Endothelial Cell Apoptosis Induced by the Peroxisome Proliferator-activated Receptor (PPAR) Ligand 15-Deoxy-Δ12,14-prostaglandin J2

Abstract

15-Deoxy-⌬12,14 -prostaglandin J 2 (15d-PGJ 2 ) is a bioactive prostanoid produced by dehydration and isomerization of PGD 2 , a cyclooxygenase product. It was recently shown to activate the nuclear peroxisome proliferatoractivated receptor ␥ (PPAR␥), 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 apoptosis. PPAR␣, -␦, and -␥ were expressed by endothelial cells, 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␥, also induced transcriptional activation and endothelial cell apoptosis. Endothelial apoptosis induced by 15d-PGJ 2 was inhibited by treatment of cells with an oligonucleotide decoy to a consensus PPAR response element sequence. Furthermore, overexpression of the PPAR␥ isotype induced endothelial cell apoptosis, which was further potentiated by 15d-PGJ 2 treatment. We conclude that 15d-PGJ 2 induces endothelial cell apoptosis via a PPARdependent pathway. The PPAR pathway may be a therapeutic target for numerous pathologies in which excessive angiogenesis is implicated.

Activation of Peroxisome Proliferator-Activated Receptors in Human Airway Smooth Muscle Cells Has a Superior Anti-inflammatory Profile to Corticosteroids: Relevance for Chronic Obstructive Pulmonary Disease Therapy

“…15d-PGJ 2 also inhibited cytokine-induced GM-CSF and G-CSF release; however, in this case, 15d-PGJ 2 did so in a concentration-dependent manner and with equal potency for both survival factors. The effective concentrations used are similar to that required for functional responses in other cells types such as human lung cancer cells (42), epithelial cells (20), endothelial cells (22), and vascular smooth muscle cells (23). The inhibitory effect of 15d-PGJ 2 and ciglitazone on survival factor release is seen at concentrations that also inhibit serum-induced growth.…”

“…PPAR␥ ligands have been shown to inhibit the release of proinflammatory cytokines from activated macrophages (19) and airway epithelial cells (20). Furthermore, PPAR␥ ligands have been shown to inhibit vascular smooth muscle cell proliferation (21) and induce apoptosis in endothelial cells (22), vascular smooth muscle cells (23), T lymphocytes (24,25), and macrophages (26). However, the potential anti-inflammatory properties of PPAR ligands on airway smooth muscle have not been investigated.…”

15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells

“…PPARg activators may inhibit COX-2 expression, possibly through negative interference with NF-kB and/or AP-1 activation (Inoue et al, 2000;Subbaramaiah et al, 2001;Yang and Frucht, 2001). There is also evidence that supports the function of PPARg ligands as potent inhibitors of angiogenesis in vivo and in vitro, providing an additional mechanism that may partially account for the anticancer properties of PPARg (Bishop-Bailey and Hla, 1999;Xin et al, 1999). Finally, cross-talk between PPARg and other signalling molecules, such as NF-kB, AP-1 and STAT (Ricote et al, 1998;Zhou and Waxman, 1999a,b), may contribute significantly to the effects of PPARg on tumour growth.…”

Rapid induction of peroxisome proliferator–activated receptor γ expression in human monocytes by monosodium urate monohydrate crystals

“…Inoue et al demonstrated that 15deoxy-PGJ 2 could reduce PGE 2 production by monocytes in a PPAR␥-dependent manner (31). Moreover, 15deoxy-PGJ 2 and synthetic PPAR␥ ligands are capable of inducing cellular apoptosis of monocytes and endothelial cells and of inhibiting IL-1␤-induced production of NO and matrix metalloproteinase in human chondrocytes through PPAR␥-dependent pathways (32)(33)(34). Overall, both naturally occurring and synthetic ligands for PPAR␥ exert considerable influences on inflammatory responses through receptor-dependent and -independent pathways.…”