Prostacyclin-dependent Apoptosis Mediated by PPAR

Prostacyclin (PGI2) plays important roles in hemostasis both as a vasodilator and an endogenous inhibitor of platelet aggregation. PGI2 functions in these roles through a specific IP receptor, a G protein-coupled receptor linked to Gs and increases in cAMP. Here, we report that intracellular prostacyclin formed by expressing prostacyclin synthase in human embryonic kidney 293 cells promotes apoptosis by activating endogenous peroxisome proliferator-activated receptor (PPAR ). In contrast, treatment of cells with extracellular prostacyclin or dibutyryl cAMP actually reduced apoptosis. On the contrary, treatment of the cells with RpcAMP (adenosine 3 ,5 -cyclic monophosphothioate, Rp-isomer), an antagonist of cAMP, enhanced prostacyclin-mediated apoptosis. The expression of an L431A/ G434A mutant of PPAR completely blocked prostacyclin-mediated PPAR activation and apoptosis. These observations indicate that prostacyclin can act through endogenous PPAR as a second signaling pathway that controls cell fate.