biophys Res Commun. 2007 Sep 7;360(4):821-7. doi: 10.1016/j.bbrc.2007.06.135. Epub 2007 Jul 5.


Stable prostacyclin analogues can signal through cell surface IP receptors or by ligand binding to nuclear peroxisome proliferator-activated receptors (PPARs). So far these agents have been reported to activate PPARalpha and PPARdelta but not PPARgamma. Given PPARgamma agonists and prostacyclin analogues both inhibit cell proliferation, we postulated that the IP receptor might elicit PPARgamma activation. Using a dual luciferase reporter gene assay in HEK-293 cells stably expressing the IP receptor or empty vector, we found that prostacyclin analogues only activated PPARgamma in the presence of the IP receptor. Moreover, the novel IP receptor antagonist, RO1138452, but not inhibitors of the cyclic AMP pathway, prevented activation. Likewise, the anti-proliferative effects of treprostinil observed in IP receptor expressing cells, were partially inhibited by the PPARgamma antagonist, GW9662. We conclude that PPARgamma is activated through the IP receptor via a cyclic AMP-independent mechanism and contributes to the anti-growth effects of prostacyclin analogues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Proliferation / drug effects
  • Cyclic AMP / metabolism
  • Epoprostenol / analogs & derivatives
  • Epoprostenol / pharmacology
  • Humans
  • PPAR gamma / antagonists & inhibitors*
  • PPAR gamma / metabolism
  • Prostaglandins I / metabolism*
  • Receptors, Prostaglandin / metabolism*


  • PPAR gamma
  • Prostaglandins I
  • Receptors, Prostaglandin
  • Epoprostenol
  • Cyclic AMP
  • treprostinil