© 1999 American Heart Association, Inc.
Original Contributions |
PPAR
Activation in Human Endothelial Cells Increases Plasminogen Activator Inhibitor Type-1 Expression
PPAR as a Potential Mediator in Vascular Disease
From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Jorge Plutzky, MD, Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115. E-mail JPlutzky{at}BICS.BWH.HARVARD.EDU
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Abstract |
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Abstract—Plasminogen activator inhibitor type-1 (PAI-1) is a major physiological inhibitor of fibrinolysis, with its plasma levels correlating with the risk for myocardial infarction and venous thrombosis. The regulation of PAI-1 transcription by endothelial cells (ECs), a major source of PAI-1, remains incompletely understood. Adipocytes also produce PAI-1, suggesting possible common regulatory pathways between adipocytes and ECs. Peroxisomal proliferator-activated receptor-
(PPAR) is a
ligand-activated transcription factor that regulates gene
expression in response to various mediators such as
15-deoxy-
12,14-prostaglandin J2
(15d-PGJ2) and oxidized linoleic acid (9- and 13-HODE). The
present study tested the hypotheses that human ECs express PPAR
and that this transcriptional activator regulates PAI-1
expression in this cell type. We found that human ECs contain both
PPAR mRNA and protein. Immunohistochemistry of human carotid
arteries also revealed the presence of PPAR in ECs. Bovine ECs
transfected with a PPAR response element (PPRE)–luciferase construct
responded to stimulation by the PPAR agonist 15d-PGJ2 in
a concentration-dependent manner, suggesting a functional PPAR in
ECs. Treatment of human ECs with 15d-PGJ2,
9(S)-HODE, or 13(S)-HODE augmented PAI-1
mRNA and protein expression, whereas multiple PPAR
activators did not change PAI-1 levels. Introduction of
increasing amounts of a PPAR expression construct in human
fibroblasts enhanced PAI-1 secretion from these cells in proportion to
the amount of transfected DNA. Thus, ECs express functionally active
PPAR that regulates PAI-1 expression in ECs. Our results establish a
role for PPAR in the regulation of EC gene expression, with
important implications for the clinical links between obesity and
atherosclerosis.
Key Words: atherosclerosis • endothelium • peroxisomal proliferator-activated receptor • plasminogen activator inhibitor-1 • 15-deoxy-12,14-prostaglandin J2
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Introduction |
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Endothelial cells (ECs) are an important source of plasminogen activator inhibitor type-1 (PAI-1) plasma activity.1 PAI-1, a member of the serine protease inhibitor (serpin) family, is the major physiological inhibitor of tissue plasminogen activator and urokinase and thus, limits fibrinolysis.2 Considerable evidence links PAI-1 to myocardial infarction and deep venous thrombosis3 4 5 ; endothelial production of PAI-1 likely influences these events. As such, the regulation of PAI-1 expression in ECs has received focused attention.6 7 8 Cytokines such as transforming growth factor-ß and tumor necrosis factor-
increase PAI-1
expression.9 10 Circulating lipids,11 some
lipid-lowering therapies,12 and the clinical condition of
obesity itself2 all affect PAI-1 expression. This response
to lipids, as well as the evidence that adipocytes themselves can
express PAI-1,13 raises the possibility that
transcriptional mediators important in adipogenesis and adipocyte
signaling may play similar roles in ECs.
Peroxisome proliferator-activated receptors (PPARs),
members of the nuclear receptor superfamily, are
ligand-activated transcription factors that play an important
role in lipid metabolism.14 15 16 One of these
PPARs, PPAR, has been implicated in the transcriptional regulation
of several genes involved in lipid metabolism and appears
to promote the differentiation of cells toward a more adipocyte-like
phenotype.17 18 19 Both synthetic and natural
ligands for PPAR have been described. Among the synthetic ligands,
thiazolidinediones, a group of compounds that includes troglitazone,
increase insulin sensitivity.20 Naturally-occurring
PPAR ligands include fatty acids, eicosanoid
derivatives,21 and
15-deoxy-12,14-prostaglandin
J2
(15d-PGJ2).19 Recent work has
established that 9-hydroxy-(S)-10,12-octadecadienoic acid
[9(S)-HODE] and 13(S)-HODE, known components of
oxidized LDL, are PPAR activators, with concomitant
evidence invoking PPAR signaling in monocytes and
macrophages.22 23 Clinical observations
suggest that obese patients have elevated adipose tissue PPAR levels
compared with those in lean controls.24 Once
activated, PPAR binds to the PPAR response elements (PPRE)
in the promotor region of target genes.25 26 27 Although
PPAR has been extensively studied in adipocytes,
monocytes/macrophages, and vascular smooth muscle
cells,22 23 28 29 30 essentially nothing is known about
PPAR in EC biology and gene expression.
The present study investigated whether PPAR was expressed
and active in human ECs, and if so, whether PPAR might regulate
PAI-1 expression in this cell type, abundant in adipose tissue. In
addition to focusing attention on the possible role of PPAR
signaling in ECs, such findings offer a novel molecular link between
the clinical associations between obesity, coagulation status, and
vascular events.
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Methods |
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Cell Culture
Human saphenous vein ECs were isolated from outgrowths of explants from unused portions of saphenous veins harvested at coronary artery bypass surgery. Cells were cultured in medium 199 (BioWhittaker) containing 25 mmol/L HEPES, 1% heparin, 50 mg/L EC growth factor, 1% glutamine, 1% penicillin-streptomycin, and 5% FCS on low-pyrogen fibronectin (1.5 mg/cm2). The cells used were>99% von Willebrand factor–positive by flow cytometry analysis and exhibited in culture the typical "cobblestone" growth pattern seen in ECs. These experiments used ECs at passages 2 to 5. For treatment with PPAR
activators [docosahexaenoic acid
(DHA); eicosapentaenoic acid (EPA);
5,8,11,14-eicosatetraenoic acid (ETYA); fenofibrate; and clofibrate;
all from Sigma; and WY14643 from Biomol] or PPAR
activators [15d-PGJ2 (Calbiochem);
9-hydroxy-(S)-10,12-octadecadienoic acid
(9(S)-HODE) and 13(S)-HODE, both from Cayman
Chemical], ECs were preincubated in low-serum medium (0.1% FCS)
for 12 hours and then stimulated for the times indicated. Bovine ECs
and human fibroblasts were cultured in Dulbecco's modified
Eagle's medium (DMEM, BioWhittaker) containing 1% glutamine, 1%
penicillin-streptomycin, and 10% FCS. NIH3T3-L1 preadipocytes, originally obtained from American Type Culture Collection (Manassas, Va) and generously provided to us by Dr Bruce Spiegelman, Dana Farber Cancer Institute, Boston, Mass, were cultured in DMEM, 10% bovine calf serum, and 1% penicillin-streptomycin. Differentiation of preadipocytes into adipocytes was induced as described by others.17 Monocyte-derived macrophages were cultured as described before.30
RNA Extraction and Reverse Transcriptase–Polymerase Chain
Reaction (RT-PCR)
Total RNA from 107 cells was
isolated by the single-step guanidinium thiocyanate–phenol-chloroform
method with the use of RNAzol from Tel-Test. Two microgram of total RNA
was reverse-transcribed into cDNA with 1 U/mL reverse transcriptase
(Superscript, Gibco-BRL) at 37°C for 1 hour in standard buffer.
Amplification of PPAR cDNA used 2 oligonucleotide
primers from nucleotides +384 to +705 (a 321-bp fragment):
sense-primer, 5'-CGCGGGAATTCGGTGAAAC-TCTGGGGAGATTC-3'; antisense
primer, 5'-CGCGGGATTCGT-TGACACAGAGATGCCATTC-3'. The primers were
designed to detect all PPAR isoforms. For the amplification of GAPDH
cDNA, 2 oligonucleotide primers were used (a 452-bp
fragment): sense-primer, 5'-ACCACAGTCCATGCCATCAC-3'; antisense primer,
5'-TCCAC-CACCCTGTTGCTGTA-3'. PCR was carried out in a standard
buffer (Gibco-BRL) with 200 ng of each primer (IDT), 33 mmol/L
MgCl2, and 0.5 U Taq polymerase
(Gibco-BRL) for 30 cycles. PCR products (10 µL/25 µL) were
analyzed on a 2% agarose gel.
Northern Blot Analysis
Five micrograms of total RNA from unstimulated or
15d-PGJ2–stimulated ECs was used for standard
Northern blot analysis. After electrophoresis, RNA was
transferred to nylon membranes (ICN) in 20x SSC by using a capillary
blotting technique. Blots were UV cross-linked, prehybridized (50%
formamide, 5x Denhardt's solution, 5x SSC, 0.5% SDS, and 20
mmol/L salmon sperm DNA), and hybridized in the same buffer with a
radiolabeled ([-32P]dATP) PAI-1
oligonucleotide (Calbiochem). The membranes were washed
at 60°C in 1% SDS–2x SSC and autoradiographed with Kodak X-OMAT
film at -70°C with an intensifying screen.
Preparation of Nuclear and Cytosolic Extracts and Western Blot
Analysis
For Western blotting, nuclear and cytosolic extracts
of 107 cells were prepared. Cells were lysed in
10 mmol/L HEPES, pH 7.9, 1.5 mmol/L
MgCl2, 10 mmol/l KCl, and 0.5% NP-40.
Nuclei were pelleted at 13 000g for 5 minutes, and the
resulting supernatant was used as the cytosolic fraction. Nuclei were
lysed in 20 mmol/L HEPES, pH 7.9, 1.5 mmol/L
MgCl2, 420 mmol/L NaCl, and 0.2 mmol/L
EDTA. After centrifugation at 13 000g for 5
minutes, the supernatant was diluted in an equal volume of 20
mmol/L HEPES, pH 7.9, 100 mmol/L KCl, 0.2 mmol/L EDTA, and
20% glycerol and used as the nuclear extract. Protein concentration of
nuclear and cytosolic extracts was determined
colorimetrically (Pierce). Processed samples were
applied to 10% SDS–polyacrylamide gel electrophoresis (PAGE)
gels and transferred to nitrocellulose membranes (Millipore) by
semi-dry blotting, as described previously.31
Membranes were treated overnight with Tris-buffered saline–Tween
containing 5% dry milk and incubated with goat anti-human PPAR
antibodies (mAbs; Santa Cruz, San Diego, Calif) for 1 hour. After being
washed, the membranes were incubated with horseradish
peroxidase–conjugated rabbit anti-goat mAbs. Antigen detection was
performed with a chemiluminescence detection system (NEN). Nuclear
extracts from PPAR-transfected human skin fibroblasts served as a
positive control.
For the detection of secreted PAI-1 in supernatants from unstimulated or stimulated ECs, 50 µL from 500 µL total supernatant was subjected to 10% SDS-PAGE and processed as indicated above. For the detection of PAI-1, membranes were stained with a mouse anti-human PAI-1 mAb (American Diagnostica Inc, Greenwich, Conn). Quantification was performed using the NIH-Image densitometry software.
Immunohistochemistry of Human Carotid Artery Specimens
Surgical specimens of human carotid arteries were obtained
by protocols approved by the Human Investigation Review Committee at
the Brigham and Women's Hospital, Boston, Mass. Serial cryostat
sections (5 mm) were cut, air dried onto microscopic slides, and
fixed in acetone at -20°C for 5 minutes. Staining for PPAR was
performed with a polyclonal rabbit anti-human PPAR peptide antibody
(a generous gift from Dr Mitchell Lazar, University of Pennsylvania,
Philadelphia) ECs were identified by staining with anti-CD31
antibody (Dako, Carpinteria, Calif). Sections were preincubated with
PBS containing 0.3% hydrogen peroxidase activity and stained for 1
hour with primary antibody diluted in PBS supplemented with 5%
appropriate serum. Negative control was performed by preabsorbing the
anti-PPAR antibodies with the peptide from which the antibody had
been derived, subsequently using these "preabsorbed PPAR
antibodies" at similar concentrations as in experimental conditions.
Finally, sections were incubated with the respective biotinylated
secondary antibody (Vector Laboratories, Burlingame, Calif) followed by
avidin-biotin-peroxidase complex (Vectastain ABC kit). Antibody binding
was visualized with 3-amino-9-ethylcarbazole (Vector Laboratories) or
with true blue peroxidase substrate (Kirkegaard & Perry Laboratories).
Sections were counterstained with Gill's hematoxylin or contrast red
(Kirkegaard & Perry Laboratories).
Transient Transfection Assay
Bovine ECs were transiently transfected with
PPRE3-TK-luciferase (LUC)17
(generously provided by Dr Bruce Spiegelman, DFCI) and
pCMV–ß-galactosidase (ß-gal), by using lipofectamine, according to
the manufacturer's protocol (Gibco-BRL). After incubation for 5 hours
liposomes were removed, and after 12 hours of culture in DMEM with 10%
FCS, cells were stimulated in DMEM containing 0.1% FCS with
15d-PGJ2 at the indicated concentrations. Cells
were harvested after 24 hours, and luciferase and ß-gal activity was
measured using the dual-light assay (Tropix).
With similar techniques, human skin fibroblasts were transfected
with the PPAR expression construct (pCMX-PPAR; generously
provided by Dr Bruce Spiegelman, DFCI) at different concentrations (100
ng/5x106 cells or 250
ng/5x106 cells). To verify similar transfection
efficiency under all conditions tested, we cotransfected cells with
pCMV–ß-gal (500 ng/5x106 cells). Cells were
stimulated for 24 hours in serum-free medium with or without 5
µmol/L 15d-PGJ2, harvested, and processed as
described above.
Statistical Analysis
Results of the experimental studies are reported as
mean±SEM. Differences were analyzed by Student's paired
t test. A value of P<0.05 in the 2-tailed test
was regarded as significant.
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Results |
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Human ECs Express PPAR
mRNA and ProteinCultured human ECs express PPAR
mRNA as determined
by RT-PCR (Figure 1A
). Western blot analysis revealed
PPAR protein expression in the nuclear fraction but not in the
cytosolic preparation (Figure 1B, top). The identity of the
detected band was confirmed by its size and comigration with a signal
from the nuclei of PPAR-transfected human fibroblasts. Nuclei from
untransfected fibroblasts exhibited no similar signal of this size.
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Comparison of PPAR expression in ECs with other known
PPAR-expressing cells (preadipocytes, adipocytes, and
monocyte-derived macrophages) by both RT-PCR and Western
blotting suggests that PPAR is present at levels slightly less
than in preadipocytes and monocyte-derived macrophages and
substantially less than in differentiated adipocytes (Figure 1A
, top, and 1B, bottom). Northern blotting revealed barely detectable
PPAR in ECs (data not shown).
ECs in Human Carotid Arteries Express PPAR
Immunohistochemistry of human carotid arteries revealed
PPAR staining in the nuclei of ECs (Figure 2B). ECs were
identified by immunoreactive CD31 (PECAM-1) in parallel sections
(Figure 2A) No immunostaining was observed when
parallel sections were stained with anti-PPAR antibodies preabsorbed
with peptide (Figure 2C), indicating the specificity of the
detected signals.
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Treatment of PPRE-Luciferase–Transfected Bovine ECs With the
PPAR Activator 15d-PGJ2 Increases
Luciferase Activity
To assess the presence of functional
endogenous PPAR in ECs, we transiently transfected
bovine ECs with a PPRE-luciferase construct and stimulated these cells
with increasing amounts of the PPAR activator
15d-PGJ2. Luciferase activity was assayed and
normalized to the ß-gal activity of a cotransfected pCMV–ß-gal
construct. Stimulation with 15d-PGJ2 increased
normalized luciferase activity in a concentration-dependent manner,
with a maximal 5.9±1.2-fold increase (P<0.05, n=3) at
10 µmol/L 15d-PGJ2 (Figure 3).
These results suggest the presence of inducible PPAR activity in
these cells.
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PPAR, but Not PPAR, Activators Increase PAI-1
mRNA and Protein Expression in Human ECs
To investigate the effect of PPAR activation on PAI-1
mRNA expression in human ECs, they were stimulated with the PPAR
activators 15d-PGJ2 (10
µmol/L), 9(S)-HODE (20g/L), or 13(S)-HODE
(20g/L) for 18 hours, and Northern blot analysis was then
performed. Unstimulated cells showed low PAI-1 mRNA expression, whereas
stimulation with all tested PPAR activators increased
PAI-1 mRNA levels, with a maximum response seen with
15d-PGJ2 (Figure 4A).
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Western blotting of EC supernatants collected after 24 hours of
treatment with the same PPAR activators as above
revealed an increase in PAI-1 protein (Figure 4B) in a pattern
consistent with the Northern blot data. Using the most potent
PPAR activator, 15d-PGJ2, we found
a concentration-dependent increase in PAI-1 secretion from human ECs,
with a maximal 6.0±1.7-fold rise at 10 µmol/L
15d-PGJ2 compared with unstimulated cells
(P=0.03, n=3; Figure 4C). In contrast, none of 6
different PPAR activators increased PAI-1 protein levels
in human ECs (Figure 4D).
Overexpression of PPAR in Human Fibroblasts Increases PAI-1
Expression in Response to 15d-PGJ2 in a
Concentration-Dependent Manner
To investigate whether PPAR can indeed increase PAI-1
levels, we turned to an artificial approach that would permit a
demonstration of PPAR's influence on PAI-1 expression. To do so, we
overexpressed PPAR in human fibroblasts and measured PAI-1 protein
levels in supernatants of cells incubated with or without
15d-PGJ2. This strategy allowed studies to be
done in readily transfectable cells that endogenously
express PAI-1 but that have only low levels of PPAR. Untransfected
fibroblasts, expressing PPAR at negligible levels (Figure 1B), secrete PAI-1 under basal conditions at very low levels.
Introduction of increasing amounts of the PPAR expression construct
enhanced PAI-1 secretion from these cells in proportion to the amount
of transfected DNA. Consistent with our finding in ECs,
treatment with 15d-PGJ2 further augmented PAI-1
in the supernatants of these transfected fibroblasts compared with
unstimulated cells (Figure 5A, top). Densitometry of
15d-PGJ2 (5 µmol/L) –stimulated cells
indicated a 2.6±0.6-fold increase in secreted PAI-1 in the
supernatants of cells transfected with 250 ng pCMX-PPAR DNA compared
with untransfected, stimulated cells (Figure 5B;
P=0.01, n=4). Analysis of cotransfected ß-gal
activity indicated comparable transfection efficiency among the groups
(Figure 5A, bottom).
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Discussion |
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We hypothesized that PPAR
might be expressed and active
in regulating gene transcription in human ECs. If so, associations
between triglyceride levels, obesity, and coagulation
suggested that PAI-1 might be a PPAR target gene. Our findings
support both of these hypotheses.
Human ECs express PPAR mRNA, as demonstrated by RT-PCR.
Western blots showing a band co-migrating with PPAR-transfected
fibroblasts established that human ECs express PPAR protein. ECs
contain slightly less but comparable amounts of PPAR protein
relative to preadipocytes and monocyte-derived macrophages. The
lack of a strong PPAR signal in Northern blot analysis
agrees with other PPAR reports.27 32 The functional
relevance of a given protein does not depend solely on mRNA levels but
also on its in vivo translation and protein
half-life.33 34 Importantly, ECs in vivo clearly contain
PPAR protein, as shown by immunohistochemistry of human carotid
arteries. Furthermore, the ability to activate a canonical PPRE
transfected into bovine ECs with 15d-PGJ2
strongly supports the presence of a functional PPAR. We found that
PPAR activation in ECs, with either 15d-PGJ2
or the HODEs, increased PAI-1 expression.
15d-PGJ2, a metabolite of
PGD2, potently stimulates PPAR, exhibits much
less activity toward PPAR or PPAR
,19 21 35 and lacks
a known role in other transcriptional signaling pathways. PPAR
activation is an unlikely mechanism for PAI-1 induction in ECs, given
the lack of an effect of multiple PPAR activators on
PAI-1 protein levels. Furthermore, the stronger induction of PAI-1 by
15d-PGJ2 reported here, compared with that
elicited by the HODEs, agrees with previous studies suggesting that
15d-PGJ2 is a more potent PPAR
ligand.23 Finally, the proportionate induction of
endogenous PAI-1 expression through increasing heterologous
expression of PPAR in fibroblasts bolsters the hypothesis that PAI-1
expression can be influenced by PPAR.
The PPAR family thus far is known to consist of 3 members, ,
, and . Like all PPARs, PPAR on activation forms heterodimeric
complexes with the retinoic X receptor and associates with a PPRE site
in the promoter of target genes.25 27 36 PPAR, strongly
implicated in adipogenesis, is induced early in adipocyte
differentiation, after which it remains expressed at high
levels.37 38 Little is known about PPAR in
nonadipocytes. Recent work suggests that PPAR inhibits
macrophage activation, thereby reducing cytokine
production and macrophage gene
expression.28 29 Similarly, we have localized PPAR in
macrophages in human atheromas and demonstrated a
functional role for PPAR in inhibiting matrix metalloproteinase-9
gelatinolytic activity elaborated by human
monocyte–derived macrophages.30 In contrast,
recent reports, in addition to suggesting that components of oxidized
LDL act as PPAR ligands, also found that activation of PPAR
induced macrophage differentiation toward foam cells by
increasing scavenger receptor expression.22 23 The net
effect of PPAR stimulation in atherogenesis thus remains
unresolved39 but could well be influenced by PPAR in
the endothelium.
PPAR signaling in ECs is quite plausible. Adipose tissue is
highly vascularized and, as such, rich in endothelium.
ECs localize strategically at the interface between circulating lipid
components and tissues. Some of these same lipid components, eg, 9- and
13-HODE, long known to activate ECs, have recently been found
to act as PPAR ligands.23 Hence, ECs may well encounter
at least 3 naturally occurring PPAR ligands:
15d-PGJ2, 9(S)-HODE, and
13(S)-HODE.
PPAR regulation of PAI-1 expression presents intriguing
possibilities for insight into the known links between obesity and deep
venous thrombosis, insulin resistance, non–insulin-dependent diabetes
mellitus, myocardial infarction, and accelerated
atherosclerosis.2 PPAR has been
implicated in both mouse models and human forms of
obesity.24 Abundant laboratory and epidemiological evidence
suggests the dysregulation of various metabolic and
circulatory factors in obesity.2 PAI-1 is one such example.
PAI-1 levels correlate with serum triglycerides, increase
with obesity, and fall with weight reduction,2 findings
that may reflect high adipocyte PAI-1 message levels.40 In
fact, adipose tissue, in addition to ECs and hepatocytes,
may be an important source of PAI-1.13 Elevated PAI-1
levels may explain in part findings such as those from the Nurses'
Health Study, demonstrating obesity as an independent risk factor for
pulmonary embolism.41
Recent work reported a VLDL response element in the promotor
region of the PAI-1 gene, located at residues -672 to
-657.42 Of note, this site has some characteristics of a
PPAR binding site, although no data supporting an interaction with any
PPAR were reported. It remains unclear where in the PAI-1 promotor
PPAR is acting. PPAR-dependent regulation of PAI-1 in ECs
suggests the need for promoter studies in this cell type. It will also
be of interest to investigate PPAR regulation of PAI-1 in other
cells such as adipocytes.
The present data implicate PPAR as a novel regulator of
gene expression in vascular cells, suggesting that PPAR positively
controls gene expression of PAI-1 in ECs, thus potentially promoting
thrombosis. Of note, the PPAR ligands used here were
naturally-occurring activators. It remains unclear if the synthetic
thiazolidinediones such as troglitazone would have similar effects. In
fact, clinical studies suggest that troglitazone decreases serum PAI-1
levels in some groups of patients with insulin
resistance.43 This PPAR effect, like the induction of
foam cells, might promote atherogenesis; in contrast, inhibition of
macrophage activation and matrix metalloproteinase-9 activity
through PPAR might limit it. PPAR, as a highly regulated central
transcriptional pathway present in various cell types, might well
have varying effects on a complex pathological process like
atherosclerosis. The data presented here
suggest that PPAR, as a novel mediator in EC signaling, must be
considered in attempting to understand atherogenic mechanisms.
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Acknowledgments |
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This work was supported in part by grants from the Deutsche Forschungsgemeinschaft to Dr Nikolaus Marx (MA 2047/1-1) and from the National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, Md, to Dr Peter Libby (HL48743) and to Dr Jorge Plutzky (HL03107). We thank Curran Murphy, Eugenia Shvartz, and Dr Maria Muszynski (Brigham and Women's Hospital) for their skillful assistance, and Drs Mitch Lazar and Doug Vaughn for their help and insightful comments.
Received April 14, 1998; accepted August 5, 1998.
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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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M. Fu, J. Zhang, X. Zhu, D. E. Myles, T. M. Willson, X. Liu, and Y. E. Chen Peroxisome Proliferator-activated Receptor gamma Inhibits Transforming Growth Factor beta -induced Connective Tissue Growth Factor Expression in Human Aortic Smooth Muscle Cells by Interfering with Smad3 J. Biol. Chem., November 30, 2001; 276(49): 45888 - 45894. [Abstract] [Full Text] [PDF]
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 U. P. Kelavkar, J. B. Nixon, C. Cohen, D. Dillehay, T. E. Eling, and K. F. Badr Overexpression of 15-lipoxygenase-1 in PC-3 human prostate cancer cells increases tumorigenesis Carcinogenesis, November 1, 2001; 22(11): 1765 - 1773. [Abstract] [Full Text] [PDF]
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X. Xu, M. Otsuki, H. Saito, S. Sumitani, H. Yamamoto, N. Asanuma, H. Kouhara, and S. Kasayama PPAR{alpha} and GR Differentially Down-Regulate the Expression of Nuclear Factor-{kappa}B-Responsive Genes in Vascular Endothelial Cells Endocrinology, August 1, 2001; 142(8): 3332 - 3339. [Abstract] [Full Text] [PDF]
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P. Libby Current Concepts of the Pathogenesis of the Acute Coronary Syndromes Circulation, July 17, 2001; 104(3): 365 - 372. [Full Text] [PDF]
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A. Tedgui and Z. Mallat Anti-Inflammatory Mechanisms in the Vascular Wall Circ. Res., May 11, 2001; 88(9): 877 - 887. [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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M. Inoue, H. Itoh, T. Tanaka, T.-H. Chun, K. Doi, Y. Fukunaga, N. Sawada, J. Yamshita, K. Masatsugu, T. Saito, et al. Oxidized LDL Regulates Vascular Endothelial Growth Factor Expression in Human Macrophages and Endothelial Cells Through Activation of Peroxisome Proliferator-Activated Receptor-{{gamma}} Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 560 - 566. [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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W. A. Hsueh, S. Jackson, and R. E. Law Control of Vascular Cell Proliferation and Migration by PPAR-{gamma}: A new approach to the macrovascular complications of diabetes Diabetes Care, February 1, 2001; 24(2): 392 - 397. [Abstract] [Full Text]
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 A. A. Parulkar, M. L. Pendergrass, R. Granda-Ayala, T. R. Lee, and V. A. Fonseca Nonhypoglycemic Effects of Thiazolidinediones Ann Intern Med, January 2, 2001; 134(1): 61 - 71. [Abstract] [Full Text] [PDF]
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J. Padilla, K. Kaur, H. J. Cao, T. J. Smith, and R. P. Phipps Peroxisome Proliferator Activator Receptor-{gamma} Agonists and 15-Deoxy-{Delta}12,1412,14-PGJ2 Induce Apoptosis in Normal and Malignant B-Lineage Cells J. Immunol., December 15, 2000; 165(12): 6941 - 6948. [Abstract] [Full Text] [PDF]
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I. Brocheriou, D. Stengel, L. Mattsson-Hulten, J. Stankova, M. Rola-Pleszczynski, F. Koskas, O. Wiklund, Y. Le Charpentier, and E. Ninio Expression of Platelet-Activating Factor Receptor in Human Carotid Atherosclerotic Plaques : Relevance to Progression of Atherosclerosis Circulation, November 21, 2000; 102(21): 2569 - 2575. [Abstract] [Full Text] [PDF]
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 T. Murata, S. He, M. Hangai, T. Ishibashi, X.-P. Xi, S. Kim, W. A. Hsueh, S. J. Ryan, R. E. Law, and D. R. Hinton Peroxisome Proliferator-Activated Receptor-{gamma} Ligands Inhibit Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., July 1, 2000; 41(8): 2309 - 2317. [Abstract] [Full Text]
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N. Marx, F. Mach, A. Sauty, J. H. Leung, M. N. Sarafi, R. M. Ransohoff, P. Libby, J. Plutzky, and A. D. Luster Peroxisome Proliferator-Activated Receptor-{gamma} Activators Inhibit IFN-{gamma}-Induced Expression of the T Cell-Active CXC Chemokines IP-10, Mig, and I-TAC in Human Endothelial Cells J. Immunol., June 15, 2000; 164(12): 6503 - 6508. [Abstract] [Full Text] [PDF]
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G. Chinetti, F. G. Gbaguidi, S. Griglio, Z. Mallat, M. Antonucci, P. Poulain, J. Chapman, J.-C. Fruchart, A. Tedgui, J. Najib-Fruchart, et al. CLA-1/SR-BI Is Expressed in Atherosclerotic Lesion Macrophages and Regulated by Activators of Peroxisome Proliferator-Activated Receptors Circulation, May 23, 2000; 101(20): 2411 - 2417. [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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P. Delerive, F. Martin-Nizard, G. Chinetti, F. Trottein, J.-C. Fruchart, J. Najib, P. Duriez, and B. Staels Peroxisome Proliferator-Activated Receptor Activators Inhibit Thrombin-Induced Endothelin-1 Production in Human Vascular Endothelial Cells by Inhibiting the Activator Protein-1 Signaling Pathway Circ. Res., September 3, 1999; 85(5): 394 - 402. [Abstract] [Full Text] [PDF]
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N. Marx, G. K. Sukhova, T. Collins, P. Libby, and J. Plutzky PPAR{alpha} Activators Inhibit Cytokine-Induced Vascular Cell Adhesion Molecule-1 Expression in Human Endothelial Cells Circulation, June 22, 1999; 99(24): 3125 - 3131. [Abstract] [Full Text] [PDF]
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P. Delerive, P. Gervois, J.-C. Fruchart, and B. Staels Induction of Ikappa Balpha Expression as a Mechanism Contributing to the Anti-inflammatory Activities of Peroxisome Proliferator-activated Receptor-alpha Activators J. Biol. Chem., November 17, 2000; 275(47): 36703 - 36707. [Abstract] [Full Text] [PDF]
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M. Fu, X. Zhu, Q. Wang, J. Zhang, Q. Song, H. Zheng, W. Ogawa, J. Du, and Y. E. Chen Platelet-Derived Growth Factor Promotes the Expression of Peroxisome Proliferator-Activated Receptor {gamma} in Vascular Smooth Muscle Cells by a Phosphatidylinositol 3-Kinase/Akt Signaling Pathway Circ. Res., November 23, 2001; 89(11): 1058 - 1064. [Abstract] [Full Text] [PDF]
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N. Marx, B. Kehrle, K. Kohlhammer, M. Grub, W. Koenig, V. Hombach, P. Libby, and J. Plutzky PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes: Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis Circ. Res., April 5, 2002; 90(6): 703 - 710. [Abstract] [Full Text] [PDF]
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