Prostacyclin-dependent Apoptosis Mediated by PPARÎ

• Published in: The Journal of biological chemistry 2001-12, Vol.276 (49), p.46260
• Main Authors: Toshihisa Hatae, Masayuki Wada, Chieko Yokoyama, Manabu Shimonishi, Tadashi Tanabe
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M107180200

Prostacyclin (PGI 2 ) plays important roles in hemostasis both as a vasodilator 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 s 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 δ (PPARδ). 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 PPARδ completely blocked prostacyclin-mediated PPARδ activation and apoptosis. These observations indicate that prostacyclin can act through endogenous PPARδ as a second signaling pathway that controls cell fate.