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

doi:10.1074/jbc.274.24.17042

Endothelial Cell Apoptosis Induced by the Peroxisome Proliferator-activated Receptor (PPAR) Ligand 15-Deoxy-Δ^12,14-prostaglandin J₂*

David Bishop-Bailey and
Timothy Hla‡

From the Center for Vascular Biology, Department of Physiology, University of Connecticut Health Center, Farmington, Connecticut 06030-3505

Abstract

15-Deoxy-Δ^12,14-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 γ (PPARγ), 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. PPARα, -δ, and -γ 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 PPARγ, 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 PPARγ isotype induced endothelial cell apoptosis, which was further potentiated by 15d-PGJ₂ treatment. We conclude that 15d-PGJ₂induces 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.

Footnotes

↵* This work was supported by National Institutes of Health Grants HL-49094 and HL-54710.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵‡ An established investigator of the American Heart Association. To whom correspondence should be addressed: Center for Vascular Biology, Dept. of Physiology, mail code 3505, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-3505. Tel.: 860-679-4128; Fax: 860-679-1269; E-mailhla{at}sun.uchc.edu.
↵2 D. Bishop-Bailey and T. Hla, unpublished observations.
Abbreviations:

PPAR

peroxisome proliferator-activated receptor

PG

prostaglandin

15d-PGJ₂

15-deoxy-Δ^12,14-prostaglandin J₂

HUVEC

human umbilical vein endothelial cells

BMEC-b

bovine brain microvascular endothelial cells

PPRE

PPAR response element

COX

cyclooxygenase

ZVAD-fmk

benzyloxocarbonyl-Val-Ala-Asp(OCH₃)-CH₂F

ACO

acyl-CoA oxidase

PARP

poly(A)DP-ribose polymerase

GFP

green fluorescent protein

FBS

fetal bovine serum

MTT

3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

kb

kilobase(s)

PBS

phosphate-buffered saline

BSA

bovine serum albumin

HEK

human embryonic kidney
- Received August 13, 1998.
- Revision received March 17, 1999.
The American Society for Biochemistry and Molecular Biology, Inc.