Prostacyclin-dependent apoptosis mediated by PPAR delta.
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 delta (PPAR delta). 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 delta completely blocked prostacyclin-mediated PPAR delta activation and apoptosis. These observations indicate that prostacyclin can act through endogenous PPAR delta as a second signaling pathway that controls cell fate.
Hatae
T
T
Department of Pharmacology, National Cardiovascular Center Research Institute, Fujishiro-dai, Suita, Osaka 565-8565, Japan.
Wada
M
M
Yokoyama
C
C
Shimonishi
M
M
Tanabe
T
T
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D017931:DNA Primers; D011464:Epoprostenol / Q000502:physiology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008969:Molecular Sequence Data; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000502:physiology*
D017931:DNA Primers; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase