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J Biol Chem, Vol. 274, Issue 24, 17042-17048, June 11, 1999
From the Center for Vascular Biology, Department of Physiology,
University of Connecticut Health Center,
Farmington, Connecticut 06030-3505
15-Deoxy- Peroxisome proliferator-activated receptors
(PPAR)1 are a family of at
least three nuclear receptors ( All the commonly occurring prostanoids are formed from the
cyclooxygenase (COX; prostaglandin G/H synthase) product
PGH2 (10). COX is known to exist in at least two isoforms,
a constitutively expressed (COX-1), and mitogen/cytokine-inducible
isoform (COX-2). Prostaglandins of the A and J series in particular
cause tumor cell apoptosis (11) and can also regulate endothelial cell
function by inducing heat shock proteins (12). The mechanism by which PGA and PGJ cause these effects is presently unclear but appear to be
associated with nuclear localization (13). Whether 15d-PGJ2 shares the same properties as other J series PGs tested is unknown. Likewise, it is also not known whether any of the previously known responses of J series PGs are mediated through the PPAR pathway. Interestingly, aberrant PPAR In the present study we demonstrate that 15d-PGJ2 induces
endothelial cell apoptosis. Furthermore, using a decoy oligonucleotide approach against the PPAR response element (PPRE) to inhibit receptor function and overexpression of the PPAR receptors, we provide evidence
that the mechanism of action by which 15d-PGJ2 causes apoptosis is through a PPAR-dependent pathway.
Materials--
pCMX-PPAR Cell Culture--
HUVEC and ECV were cultured as described
previously (18). BMEC-b were cultured in medium 199 containing 10%
FBS, 0.15 mg/ml crude fibroblast growth factor, 5 units/ml heparin
antibiotics, and antimycotic mix (Life Technologies) on gelatin
(0.1%)-coated plates.
Viability and Apoptosis Assays--
Cell viability was measured
by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium
bromide) assay (19) and presented as the % of control culture
conditions. Nuclear morphology was assessed using Hoechst 33258 staining (20). Apoptotic cells were distinguished by their
characteristic patterns of nuclear condensation, cytoplasmic rounding,
and membrane blebbing. Cells were imaged by either confocal (Zeiss
CLSM410 laser-scanning confocal microscope at the Center for Biomedical
Imaging at the University of Connecticut Health Center; ×1000
magnification) or a Zeiss TV100 inverted fluorescence microscope. The
% of apoptotic cells in 2-5 fields (×100 magnification) per data
point were counted. Apoptosis was also demonstrated by Western blot for
PARP cleavage. Nonadherent cells were pelleted (800 × g for 5 min), and protein was extracted from pooled adherent
and floating cells using a gel-loading buffer consisting of 62.5 mM Tris (pH 6.8), 6 M urea, 10% glycerol, 2%
SDS, 0.0012% bromphenol blue, and 5% Endothelial Cell Differentiation Assay--
HUVEC were seeded
on Matrigel in 24-well plates, and network formation was stimulated by
the addition of FBS (21). Cells were treated for 24 h in the
presence or absence of 15d-PGJ2, and cell death was
assessed morphologically.
Northern Blot Analysis for PPAR
Isoforms--
Poly-(A)+ RNA was prepared from ECV using
Fastrack 2.0 RNA isolated kit, according to the manufacturer's
protocol. 3 µg of poly-(A)+ RNA were size-fractionated on
a 1% agarose/formaldehyde gel and transferred onto Zeta Probe
(Bio-Rad) filters, and UV cross-linked. Probes corresponding to the
full-length open reading frames of PPAR isoforms were labeled to high
specific activity (>108 cpm/µg) using the Random primer
labeling kit (Roche Molecular Biochemicals). The probe for PPAR Immunofluorescence of PPAR Isoforms--
Cells cultured on
coverslips were fixed in methanol:acetone (1:1, Reporter Assay for PPAR Activation--
All transient
transfections were performed using Lipofectamine (Life Technologies) or
Novafector (Venn-Nova, Pompano Beach, FL) according to the
manufacturer's recommended protocol. ECV cells were used throughout
for transfections because of the low transfection efficiency of
nonimmortalized endothelial cell strains. To measure activation of
PPARs, the well characterized PPAR-responsive promoter region for
acyl-CoA oxidase ( Morphology of Cells Transiently Transfected with
PPAR Decoy Experiments--
PPRE decoy Zd5 was selected on the basis
of binding of PPAR Effect of PPAR Agonists on Endothelial Cell
Apoptosis--
Immortalized human endothelial cells (ECV-304) were
treated with various prostanoids, and cell viability was determined. As shown in Fig. 1a,
PGD2, 15d-PGJ2, and PGA1
significantly reduced endothelial cell viability as determined by the
MTT assay. Other prostanoids such as carbaprost (a stable prostacyclin
analog), PGE2, PGF2
The reduction in endothelial cell viability induced by
15d-PGJ2 is associated with a dramatic increase in
apoptosis. As shown in Fig. 2, treated
ECV-304 cells grown on plastic exhibit cytoplasmic rounding, nuclear
condensation, and fragmentation into "apoptotic" bodies.
Quantitative analysis of apoptosis was done by counting apoptotic
nuclei after staining with the Hoechst 33258 dye. Within 20 h
after treatment with 10 µM 15d-PGJ2, 33 ± 5% of cells possessed apoptotic nuclei. In contrast, similar
treatment with vehicle or the inactive prostanoid PGE2
resulted in 1 ± 0.5% and 2 ± 0.5% of apoptotic nuclei,
respectively. In addition, 15d-PGJ2 potently induced
apoptosis to differentiating HUVEC grown on the three-dimensional matrix Matrigel (Fig. 2). These data suggest that 15d-PGJ2
reduced endothelial cell viability by inducing apoptosis.
To further characterize the endothelial cell apoptosis induced by
15d-PGJ2, ECV-304 cells were treated with the inhibitor ZVAD-fmk, which potently inhibit the caspase enzymes, the common executors of cell death (24). As shown in Fig.
3a, 10-30 µM ZVAD-fmk reversed the ability of 10 µM
15d-PGJ2 to induce endothelial cell apoptosis. Caspase
activation results in the specific cleavage of cellular substrates such
as PARP (24). As shown in Fig. 3b, 15d-PGJ2
induced a characteristic cleavage pattern of a PARP immunoreactive band
of 83 kDa, which was inhibited by preincubation with 30 µM ZVAD-fmk. These data strongly suggest that
15d-PGJ2 induces caspase-dependent apoptosis in
endothelial cells.
Expression and Activation of PPAR Isoforms in Vascular Endothelial
Cells--
To determine whether endothelial cells express PPAR
isoforms, poly(A)+ RNA from ECV-304 cells were analyzed by
a Northern blot analysis with cDNA probes for PPAR
To determine whether the PPAR isoforms are active in endothelial cells,
we transfected the ECV-304 endothelial cells with the PPRE reporter
construct (pACO.gLuc) and measured the luciferase activity. As shown in
Fig. 5, pACO.gLuc construct alone
exhibited 4-fold enhanced luciferase activity over the control pGL2
basic vector. Treatment with 15d-PGJ2 induced the
PPRE-driven luciferase activity in a dose-dependent manner.
At higher doses of 15d-PGJ2, significant cell death was
observed, and thus, activation of transcription was reduced. These data
strongly suggest 15d-PGJ2 activates the PPAR-dependent transcriptional responses in endothelial
cells.
PPAR Regulation of Endothelial Cell Apoptosis--
We next
determined if activation of PPAR receptors is responsible for the
15d-PGJ2-induced apoptosis of vascular endothelial cells.
First, we tested the known PPAR
To provide further evidence that the PPAR pathway is required for
15d-PGJ2-induced endothelial cell apoptosis, we developed a
double-stranded decoy oligonucleotide that corresponds to the PPAR
response element (22). The rationale for this approach is that the
decoy will compete for the activated receptor binding to the promoter
and thus block PPAR-dependent transcriptional responses.
Double-stranded decoy oligonucleotide or a scrambled control was
introduced into cells by a Lipofectin-mediated technique (23). To
determine the efficacy of this approach in inhibiting PPAR-dependent transcription, HEK293 cells were used
because higher efficiency of transfection was obtained. Under optimal
conditions, we obtained up to 2800 relative light units/unit of
We next determined if overexpression of PPAR receptors modulated
endothelial cell apoptosis. ECV-304 cells were transiently transfected
with the PPAR In this report, we demonstrate that 15d-PGJ2,
PGD2, and PGA1 induced endothelial apoptosis.
Prostanoids that act via plasma membrane receptors, such as
PGE2, carbaprost, and U46619 did not induce endothelial
cell apoptosis. Removal of serum increased the potency of all these
agonists, with the exception of PGD2, suggesting that
mitogens and survival factors present in serum counteract cell death.
The lack of increased potency observed with PGD2 in
serum-free medium may be because of the requirement for dehydration and
isomerization of PGD2 to 15d-PGJ2 by the
enzymes and carriers present in serum.
15d-PGJ2-induced reduction in endothelial cell viability
was characterized morphologically by rounded cells, condensed nuclei, and by the cleavage of the caspase-3 substrate PARP (24). These are the
hallmarks of apoptosis, and indeed, the caspase inhibitor ZVAD-fmk
reversed the effects of 15d-PGJ2 on loss of cell viability, morphology, and the cleavage of the PARP protein. 15d-PGJ2
also induces apoptosis of endothelial tubular networks in
three-dimensional gels, suggesting that in vivo anti-tumor
activity of PGJ may not only be because of an effect on the tumor cells
themselves but may also be because of an anti-angiogenic affect on
tumor capillaries. Apoptosis was induced by 15d-PGJ2 in the
nonimmortalized endothelial cell strain HUVEC, the immortalized human
endothelial cell line ECV-304, and in microvascular endothelial cells
BMEC-b, a consistent effect between different species and endothelial subtypes.
Recent studies have shown that nuclear-acting prostanoids including
15d-PGJ2 are potent activators of the PPAR We next provided evidence that the activation of PPAR The regulation of PPAR receptor activation is extremely complex,
involving heterodimerization with retinoid X receptors, the presence of
different co-activators/repressors, and the binding to different PPREs
(7). The exogenous activation of retinoid X receptors does not appear
to be required for PPAR pathway activation. However, the presence of
other nuclear binding partners for retinoid X receptors, different
co-activators, or repressors for the individual receptors and the
selectivity of different receptors for the PPREs involved in this
apoptotic response is not known. Differences in these pathways may
occur between cell types and reflect the responses of a particular
ligand such as 15d-PGJ2 to activate apoptotic pathways
through the different PPRE-containing genes. Nevertheless,
15d-PGJ2 activation of PPAR The up-regulation of COX-1 (29, 30) or COX-2 (30) in the proximity of
endothelial cells may regulate angiogenesis, a critical event in tumor
formation and chronic inflammatory diseases. Although, these may not be
due exclusively to the products of the cyclooxygenase (as opposed to
the peroxidase activity) of COX (29), PG synthesis, especially
prostacyclin, and PGE2, a known angiogenic mediator, are
greatly elevated. The pattern of release of COX metabolites is governed
by the presence of secondary metabolizing enzymes (31). It is therefore
possible that a novel specific anti-angiogenic therapy may be utilized
by targeting PGD synthase to the angiogenic site. The elevated
endogenous COX activity would divert prostanoid production to
PGD2, causing an autocrine apoptosis of the capillary
network. Nonetheless, the use of PPAR ligands as anti-tumor,
anti-angiogenic therapies, may well have considerable potential for
novel therapeutic intervention. Indeed, recently PPAR In conclusion, our data demonstrate that (i) PPAR isotypes are
expressed in endothelial cells, (ii) activation of these receptors by
15d-PGJ2 results in nuclear localization and
transcriptional responses, and (iii) PPAR signaling in endothelial
cells is a critical event in 15d-PGJ2-induced apoptosis.
Modulation of this pathway may lead to important therapeutic
interventions in the diverse pathological conditions where endothelial
cells play such critical roles.
We thank Dr. Ronald Evans, Dr. Christopher
Glass, and Dr. Ruth Roberts for the generous gift of plasmids.
*
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.
2
D. Bishop-Bailey and T. Hla, unpublished observations.
The abbreviations used are:
PPAR, peroxisome
proliferator-activated receptor;
PG, prostaglandin;
15d-PGJ2, 15-deoxy-
Endothelial Cell Apoptosis Induced by the Peroxisome
Proliferator-activated Receptor (PPAR) Ligand
15-Deoxy-
12,14-prostaglandin J2*
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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 
(PPAR), 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. PPAR
,
-
, and - 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 PPAR, 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 PPAR 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.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
, (also referred to as NUC1), and
), which heterodimerize with the retinoid X receptors (1). PPAR
is found predominantly in the liver, heart, kidney, brown adipose, and
stomach mucosa, and PPAR is found primarily in adipose tissue, where
it plays a critical role in the differentiation of pre-adipocytes into
adipocytes; PPAR is almost ubiquitously expressed, but its function
is relatively unknown (2, 3). Recently, PPAR and - have been
suggested to be important immunomodulatory mediators. PPAR knockout
mice have exacerbated inflammatory responses (4), whereas activation of
PPAR in monocyte/macrophages inhibits inflammatory mediator and
cytokine production (5, 6). PPAR receptors can be activated by a number
of ligands (7), including docosahexaenoic acid, linoleic acid, WY-14643
(selective for PPAR), the antidiabetic thiazoldinediones, and a
number of eicosanoids, including 5,8,11,14-eicosatetraynoic acid and
the prostanoids PGA1, PGA2, PGI2,
and PGD2. Interestingly, the PGD2 dehydration product 15-deoxy-12,14-PGJ2
(15d-PGJ2) is the most potent endogenous ligand for PPAR yet discovered (8, 9).
expression is often found in colon cancer, where COX-2 is known to be elevated (14).
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
, pCMX-PPAR, and pCMX-PPAR,
were a gift from Drs. Ronald Evans (Salk Institute) and Christopher
Glass (University of California, San Diego, CA). h6/29 PPAR, and
pACO.gLuc. (15, 16) were gifts from Dr. Ruth Roberts, Zeneca
Pharmaceuticals (Macclesfield, UK). pGL2 and pSV-
-galactosidase were
from Promega. Antisera against PPAR, -, and - were from Santa
Cruz, and fluorescein isothiocyanate-conjugated rabbit anti-goat
antibody was from Cappel. Prostaglandins were from Cayman Chemical Co.
Ciglitizone, WY-14643, and anti-poly(A)DP-ribose polymerase (PARP)
antibody was from Biomol. [32P]dCTP was from NEN Life
Science Products.
Benzyloxocarbonyl-Val-Ala-Asp(OCH3)-CH2F (ZVAD-fmk) was from Calbiochem. Immortalized human endothelial cells
(ECV-304) were from ATCC, and human umbilical vein endothelial cells
(HUVEC) and brain bovine microvascular endothelial cells (BMEC-b) were
from Cell Systems. Matrigel basement membrane matrix was from Becton
Dickinson. Lipofectamine and Lipofectin were from Life Technologies,
Inc. Novafector was from Venn-Nova. Fastrack 2.0 poly(A)+
RNA isolation kit was from Invitrogen. Luciferin and coenzyme A were
from Roche Molecular Biochemicals. Cell culture reagents were from
Fisher. Crude fibroblast growth factor was purified from sheep brain
(17). Unless stated, all other reagents were from Sigma.
-mercaptoethanol. Extracts
were freeze thawed (
80 °C), sonicated, denatured by boiling, then
separated by SDS-polyacrylamide gel electrophoresis. Protein was
blotted onto nitrocellulose, and PARP was detected using a monoclonal
anti-PARP and secondary goat-anti-mouse peroxidase-conjugated antibody
(Cappel) using the ECL (Amersham Pharmacia Biotech)
chemiluminescent visualization system. Apoptosis is
characterized by the caspase-dependent appearance of an
83-kDa fragment.
was
the 1.8-kb XhoI fragment of h6/29 PPAR, a dominant
negative isoform isolated from human liver (16), which differs from
wild type hPPAR by only 4 point mutations. The probe for PPAR was
the 1.3-kb HindIII-BamHI fragment from
pCMX-PPAR, and the probe for PPAR was the 1.6-kb
KpnI-NheI fragment of pCMX-PPAR. Filters were
hybridized in 0.5 M sodium phosphate (pH 7.2) containing
7% SDS, 0.5% BSA, 40 mM EDTA, and 20% formamide for
16-20 h at 55 °C, and then washed (each 2 × 15 min at
55 °C) in (i) 40 mM sodium phosphate containing 1 mM EDTA, 5% SDS, 0.5% BSA; (ii) 40 mM sodium
phosphate containing 1 mM EDTA and 1% SDS, and (iii) 2×
SSC (1× SSC = 0.15 M NaCl and 0.015 M
sodium citrate) containing 0.5% SDS. To control for differences in
loading or transfer of the RNA, the filters were hybridized with
cDNA from human glyceraldehyde-3-phosphate dehydrogenase (from
ATCC; 1kb).
20 °C). Cells were
then washed with PBS and blocked for 30 min with 1% BSA in PBS. Cells
were then incubated with primary antibody (1:250 dilution; 0.1% BSA in
PBS) at 4 °C overnight, followed by 2 washes with PBS. Secondary
fluorescein isothiocyanate-conjugated antibody (1:500, in 0.1% BSA in
PBS) was then added for 30 min, after which the cells were further
washed 3 times with PBS and viewed by fluorescence microscopy. In some
experiments, primary antibody was excluded, or primary antibody was
preincubated for 1 h with a 50-fold excess of blocking peptide
before the combination being added to the cells.
581 to 471) fused to the minimal -globin
promoter upstream of a luciferase reporter (pGL2 Basic; Promega),
termed pACO.gLuc (15, 16), was used. pACO.gLuc, and
pSV--galactosidase in the presence or absence of pCMX-PPAR, pCMX-PPAR, or pCMX-PPAR were co-transfected into ECV grown in 6-well plates. As a negative control, the promoter-less pGL2 Basic (Promega) was utilized. The total amount of DNA transfected (1-2 µg)
was normalized with a carrier DNA (pcDNA3.1; Invitrogen). After
24 h, cells were stimulated with test drugs for a further 24 h. Luciferase activity was normalized to -galactosidase content. Both activities were measured according to the manufacturer's protocol (Promega).
--
The effect of expression of PPAR in living cells was
measured indirectly by co-transfected green fluorescent protein (GFP). ECV were co-transfected with pCMX-PPAR (2 µg) or carrier DNA alone
in the presence of the GFP expression vector (0.3 µg; p-EGFPN-1; CLONTECH). After 24 h, the morphology of cells
expressing GFP was analyzed by fluorescence microscopy.
to PPREs as reported by Palmer (22). Decoy (ACT
TGA TCC CGT TTC AAC TC) or scrambled (TTA GGG AAT CAG CAA GAG GT)
oligonucleotides were annealed to their respective complementary
sequence in the buffer containing 20 mM Tris·HCl (pH
8.4), 150 mM NaCl, 50 mM KCl, and 1.5 mM MgCl2. ECV cells cultured on 24-well plates
were transfected with either decoy (0.1-1 µM) or
scrambled (1 µM) oligonucleotides using 5 µg/ml
Lipofectin for 4 h. The medium was then replaced, and cells were
either left untreated or supplemented with 10 µM 15d-PGJ2 for 24 h. The % of apoptosis was measured
morphologically by Hoechst staining (as above). To test the efficacy of
the oligonucleotide decoy at blocking responses through PPRE, we used
the human embryonic kidney (HEK) 293 cell line. HEK293 contained low
level messages for PPAR, -, and - as measured by reverse
transcription-polymerase chain
reaction.2 HEK293 were
transfected with pACO.gLuc and pSV--galactosidase in the presence or
absence of decoy (0.1-1 µM) or scrambled (1 µM) oligonucleotide. After 24 h, the medium was
replaced with medium without FBS, and decoy (0.1-1 µM)
or scrambled (1 µM) oligonucleotide added again to the
cell for a further 24 h. Luciferase activity was normalized to
-galactosidase content. Both activities were measured according to
the manufacturer's protocol (Promega).
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
, and U46619 (a
thromboxane mimetic) did not induce endothelial cell toxicity. Because
15d-PGJ2 is a dehydration product of PGD2 and
15d-PGJ2 is a potent activator of PPAR, these data are
consistent with the involvement of this pathway in the reduction of
endothelial cell viability. This effect was partially reversed by 10%
FBS, consistent with the survival-promoting activity of the serum-borne
polypeptide growth factors and lipids. Dose-response analysis of
15d-PGJ2 was conducted on HUVEC and BMEC-b, two
nonimmortalized endothelial cell strains, as well as the ECV-304. As
shown in Fig. 1b, 15d-PGJ2 induced the reduction
of endothelial cell viability with an IC50 in the range of
2-10 µM. This is consistent with the effective
dose-range for PPAR activation (8, 9).
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Fig. 1.
Effect of 15d-PGJ2 on endothelial
cell viability. a, ECV-304 cells were treated with
various prostanoids (10 µM) or vehicle for 20 h, and
cell viability was measured by the MTT assay and expressed as % of
control culture conditions. These data represent n = 9-23 incubations from 4-9 separate experiments. * denotes significant
difference (p < 0.05) by one sample t test
between viability under control and drug induced conditions.
Carb, carbaprostacyclin. b shows the
dose-response analysis of endothelial cell viability, measured by MTT
assay of HUVEC, ECV-304, and BMEC-b cells treated with
15d-PGJ2 (20 h; 0 10 µM). Data represent
the mean ±S.E. for n = 9-14 replications from 5 separate experiments.
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Fig. 2.
Endothelial cell apoptosis induced by
15d-PGJ2. Differential interference contrast
(Normaski) microscopic image (a) and corresponding Hoechst
staining of nuclei (b) is shown of ECV-304 cells treated or
not with 10 µM 15d-PGJ2 (20 h; ×1000
magnification) and a low power field of Hoechst-stained ECV-304 cells
(c), indicating the widespread occurrence of apoptotic
nuclei after treatment (20 h; ×200 magnification). The scale
bar (b, right hand panel) represents a
distance of 10 µm (for a and b).
15d-PGJ2 induces the characteristic cytoplasmic rounding
and blebbing (a), nuclear condensation and fragmentation
(b and c) associated with the apoptotic process,
viewed by Zeiss CLSM410 laser-scanning confocal or Zeiss TV100 inverted
microscopy. These pictures are representative of n = 6 separate experiments, with at least 3 random fields taken per
experiment. d shows the cell death induced by
15d-PGJ2 (20 h; 10 µM) of HUVEC plated on
Matrigel (×100 magnification).
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Fig. 3.
Endothelial cell apoptosis induced by
15d-PGJ2 is mediated via caspase activation.
a shows the inhibition of 15d-PGJ2 (10 µM)-induced cell viability in ECV by increasing
concentrations of the selective caspase-inhibitor ZVAD-fmk (1-100
µM). Data represent the mean ±S.E. for n = 6 replications from 3 separate experiments. b shows a
Western blot for PARP (112 kDa) in ECV. Compared with control (first
lane) 15d-PGJ2 (10 µM; 2nd
lane) causes the characteristic cleavage of PARP, leaving a
detectable fragment at approximately 83 kDa. When ZVAD-fmk (30 µM; ZVAD-fmk alone, 3rd lane) was included in
the incubations, 15d-PGJ2-induced PARP cleavage was
abolished (4th lane).
, -, and
- isoforms. As shown in Fig. 4a, transcripts of
approximately 9.5, 4, and 2 kb were detected by PPAR, -, and -
probes, respectively. To determine whether PPAR polypeptides were
expressed, we stained the endothelial cells with subtype-specific
antisera for the PPAR isotypes in the indirect immunofluorescence
assay. As shown in Fig. 4b, specific signals for PPAR,
-, and - receptor immunoreactivity were detected. Immunoreactivity was localized in the cytoplasmic, perinuclear region
of the endothelial cells. However, the PPAR receptor
immunoreactivity was the strongest and exhibited a punctate perinuclear
reticular pattern. Treatment with 10 µM
15d-PGJ2 for 20 h resulted in the nuclear
translocation of all three receptor isoforms. Treatment with other
prostanoids PGE2 or carbaprost did not alter the
subcellular localization of any of the PPAR isoforms (data not shown).
These data suggest that 15d-PGJ2 interacts with all three
PPAR isoforms in endothelial cells.
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Fig. 4.
PPAR expression and activation in ECV.
a shows mRNA expression by Northern blot analysis for
PPAR , PPAR, and PPAR in ECV-304. Poly(A)+ RNA (3 µg/lane) was separated on a 1% formaldehyde-agarose gel,
transferred to a nylon membrane, and probed with the radiolabeled open
reading frames of human 6/29PPAR or murine PPAR or PPAR (see
"Experimental Procedures"). GADPH,
glyceraldehyde-3-phosphate dehydrogenase. b shows
immunofluorescence micrographs of PPAR, PPAR, and PPAR, in
ECV-304 under control culture conditions or treated with
15d-PGJ2 (20 h; 10 µM). The figure shows
PPARs stained using specific antibodies or in the absence of a primary
antibody (Ab, 2o antibody). The figure is
representative of four separate experiments. The scale bar
represents a distance of 11 µm.
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Fig. 5.
Activation of PPAR mediated transcription by
15d-PGJ2. ECV-304 cells were transiently transfixed
with the PPAR response element reporter gene (pACO.gLuc) or the
promoter-less control vector pGL2 basic, and the reporter activity was
quantitated as described. To control for transfection efficiency, a
-galactosidase expression plasmid was also co-transfected.
15d-PGJ2 was added 24 h after the start of
transfection and dose-dependently activated the reporter
gene. Normalized luciferase activity was represented as fold increase
over control (pACO) conditions. These data represent the mean ±S.E. of
3 separate experiments. * denotes p < 0.05 (one sample
t test) between pACO.gLuc and 15d-PGJ2.
agonist ciglitizone. As shown in
Fig. 6, ciglitizone induced
PPRE-luciferase activity in a dose-dependent manner in
vascular endothelial cells. The effect of ciglitizone is most
pronounced in the absence of serum. Similarly, it induced endothelial
cell apoptosis most potently in the absence of serum. These data
provide pharmacological evidence that activation of the PPAR pathway
induces endothelial cell apoptosis.
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Fig. 6.
Ciglitizone induction of PPAR activation and
endothelial cell death. a shows the activation of PPRE
by ciglitizone. ECV-304 cells were transiently transfected with the
PPAR response element reporter gene (pACO.gLuc). 24 h after the
start of transfection, the medium was changed so that ECV were
incubated in the presence (open bars) or absence
(closed bars) of FBS (FCS, 10%) and ciglitizone
(24 h; 1-100 µM) added. Luciferase activity is
represented as the fold increase of luciferase (normalized to
-galactosidase content) compared with control culture incubations.
ND indicates that luciferase could not be determined because
of high levels of cell death. These data represent the mean ±S.E. of
four separate experiments. b shows the decrease in
endothelial cell viability, measured by MTT assay of ECV-304 cells
incubated in the presence (open squares) or absence
(closed squares) of FBS (10%) treated with ciglitizone (20 h; 0 100 µM). The data represent the mean ±S.E. for
n = 9-14 replications from 5 separate
experiments.
-galactosidase activity in HEK293 cells, whereas we obtained only up
to 100 relative light units/unit of -galactosidase activity of
luciferase activity in ECV-304 cells. As shown in Fig.
7a, Lipofectin-mediated
loading of HEK293 cells with the PPRE decoy oligonucleotide (Zd5)
attenuated 10 µM 15d-PGJ2-induced
PPAR-dependent transcription. Neither Lipofectin alone nor
the scrambled oligonucleotide inhibited transcriptional activity.
Introduction of the decoy and the scrambled counterpart into ECV-304
cells also had a similar effect on the 15d-PGJ2-induced PPRE-dependent transcriptional responses (data not shown).
These data suggest that the decoy oligonucleotide is capable of
blocking PPRE-dependent transcriptional responses.
Introduction of the PPRE decoy (Zd5) oligonucleotide but not the
scrambled counterpart, inhibited in part 15d-PGJ2-induced
ECV-304 cell apoptosis (Fig. 7b). These data suggest that
PPAR-dependent transcriptional responses are required, at
least in part, for the 15d-PGJ2-induced endothelial cell
apoptosis. Similarly, the PPRE decoy oligonucleotide but not the
scrambled counterpart inhibited the ciglitizone-induced apoptosis of
ECV-304 cells (Fig. 7c), suggesting that PPAR-induced transcription is required for 15d-PGJ2-induced endothelial
cell death.
View larger version (15K):
[in a new window]
Fig. 7.
Effect of PPRE decoy oligonucleotide on
endothelial cell transcriptional responses and apoptosis.
a shows the inhibition of PPRE activation by administration
of a decoy oligonucleotide (Zd5) to a consensus PPRE sequence. Decoy
(0.1-1 µM) or scrambled oligonucleotides (1 µM) together with pACO.gLuc were transfected to HEK293
cells (4 h), after which time fresh medium was added to recover the
cells for 20 h. Cells were incubated with serum-free medium and
decoy (0.1-1 µM) or scrambled oligonucleotides (1 µM) for a further 4 h. At that time 10 µM 15d-PGJ2 was added for 20 more h in
serum-free medium, and luciferase activity normalized to
-galactosidase was quantitated. Reporter gene activity is
represented as fold activation over control levels. The absolute values
of normalized luciferase activity in HEK293 cells under control
conditions are 415 ± 39 (n = 3) relative light
units/units of -galactosidase activity. These data represent the
mean ±S.E. of four separate experiments. * denotes significance
p < 0.05 (unpaired t test) between
scrambled transfected cells and Zd5 decoy transfected cells.
b shows the inhibition of 10 µM
15d-PGJ2-induced endothelial cell apoptosis (% apoptotic
nuclei as determined by Hoechst staining) by addition of the decoy but
not the scrambled oligonucleotide Zd5 (0.1-1 µM) to a
consensus PPRE. These results represent the mean ±S.E. % apoptotic
cells from 4 separate experiments, each experimental n being
the mean of 4-5 random (×100) fields. * denotes significance
p < 0.05 (one way ANOVA) between 15d-PGJ2
and decoy or scrambled oligonucleotide-treated cells. c
shows the inhibition of cigliti zone-induced endothelial cell apoptosis (% apoptotic nuclei as
determined by Hoechst staining) by the addition of the decoy but not
the scrambled oligonucleotide Zd5 (0.1-1 µM) to a
consensus PPRE. Ciglitizone (30 µM) was incubated with
the ECV-304 cells in the absence of serum. These results represent the
mean ±S.E. % apoptotic cells from 3 separate experiments, each
experimental n being the mean of 4 random (×100) fields. *
denotes significance p < 0.05 (one way ANOVA) between
ciglitizone-treated and decoy or scrambled oligonucleotide-treated
cells.
expression vector along with the GFP expression vector
plasmid. Cells expressing transfected plasmids can be readily observed
by GFP autofluorescence in this assay. As shown in Fig.
8a, ECV-304 cells transfected
with vector and GFP plasmids expressed GFP predominantly in flattened,
healthy cells. In contrast, cells transfected with PPAR expression
vector and GFP exhibited rounded and fragmented morphology,
characteristic of apoptotic cells. Quantitative analysis of
transfected cells indicated that PPAR transfection resulted in
~3.5-fold increase in apoptotic cells in ECV-304 cells.
This was further enhanced by treatment with 15d-PGJ2 (Fig.
8b). These data indicate that 15d-PGJ2
activation of PPAR induces endothelial apoptosis.
View larger version (41K):
[in a new window]
Fig. 8.
Effects of overexpression of
PPAR receptor on endothelial cell
apoptosis. a, ECV-304 cells were transfected with
either vector (pCDNA) (Control) or pCMX-PPAR in the
presence of GFP expression vector (pEGFPN-1). At 24 h
post-transfection, cells were treated with indicated doses of
15d-PGJ2 for a further 24 h, and cells were observed
for apoptotic morphology. a shows representative pictures of
GFP expressing healthy flattened ECV cells (Control) and the
rounded cell morphology observed in cells transiently transfected with
pCMX-mPPAR. The scale bar represents 10 µm.
b shows % rounded ECV cells transfected with pEGFPN-1
(Control) or pCMX-PPAR. These experiments represent the
mean ±S.E. from 3 separate ×200 magnification fields, each from 4 separate transfections. * denotes significance p < 0.05 (one unpaired t test) between control and
PPAR-transfected cells.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
12-PGJ2, another nuclear-acting prostanoid,
was shown to be an inducer of tumor cell apoptosis (11). These data
suggest that nuclear-acting prostanoids have distinct effects on
endothelial cell behavior from their counterparts, which signal via
plasma membrane receptors.
receptor
isoform (1, 2). Indeed various eicosanoids were shown to be activators of PPAR isoforms (4, 8, 9). We present evidence that transcripts for
PPAR, -, and - are present in endothelial cell poly(A)+ mRNA preparations, and the proteins were
detected by immunofluorescence. These results are consistent with the
recent finding using reverse transcription-polymerase chain reaction,
that PPAR is expressed in human endothelial cells (25). Northern
blot analysis using total RNA preparations did not yield a detectable
signal for any PPAR isoform, suggesting that endothelial cells have low
expression of PPARs. Although we could not detect PPAR isoforms in ECV
cells using immunoblot methodology, a highly sensitive
immunofluorescence method was capable of detecting specific PPAR
isoforms. In unstimulated cells, PPAR isotypes were localized
predominantly in the peri-nuclear region and the cytoplasm. Treatment
of endothelial cells with 15d-PGJ2 caused all three PPAR
receptor isoforms to become nuclear-localized. Often visible also in
stimulated cells was the appearance of cytoplasmic vacuolar
compartments, which may be indicative of cytoplasmic breakdown. These
results differ from differentiated macrophages, where PPAR was found
predominantly in the cytoplasm, but PPAR was found predominantly the
nucleus (26). This ability of 15d-PGJ2 to induce nuclear
localization of all three isoforms may be an initial step in PPAR
activation. These data agree with the data in the literature that,
although 15d-PGJ2 is considered primarily a PPAR
activator, it can activate all PPAR receptors (9, 27, and 28). Using a
transient reporter gene assay utilizing the rat acyl-CoA oxidase PPRE
linked to a luciferase reporter (16), we show that 15d-PGJ2
and ciglitizone dose-dependently stimulate endogenous PPAR
receptors. These data suggest that PPAR receptors are present and are
functional in vascular endothelial cells.
is a critical
event in 15d-PGJ2-induced endothelial cell death. First, ciglitizone induced PPAR transcriptional activation and endothelial cell death. Both effects were maximal in serum-free medium, probably because of either the inactivation of ciglitizone by serum factors or
because of the survival-promoting actions of serum-borne factors. Because ciglitizone is a selective indicia of PPAR, these data provide a pharmacological evidence that PPAR is critical for endothelial cell apoptosis. Second, the double-stranded PPRE decoy, but
not the scrambled counterpart, inhibited the PPAR transcriptional responses and 15d-PGJ2-induced apoptosis. Third, in
experiments where PPAR was overexpressed, cell viability was
concomitantly reduced. These data strongly suggest that
15d-PGJ2 activates the PPAR pathway in endothelial
cells, and such activation is required, at least in part, for the
induction of endothelial cell apoptosis.
pathway appears to be
critical for endothelial cell apoptosis.
ligands have
been shown to inhibit tumor cell growth in vitro and
in vivo (32). Moreover, endothelial damage or dysfunction is
considered one of the primary causes of large vessel disease. Oxidized
low density lipoproteins and associated lipid components (HODEs,
hydroxyoctadecadienoic acids) were recently shown to be PPAR ligands
involved in monocyte/macrophage foam cell formation in atherosclerotic
lesions (33, 34). Oxidized low density lipoprotein also causes
endothelial cell apoptosis, in part via caspase activation and the
generation of superoxides (35). Similarly, PGD2 synthesis
is elevated in human coronary artery disease via lipocalin-type
prostaglandin D synthase (36). It is conceivable that oxidized low
density lipoprotein or indeed PGD2, through the conversion
to 15d-PGJ2, may induce endothelial cell death or
dysfunction in the atherosclerotic lesion. Interestingly, activation of
the PPAR (also PPAR) pathway in differentiated macrophages was
also shown to lead to their apoptosis (36).
ACKNOWLEDGEMENTS
FOOTNOTES
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.
ABBREVIATIONS
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.
REFERENCES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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 Y. Taba, M. Miyagi, Y. Miwa, H. Inoue, F. Takahashi-Yanaga, S. Morimoto, and T. Sasaguri 15-Deoxy-{Delta}12,14-prostaglandin J2 and laminar fluid shear stress stabilize c-IAP1 in vascular endothelial cells Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H38 - H46. [Abstract] [Full Text] [PDF]
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H. J. Patel, M. G. Belvisi, D. Bishop-Bailey, M. H. Yacoub, and J. A. Mitchell 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 J. Immunol., March 1, 2003; 170(5): 2663 - 2669. [Abstract] [Full Text] [PDF]
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 A. Castrillo, P. G. Traves, P. Martin-Sanz, S. Parkinson, P. J. Parker, and L. Bosca Potentiation of Protein Kinase C {zeta} Activity by 15-Deoxy-{Delta}12,14-Prostaglandin J2 Induces an Imbalance between Mitogen-Activated Protein Kinases and NF-{kappa}B That Promotes Apoptosis in Macrophages Mol. Cell. Biol., February 15, 2003; 23(4): 1196 - 1208. [Abstract] [Full Text] [PDF]
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L. Pang, M. Nie, L. Corbett, and A. J. Knox Cyclooxygenase-2 Expression by Nonsteroidal Anti-inflammatory Drugs in Human Airway Smooth Muscle Cells: Role of Peroxisome Proliferator-Activated Receptors J. Immunol., January 15, 2003; 170(2): 1043 - 1051. [Abstract] [Full Text] [PDF]
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 M. Arici, R. Chana, A. Lewington, J. Brown, and N. J. Brunskill Stimulation of Proximal Tubular Cell Apoptosis by Albumin-Bound Fatty Acids Mediated by Peroxisome Proliferator Activated Receptor-{gamma} J. Am. Soc. Nephrol., January 1, 2003; 14(1): 17 - 27. [Abstract] [Full Text] [PDF]
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 C. E. Clay, A. Monjazeb, J. Thorburn, F. H. Chilton, and K. P. High 15-Deoxy-{Delta}12,14-prostaglandin J2-induced apoptosis does not require PPAR{gamma} in breast cancer cells J. Lipid Res., November 1, 2002; 43(11): 1818 - 1828. [Abstract] [Full Text] [PDF]
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 S. Goetze, A. Bungenstock, C. Czupalla, F. Eilers, P. Stawowy, U. Kintscher, C. Spencer-Hansch, K. Graf, B. Nurnberg, R. E. Law, et al. Leptin Induces Endothelial Cell Migration Through Akt, Which Is Inhibited by PPAR{gamma}-Ligands Hypertension, November 1, 2002; 40(5): 748 - 754. [Abstract] [Full Text] [PDF]
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M. L. Martelli, R. Iuliano, I. Le Pera, I. Sama', C. Monaco, S. Cammarota, T. Kroll, L. Chiariotti, M. Santoro, and A. Fusco Inhibitory Effects of Peroxisome Proliferator-Activated Receptor {gamma} on Thyroid Carcinoma Cell Growth J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4728 - 4735. [Abstract] [Full Text] [PDF]
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 R. M. Moore, D. W. Lundgren, R. J. Silver, and J. J. Moore Lactosylceramide-Induced Apoptosis in Primary Amnion Cells and Amnion-Derived WISH Cells Reproductive Sciences, September 1, 2002; 9(5): 282 - 289. [Abstract] [PDF]
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Y. L. Wang, K. A. Frauwirth, S. M. Rangwala, M. A. Lazar, and C. B. Thompson Thiazolidinedione Activation of Peroxisome Proliferator-activated Receptor gamma Can Enhance Mitochondrial Potential and Promote Cell Survival J. Biol. Chem., August 23, 2002; 277(35): 31781 - 31788. [Abstract] [Full Text] [PDF]
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D. Bishop-Bailey, T. Hla, and T. D. Warner Intimal Smooth Muscle Cells as a Target for Peroxisome Proliferator-Activated Receptor-{gamma} Ligand Therapy Circ. Res., August 9, 2002; 91(3): 210 - 217. [Abstract] [Full Text] [PDF]
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 R. Yamazaki, N. Kusunoki, T. Matsuzaki, S. Hashimoto, and S. Kawai Nonsteroidal Anti-Inflammatory Drugs Induce Apoptosis in Association with Activation of Peroxisome Proliferator-Activated Receptor gamma in Rheumatoid Synovial Cells J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 18 - 25. [Abstract] [Full Text] [PDF]
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C. Ward, I. Dransfield, J. Murray, S. N. Farrow, C. Haslett, and A. G. Rossi Prostaglandin D2 and Its Metabolites Induce Caspase-Dependent Granulocyte Apoptosis That Is Mediated Via Inhibition of I{kappa}B{alpha} Degradation Using a Peroxisome Proliferator-Activated Receptor-{gamma}-Independent Mechanism J. Immunol., June 15, 2002; 168(12): 6232 - 6243. [Abstract] [Full Text] [PDF]
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T Shimada, K Kojima, K Yoshiura, H Hiraishi, and A Terano Characteristics of the peroxisome proliferator activated receptor {gamma} (PPAR{gamma}) ligand induced apoptosis in colon cancer cells Gut, May 1, 2002; 50(5): 658 - 664. [Abstract] [Full Text] [PDF]
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 T. E. Akiyama, C. T. Baumann, S. Sakai, G. L. Hager, and F. J. Gonzalez Selective Intranuclear Redistribution of PPAR Isoforms by RXR{alpha} Mol. Endocrinol., April 1, 2002; 16(4): 707 - 721. [Abstract] [Full Text] [PDF]
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T. Shibata, M. Kondo, T. Osawa, N. Shibata, M. Kobayashi, and K. Uchida 15-Deoxy-Delta 12,14-prostaglandin J2. A PROSTAGLANDIN D2 METABOLITE GENERATED DURING INFLAMMATORY PROCESSES J. Biol. Chem., March 15, 2002; 277(12): 10459 - 10466. [Abstract] [Full Text] [PDF]
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R. B. Clark The role of PPARs in inflammation and immunity J. Leukoc. Biol., March 1, 2002; 71(3): 388 - 400. [Abstract] [Full Text] [PDF]
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 L. Kopelovich, J. R. Fay, R. I. Glazer, and J. A. Crowell Peroxisome Proliferator-activated Receptor Modulators As Potential Chemopreventive Agents Mol. Cancer Ther., March 1, 2002; 1(5): 357 - 363. [Abstract] [Full Text] [PDF]
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A. Diab, C. Deng, J. D. Smith, R. Z. Hussain, B. Phanavanh, A. E. Lovett-Racke, P. D. Drew, and M. K. Racke Peroxisome Proliferator-Activated Receptor-{gamma} Agonist 15-Deoxy-{Delta}12,1412,14-Prostaglandin J2 Ameliorates Experimental Autoimmune Encephalomyelitis J. Immunol., March 1, 2002; 168(5): 2508 - 2515. [Abstract] [Full Text] [PDF]
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S. E. Crawford, C. Qi, P. Misra, V. Stellmach, M. S. Rao, J. D. Engel, Y. Zhu, and J. K. Reddy Defects of the Heart, Eye, and Megakaryocytes in Peroxisome Proliferator Activator Receptor-binding Protein (PBP) Null Embryos Implicate GATA Family of Transcription Factors J. Biol. Chem., January 25, 2002; 277(5): 3585 - 3592. [Abstract] [Full Text] [PDF]
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A. Masamune, K. Kikuta, M. Satoh, Y. Sakai, A. Satoh, and T. Shimosegawa Ligands of Peroxisome Proliferator-activated Receptor-gamma Block Activation of Pancreatic Stellate Cells J. Biol. Chem., January 4, 2002; 277(1): 141 - 147. [Abstract] [Full Text]
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 F. TOSETTI, N. FERRARI, S. DE FLORA, and A. ALBINI Angioprevention': angiogenesis is a common and key target for cancer chemopreventive agents FASEB J, January 1, 2002; 16(1): 2 - 14. [Abstract] [Full Text] [PDF]
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C. E. Clay, G.-i. Atsumi, K. P. High, and F. H. Chilton Early de Novo Gene Expression Is Required for 15-Deoxy-Delta 12,14-prostaglandin J2-induced Apoptosis in Breast Cancer Cells J. Biol. Chem., December 7, 2001; 276(50): 47131 - 47135. [Abstract] [Full Text] [PDF]
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T. Hatae, M. Wada, C. Yokoyama, M. Shimonishi, and T. Tanabe Prostacyclin-dependent Apoptosis Mediated by PPARdelta J. Biol. Chem., November 30, 2001; 276(49): 46260 - 46267. [Abstract] [Full Text] [PDF]
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A.-L. Levonen, D. A. Dickinson, D. R. Moellering, R. T. Mulcahy, H. J. Forman, and V. M. Darley-Usmar Biphasic Effects of 15-Deoxy-{Delta}12,14-Prostaglandin J2 on Glutathione Induction and Apoptosis in Human Endothelial Cells Arterioscler. Thromb. Vasc. Biol., November 1, 2001; 21(11): 1846 - 1851. [Abstract] [Full Text] [PDF]
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 L. BENAYOUN, S. LETUVE, A. DRUILHE, J. BOCZKOWSKI, M.-C. DOMBRET, P. MECHIGHEL, J. MEGRET, G. LESECHE, M. AUBIER, and M. PRETOLANI Regulation of Peroxisome Proliferator-activated Receptor gamma Expression in Human Asthmatic Airways . Relationship with Proliferation, Apoptosis, and Airway Remodeling Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1487 - 1494. [Abstract] [Full Text] [PDF]
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 C. J. Hupfeld and R. H. Weiss TZDs inhibit vascular smooth muscle cell growth independently of the cyclin kinase inhibitors p21 and p27 Am J Physiol Endocrinol Metab, August 1, 2001; 281(2): E207 - E216. [Abstract] [Full Text] [PDF]
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C. J. de Souza, M. Eckhardt, K. Gagen, M. Dong, W. Chen, D. Laurent, and B. F. Burkey Effects of Pioglitazone on Adipose Tissue Remodeling Within the Setting of Obesity and Insulin Resistance Diabetes, August 1, 2001; 50(8): 1863 - 1871. [Abstract] [Full Text] [PDF]
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Q. N. Diep and E. L. Schiffrin Increased Expression of Peroxisome Proliferator-Activated Receptor-{alpha} and -{gamma} in Blood Vessels of Spontaneously Hypertensive Rats Hypertension, August 1, 2001; 38(2): 249 - 254. [Abstract] [Full Text] [PDF]
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D. Hornung, L. L. Waite, E. A. Ricke, F. Bentzien, D. Wallwiener, and R. N. Taylor Nuclear Peroxisome Proliferator-Activated Receptors {{alpha}} and {{gamma}} Have Opposing Effects on Monocyte Chemotaxis in Endometriosis J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3108 - 3114. [Abstract] [Full Text] [PDF]
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 T. Murata, Y. Hata, T. Ishibashi, S. Kim, W. A. Hsueh, R. E. Law, and D. R. Hinton Response of Experimental Retinal Neovascularization to Thiazolidinediones Arch Ophthalmol, May 1, 2001; 119(5): 709 - 717. [Abstract] [Full Text] [PDF]
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 C. Thevenon, M. Guichardant, and M. Lagarde Gas Chromatographic-Mass Spectrometric Measurement of 15-Deoxy-{{Delta}}12,14-prostaglandin J2, the Peroxisome Proliferator-activated Receptor {{gamma}} Ligand, in Urine Clin. Chem., April 1, 2001; 47(4): 768 - 770. [Full Text] [PDF]
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 E. C. Person, L. L. Waite, R. N. Taylor, and T. S. Scanlan Albumin Regulates Induction of Peroxisome Proliferator-Activated Receptor-{{gamma}} (PPAR{{gamma}}) by 15-Deoxy-{{Delta}}12-14-Prostaglandin J2 in Vitro and May Be an Important Regulator of PPAR{{gamma}} Function in Vivo Endocrinology, February 1, 2001; 142(2): 551 - 556. [Abstract] [Full Text] [PDF]
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 C. S. Elangbam, R. D. Tyler, and R. M. Lightfoot Peroxisome Proliferator-activated Receptors in Atherosclerosis and Inflammation--An Update Toxicol Pathol, February 1, 2001; 29(2): 224 - 231. [Abstract] [PDF]
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M. D. Boudreau, K. H. Sohn, S. H. Rhee, S. W. Lee, J. D. Hunt, and D. H. Hwang Suppression of Tumor Cell Growth Both in Nude Mice and in Culture by n-3 Polyunsaturated Fatty Acids: Mediation through Cyclooxygenase-independent Pathways Cancer Res., February 1, 2001; 61(4): 1386 - 1391. [Abstract] [Full Text]
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R. Pili, M. P. Kruszewski, B. W. Hager, J. Lantz, and M. A. Carducci Combination of Phenylbutyrate and 13-cis Retinoic Acid Inhibits Prostate Tumor Growth and Angiogenesis Cancer Res., February 1, 2001; 61(4): 1477 - 1485. [Abstract] [Full Text]
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K.-i. Inoue, Y. Kawahito, and H. Sano Endothelial Apoptosis Chest, December 1, 2000; 118(6): 1839 - 1839. [Full Text] [PDF]
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S. Hortelano, A. Castrillo, A. M. Alvarez, and L. Bosca Contribution of Cyclopentenone Prostaglandins to the Resolution of Inflammation Through the Potentiation of Apoptosis in Activated Macrophages J. Immunol., December 1, 2000; 165(11): 6525 - 6531. [Abstract] [Full Text] [PDF]
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W. T. Schaiff, M. G. Carlson, S. D. Smith, R. Levy, D. M. Nelson, and Y. Sadovsky Peroxisome Proliferator-Activated Receptor-{gamma} Modulates Differentiation of Human Trophoblast in a Ligand-Specific Manner J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3874 - 3881. [Abstract] [Full Text]
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J. W. Wilson and C. S. Potten The Effect of Exogenous Prostaglandin Administration on Tumor Size and Yield in Min/+ Mice Cancer Res., August 1, 2000; 60(16): 4645 - 4653. [Abstract] [Full Text]
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J. C. Yoon, T. W. Chickering, E. D. Rosen, B. Dussault, Y. Qin, A. Soukas, J. M. Friedman, W. E. Holmes, and B. M. Spiegelman Peroxisome Proliferator-Activated Receptor gamma Target Gene Encoding a Novel Angiopoietin-Related Protein Associated with Adipose Differentiation Mol. Cell. Biol., July 15, 2000; 20(14): 5343 - 5349. [Abstract] [Full Text]
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Y. Taba, T. Sasaguri, M. Miyagi, T. Abumiya, Y. Miwa, T. Ikeda, and M. Mitsumata Fluid Shear Stress Induces Lipocalin-Type Prostaglandin D2 Synthase Expression in Vascular Endothelial Cells Circ. Res., May 12, 2000; 86(9): 967 - 973. [Abstract] [Full Text] [PDF]
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D. J. Mancuso, C. M. Jenkins, and R. W. Gross The Genomic Organization, Complete mRNA Sequence, Cloning, and Expression of a Novel Human Intracellular Membrane-associated Calcium-independent Phospholipase A2 J. Biol. Chem., March 31, 2000; 275(14): 9937 - 9945. [Abstract] [Full Text] [PDF]
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R. B. Clark, D. Bishop-Bailey, T. Estrada-Hernandez, T. Hla, L. Puddington, and S. J. Padula The Nuclear Receptor PPAR{gamma} and Immunoregulation: PPAR{gamma} Mediates Inhibition of Helper T Cell Responses J. Immunol., February 1, 2000; 164(3): 1364 - 1371. [Abstract] [Full Text] [PDF]
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V. Pasceri, H. D. Wu, J. T. Willerson, and E. T. H. Yeh Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator-Activated Receptor-{gamma} Activators Circulation, January 25, 2000; 101(3): 235 - 238. [Abstract] [Full Text] [PDF]
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 B. Desvergne and W. Wahli Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism Endocr. Rev., October 1, 1999; 20(5): 649 - 688. [Abstract] [Full Text]
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K. Subbaramaiah, D. T. Lin, J. C. Hart, and A. J. Dannenberg Peroxisome Proliferator-activated Receptor gamma Ligands Suppress the Transcriptional Activation of Cyclooxygenase-2. EVIDENCE FOR INVOLVEMENT OF ACTIVATOR PROTEIN-1 AND CREB-BINDING PROTEIN/p300 J. Biol. Chem., April 6, 2001; 276(15): 12440 - 12448. [Abstract] [Full Text] [PDF]
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A. Castrillo, M. Mojena, S. Hortelano, and L. Bosca Peroxisome Proliferator-activated Receptor-gamma -independent Inhibition of Macrophage Activation by the Non-thiazolidinedione Agonist L-796,449. COMPARISON WITH THE EFFECTS OF 15-DEOXY-Delta 12,14-PROSTAGLANDIN J2 J. Biol. Chem., August 31, 2001; 276(36): 34082 - 34088. [Abstract] [Full Text] [PDF]
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J. G. Hunter, M. F. van Delft, R. A. Rachubinski, and J. P. Capone Peroxisome Proliferator-activated Receptor gamma Ligands Differentially Modulate Muscle Cell Differentiation and MyoD Gene Expression via Peroxisome Proliferator-activated Receptor gamma -dependent and -independent Pathways J. Biol. Chem., October 5, 2001; 276(41): 38297 - 38306. [Abstract] [Full Text] [PDF]
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V. S. Mujumdar, C. M. Tummalapalli, G. M. Aru, and S. C. Tyagi Mechanism of constrictive vascular remodeling by homocysteine: role of PPAR Am J Physiol Cell Physiol, May 1, 2002; 282(5): C1009 - C1015. [Abstract] [Full Text] [PDF]
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