Endothelial cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-Delta12, 14-prostaglandin J2.
15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) is a bioactive prostanoid produced by dehydration and isomerization of PGD2, a cyclooxygenase product. It was recently shown to activate the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma), a critical transcription factor involved in adipocyte and monocyte differentiation. In this report, we show that 15d-PGJ2 is a potent inducer of caspase-mediated endothelial cell apoptosis. PPARalpha, -delta, and -gamma were expressed by endothelial cells, which, when treated with 15d-PGJ2, induced receptor translocation into the nucleus, and an increase in PPAR response element-driven reporter gene expression. Ciglitizone, a selective activator of PPARgamma, also induced transcriptional activation and endothelial cell apoptosis. Endothelial apoptosis induced by 15d-PGJ2 was inhibited by treatment of cells with an oligonucleotide decoy to a consensus PPAR response element sequence. Furthermore, overexpression of the PPARgamma isotype induced endothelial cell apoptosis, which was further potentiated by 15d-PGJ2 treatment. We conclude that 15d-PGJ2 induces endothelial cell apoptosis via a PPAR-dependent pathway. The PPAR pathway may be a therapeutic target for numerous pathologies in which excessive angiogenesis is implicated.
Bishop-Bailey
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Center for Vascular Biology, Department of Physiology, University of Connecticut Health Center, Farmington, Connecticut 06030-3505, USA.
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D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D020169:Caspases / Q000378:metabolism; D002451:Cell Compartmentation; D002467:Cell Nucleus / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011454:Prostaglandins A / Q000494:pharmacology; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D015398:Signal Transduction; D014157:Transcription Factors / Q000819:agonists*; D014158:Transcription, Genetic
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D008024:Ligands; D011454:Prostaglandins A; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D020169:Caspases; D015230:Prostaglandin D2; C100573:prostaglandin A1