Endothelial cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-Delta(12,14)-prostaglandin J(2)

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is a bioactive prosta noid produced by dehydration and isomerization of PGD(2), a cyclooxygenase product. It was recently shown to activate the nuclear peroxisome prolifera tor-activated receptor gamma (PPAR gamma), a critical transcription factor involved in adipocyte and monocyte differentiation. In this report, we show that 15d-PGJ(2) is a potent inducer of caspase-mediated endothelial cell a poptosis. PPAR alpha, -delta, and -gamma were expressed by endothelial cell s, which, when treated with 15d-PGJ(2), induced receptor translocation into the nucleus, and an increase in PPAR response element-driven reporter gene expression. Ciglitizone, a selective activator of PPAR gamma, also induced transcriptional activation and endothelial cell apoptosis. Endothelial apo ptosis induced by 15d-PGJ(2) was inhibited by treatment of cells with an ol igonucleotide decoy to a consensus PPAR response element sequence. Furtherm ore, overexpression of the PPAR gamma isotype induced endothelial cell apop tosis, which was further potentiated by 15d-PGJ(2) treatment. We conclude t hat 15d-PGJ(2) induces endothelial cell apoptosis via a PPAR-dependent path way. The PPAR pathway may be a therapeutic target for numerous pathologies in which excessive angiogenesis is implicated.