Prostacyclin-dependent apoptosis mediated by PPAR delta

Prostacyclin (PGI(2)) plays important roles in hemostasis both as a vasodil ator and an endogenous inhibitor of platelet aggregation. PGI(2) functions in these roles through a specific IP receptor, a G protein-coupled receptor linked to G. and increases in cAMP. Here, we report that intracellular pro stacyclin formed by expressing prostacyclin synthase in human embryonic kid ney 293 cells promotes apoptosis by activating endogenous peroxisome prolif erator-activated receptor delta (PPAR delta). In contrast, treatment of cel ls with extracellular prostacyclin or dibutyryl cAMP actually reduced apopt osis. On the contrary, treatment of the cells with RpcAMP (adenosine 3',5'- cyclic monophosphothioate, Rp-isomer), an antagonist of cAMP, enhanced pros tacyclin-mediated apoptosis. The expression of an L431A/G434A mutant of PPA R delta completely blocked prostacyclin-mediated PPAR delta activation and apoptosis. These observations indicate that prostacyclin can act through en dogenous PPAR delta as a second signaling pathway that controls cell fate.