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Short Communication |
(PPAR) Expression and Reduction of MMP-9 Activitythrough PPAR Activation in Mononuclear Phagocytes inVitro
From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(PPAR), a transcription
factor in the nuclear receptor superfamily, regulates gene
expression in response to various activators, including
15-deoxy-
12,14-prostaglandin J2 and
the antidiabetic agent troglitazone. The role of PPAR in human
atherosclerosis is unexplored. We report here that
monocytes/macrophages in human atherosclerotic lesions
(n = 12) express immunostainable PPAR. Normal
artery specimens (n = 6) reveal minimal
immunoreactive PPAR. Human monocytes and monocyte-derived
macrophages cultured for 6 days in 5% human serum expressed PPAR
mRNA and protein by reverse transcription-polymerase chain reaction and
Western blotting, respectively. In addition, PPAR
mRNA expression in U937 cells increased during phorbol 12-myristate 13
acetate-induced differentiation. Stimulation of PPAR with
troglitazone or 15-deoxy-12,14-prostaglandin
J2 in human monocyte-derived macrophages inhibited MMP-9
gelatinolytic activity in a concentration-dependent fashion as revealed
by zymography. This inhibition correlates with decreased MMP-9
secretion as determined by Western blotting. Thus, PPAR is
present in macrophages in human atherosclerotic lesions and may
regulate expression and activity of MMP-9, an enzyme implicated
in plaque rupture. PPAR is likely to be an important regulator of
monocyte/macrophage function with relevance for human atherosclerotic
disease.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,9
and CD40 ligand.10
Nonetheless, the
majority of atheroma are stable. This suggests that inhibitors of MMP-9
expression must be at work, opposing the effects of proinflammatory
mediators in the plaque.
We therefore undertook an effort to identify endogenous inhibitors of
MMP-9 expression. Work from other groups has established that
activation of various nuclear hormone receptors can inhibit MMP
expression through a variety of mechanisms.11
Interest is
growing regarding the role of peroxisomal proliferation activator
receptors (PPARs), a subgroup of the nuclear receptor superfamily, as
transcriptional mediators.12,13
One of these, PPAR, has
been implicated as a "master regulator" of lipid metabolism and
adipogenesis; ectopic overexpression of PPAR in fibroblasts
redirects these cells into an adipogenic program.14,15
Like
other nuclear receptors, PPAR contains a ligand binding domain and a
central DNA binding domain, which interacts with PPAR response elements
in the promoter of target genes.16
Specific activators
identified thus far include both the naturally occurring prostaglandin
D metabolite 15-deoxy-12,14-prostaglandin J2
(15 d-PGJ2)17-19
and the synthetic
antidiabetic agent troglitazone.20-22
The role of PPAR
in nonadipocytes has received little attention, although expression had
been previously noted in hematopoietic cell lines.23
Recent
work suggests PPAR stimulation can inhibit both cytokine-induced
activation of macrophages24
and in vitro
expression of transfected promoter constructs of genes implicated in
atherogenesis, including MMP-9.25
The present study tested the hypotheses 1) that macrophages in human
atheroma express PPAR, 2) that this novel nuclear receptor is
regulated during differentiation of monocytes into macrophages, and 3)
that PPAR activation can limit MMP-9 expression and enzymatic
activity by these cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Surgical specimens of human carotid atherosclerotic lesions were
obtained by protocols approved by the Human Investigation Review
Committee at Brigham and Women's Hospital. 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 antibody19
(a
generous gift from Dr. Mitchell Lazar, University of Pennsylvania
School of Medicine, Philadelphia). Macrophages were identified by
staining with anti-CD68 antibody (DAKO, Carpinteria, CA). 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 was derived and subsequently using these
"peptide-blocked PPAR antibodies" at concentrations similar to
those of experimental conditions. Finally, sections were incubated with
the respective biotinylated secondary antibody (Vector Laboratories,
Burlingame, CA) followed by avidin-biotin-peroxidase complex
(Vectastain ABC kit, Vector Laboratories). Antibody binding was
visualized with 3-amino-9-ethyl carbazole (Vector Laboratories) or with
True Blue Peroxidase substrate (Kirkegaard & Perry Laboratories,
Gaithersburg, MD). Sections were counterstained with Gill's
Hematoxylin or Contrast Red (Kirkegaard & Perry Laboratories).
Computer-assisted image analysis was used to quantify staining on
sections using Optimas 5.2 software. Percentage area of positive
staining for PPAR or CD68 in the shoulders of the plaques, defined
as the intimal regions flanking the lipid core, was compared with the
percentage area of positive staining in other zones of the sections.
Cell Culture
Human monocytes were isolated from peripheral blood of healthy
volunteers by sequential gradient centrifugation with Lymphocyte
Separation Medium (Organon Technika, Durham, NC) and One Step Monocytes
(Accurate Chemical and Scientific Co., Westbury, NY). Monocytes were
plated at a concentration of 3 x 109
cells/L in
serum-free M199 medium (BioWhittaker, Walkersville, MD) and isolated by
adherence to plastic dishes at 37°C. Nonadherent cells were washed
three times with Hanks' buffer (Life Technologies, Gaithersburg, MD),
and the remaining adherent cells were cultured in M199 medium with 5%
human serum at 37°C/5%CO2. Medium was changed every 2
days for 6 days, and resulting cells were used as "monocyte-derived
macrophages." In some experiments, monocytes were cultured for 6 days
with 5% human serum in the absence or presence of PPAR activators
troglitazone (provided by Parke Davis (Morris Plains, NJ) and dissolved
according to manufacturer's instructions) or 15 d-PGJ2
(CalbioChem, La Jolla, CA) at concentrations indicated. After 6 days,
cells were changed to serum-free conditions, and supernatants were
collected after 24 hours for further analysis. The human monocyte-like
cell line U937, obtained from American Type Culture Collection
(Manassas, VA), was cultured in RPMI 1640 medium (BioWhittaker) with
1% glutamine (Sigma Chemical Co., St. Louis, MO), 1%
penicillin-streptomycin (Sigma) and 10% fetal calf serum.
RNA Extraction and Reverse Transcription-Polymerase Chain Reaction
Total RNA from 107
cells was isolated by the
single-step guanidium thiocyanate-phenol-chloroform method using RNAzol
from Tel-Test (Friendswood, TX). Two micrograms of total RNA was
reverse-transcribed into cDNA with 1 U/ml reverse transcriptase
(Superscript, Life Technologies) at 37°C for 1 hour in standard
buffer. For the amplification of PPAR cDNA, two oligonucleotide
primers were designed from nucleotides +235 to 708 (a 473-bp fragment):
sense primer, 5'-TCTCTCCGTAATGGAAGACC-3'; anti-sense primer,
5'-CCCCTACAGAGTATTACG-3'. The polymerase chain reaction reaction was
carried out in a standard buffer (Life Technologies) with 200 ng of
each primer (IDT, Coralville, CA), 33 mmol/L MgCl2, and 0.5
U Taq polymerase (Life Technologies) for 30 cycles. Polymerase chain
reaction products (10 µl/25µl reaction) were analyzed on a 2%
agarose gel.
Northern Blot Analysis
Five micrograms of total RNA from undifferentiated and phorbol
12-myristate 13-acetate (PMA)-differentiated U937 cells was subjected
to electrophoresis on a 1.2% agarose gel and transferred using
traditional Northern blotting techniques. The membranes were
ultraviolet-crosslinked, prehybridized at 42°C (50% formamide, 5x
Denhardt's solution, 5x standard saline citrate, 0.5% sodium dodecyl
sulfate, and 20 mmol/L salmon sperm DNA), and hybridized in the same
buffer with a random primed radiolabeled ([-P32]dCTP)
Sal-1 fragment of pCMX-PPAR (generously provided by Dr. Bruce
Spiegelman, Dana-Farber Cancer Institute, Boston, MA).14
The membranes were washed at 60°C in 1% sodium dodecyl sulfate/2x
standard saline citrate and exposed (1–3 days, -70°C) to Kodak
X-OMAT film with an intensifying screen.
Preparation of Nuclear and Cytosolic Extracts and Western Blot Analysis
For Western blot analysis, a positive control was generated by
transiently transfecting a PPAR expression construct,
pCMX-PPAR,14
into human skin fibroblasts using
lipofectamine (Life Technologies) according to the manufacturer's
protocol. Nuclear and cytosolic extracts of 107
cells were
prepared separately. Cells were lysed in 10 mmol/L Hepes (pH 7.9), 1.5
mmol/L MgCl2, 10 mmol/L KCl, and 0.5% Nonidet P-40. Nuclei
were pelleted at 13,000 x g 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 ethylenediaminetetraacetate. After
centrifugation at 13,000 x g 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 ethylenediaminetetraacetate, and 20%
glycerol and used as nuclear extract. Protein concentration of nuclear
and cystolic extracts was determined using a protein assay (Pierce,
Rockford, IL). Processed samples were applied to 10% sodium dodecyl
sulfate-polyacrylamide gel electrophoresis gels, and protein was
transferred to nitrocellulose membranes (Millipore, Bedford, MA) using
semidry blotting for 1 hour, as described previously.10
Membranes were blocked overnight in Tris-buffered saline-Tween with 5%
dry milk and incubated with goat anti-human PPAR monoclonal
antibodies (N-20, Santa Cruz Biotechnology, San Diego, CA) for 1 hour.
After washing, membranes were stained with horseradish-conjugated
rabbit anti-goat monoclonal antibodies. Antigen detection was performed
with a chemiluminescent detection system (NEN, Boston, MA). Similar
methods were used to perform Western blots on MMP-9 in monocyte-derived
macrophage supernatants using a specific rabbit anti-human MMP-9
antibody (Oncogene Science, Cambridge, MA).
Substrate Gel Zymography
Gelatinolytic activity of MMP-9 from conditioned medium (10 µl/500 µl total supernatant loaded) of monocytes or monocyte-derived macrophages was analyzed by zymography on gelatin-containing polyacrylamide.10 Equal amounts were loaded in each lane. After washing in 2.5% Triton X-100, gels were incubated overnight at 37°C in 50 mmol/L Tris-HCl (pH 7.4) containing CaCl2 and 0.05% Brij 35. Gels were stained in 0.1% Colloidal Brilliant Blue (Sigma), 10% acetic acid, and 40% methanol for 2 hours and destained in 10% acetic acid and 40% methanol. Proteins having gelatinolytic activity were visualized as clear zones in an otherwise blue gel. Photographs of the gels were scanned by an imaging densitometer and quantified using the NIH Image 1.6 software program. To ensure that differences in protein amounts did not account for the differences seen, the zymographic data were normalized to the total amount of protein applied to each lane. Of note, the total amount of protein did not vary significantly from sample to sample.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Analysis of human carotid atheroma (n = 12)
demonstrated immunoreactive PPAR co-localizing with macrophages
(Figure 1, A and C)
, so identified by
morphology and by staining of parallel sections with the
macrophage-specific antibody anti-CD68 (data not shown). PPAR
staining was mainly localized in the macrophage-rich shoulder region of
the plaque (Figure 1A)
, with 35 ± 5% of this area positive for
PPAR and 54 ± 6% positive for macrophages, as determined by
color image analysis. Quantification of staining in nonshoulder regions
revealed a 2 ± 1% area positive for PPAR and 8 ± 1%
for macrophages. Preabsorption of anti-PPAR antibodies with the
peptide antigen abrogated staining in adjacent sections (Figure 1B)
,
indicating the specificity of the immunostaining. Higher-power views of
PPAR-stained plaque (indicated by the rectangle in Figure 1A
) showed
staining predominantly in nuclei of macrophages (Figure 1C)
. Only
occasional endothelial cells or smooth muscle cells in lesions showed
immunoreactive PPAR (data not shown). Study of nonatheromatous
arterial specimens (n = 6) showed scant PPAR
in nuclei of vascular smooth muscle cells (Figure 1D)
.
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mRNA and
Protein
Freshly prepared monocytes, monocyte-derived macrophages, and
PMA-treated U937 cells all contained PPAR mRNA as detected by a
473-bp reverse transcription-polymerase chain reaction product (Figure 2A
, upper panel). For the detection of
PPAR protein, we prepared separate nuclear and cytosolic fractions
of the above-mentioned cells, as well as untransfected and
PPAR-transfected fibroblasts, and performed Western blot analysis.
Nuclear extracts of monocytes, monocyte-derived macrophages, and
differentiated U937 cells (Figure 2A
, lower panel), but not cytosolic
fractions (data not shown), contained PPAR protein. The identity
of this band as PPAR was supported by its lack of cytosolic
expression, its expected apparent molecular weight (55 kd), and
co-migration with a signal in fibroblasts transfected with a PPAR
expression construct. Untransfected fibroblasts demonstrate no
cross-reacting band of the appropriate size (Figure 2A
, lower panel).
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Expression during PMA-Induced Differentiation
of U937 Cells
To investigate further the regulation of PPAR during
differentiation of cells of the monocytic lineage, U937 cells were
stimulated with PMA (10 µg/L) for 12 hours, and Northern blotting was
performed. This treatment increased PPAR mRNA expression (Figure 2B)
. Western blot analysis showed a parallel rise in protein levels in
nuclear fractions of PMA-treated U937 cells (data not shown). Neither
undifferentiated nor differentiated U937 cells demonstrate PPAR in
the cytosol (data not shown).
PPAR Activators Troglitazone and PGJ2 Decrease Both
Protein Levels and Gelatinolytic Activity of MMP-9 Secreted from
Monocyte-Derived Macrophages
To elucidate the functional relevance of PPAR activation, we
investigated the effect of the selective PPAR activators
troglitazone and 15 d-PGJ2 on MMP-9 activity in
monocyte-derived macrophages. Monocytes were cultured initially in
human serum and then transferred to serum-free medium in the absence or
presence of troglitazone or 15 d-PGJ2. Secreted MMP-9
gelatinolytic activity was then measured using substrate zymography. As
previously reported, culture of monocytes for 6 days with human serum
substantially increases gelatinolytic activity in the supernatant
compared with freshly prepared monocytes (Figure 3A)
. Concurrent treatment of monocytes
with troglitazone or 15 d-PGJ2 in serum-free medium during
this transition toward monocyte-derived macrophages inhibited the
increase in gelatinolytic activity in a concentration-dependent manner
(Figure 3A)
. Quantification of gelatinolytic areas by densitometry
revealed a reduction of MMP-9 activity after treatment with
troglitazone (1 µM and 5 µM) to 73.5 ± 1.9% and 53.3 ±
12.2% (P < 0.01), respectively, and with 15
d-PGJ2 (1 µM and 5 µM) to 79.0 ± 14.6% and
45.5 ± 8.9% (P < 0.01), respectively, in
both cases relative to control cells (n = 3).
Similar results were seen in U937 cells (data not shown). Treatment
with either troglitazone or 15 d-PGJ2 after 6 days of
culture in human serum had no effect (data not shown), suggesting that
PPAR activation was required during differentiation for inhibition
of MMP-9 levels/activity to occur. The identity of the observed
gelatinolytic area was confirmed by the mobility of the band and
co-migration with the known 92-kd gelatinolytic activity in PMA-treated
human fibroblast supernatants (Figure 3A)
. Treatment of
monocyte-derived macrophages with either PPAR activator, troglitazone
or 15 d-PGJ2, reduces supernatant MMP-9 protein levels from
monocyte-derived macrophages (Figure 3B)
. Co-migration with the
known MMP-9 band of supernatants from PMA-stimulated vascular smooth
muscle cells confirms identity of the detected band (Figure 3B)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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expression in macrophages in human
atherosclerotic lesions. Furthermore, we find differentiation-dependent
regulation of PPAR expression in cells of the monocyte/macrophage
lineage in vitro. Treatment of differentiated
monocyte-derived macrophages in vitro with two different
PPAR activators, 15 d-PGJ2 or troglitazone, decreased
both MMP-9 protein levels and MMP-9 gelatinolytic activity in a
concentration-dependent manner. Coronary atherosclerosis is typically a diffuse process.26 Nevertheless, despite systemic risk factors, such as low-density lipoprotein levels, and the presence of macrophages and inflammatory cytokines in most plaques, some arterial plaques rupture, whereas others do not. The factors accounting for this variability are unclear. Certainly, monocytes/macrophages are intimately involved in plaque rupture.2,27 As monocytes differentiate in the subintima into macrophages and foam cells, the atherogenic microenvironment influences transcriptional regulation of genes, the products of which will determine the natural history of the lesion.1 MMPs furnish one example of proteins, the induction and expression of which by monocytes/macrophages likely contributes to subsequent plaque rupture.2 Several lines of evidence indicate that lesional macrophages synthesize MMPs de novo.28,29. These proteins are enzymatically active, as shown by zymographic analysis of human arterial specimens.30 Secretion of these MMPs, with MMP-9 prominent among them, favors destabilization of the plaque's fibrous cap.1
Our findings suggest that PPAR, as a nuclear transcription factor
present in lesional macrophages, may inhibit MMP expression and
activity. Furthermore, PPAR may control expression of other target
genes within the arterial wall, thus modulating a cascade of responses
in monocytes/macrophages after activation by its endogenous or
synthetic ligand(s).
15 d-PGJ2, a naturally occurring ligand for PPAR, likely
interacts with monocytes/macrophages. J2 prostanoids, and
the immediate upstream precursors of 15 d-PGJ2, are found
in vivo.31
Prostaglandins themselves are
synthesized from fatty acids, with arachadonic acid as the primary
source. 15 d-PGD2, the major prostaglandin in most tissues,
is converted to 15 d-PGJ2.32
This process
requires 15 d-PGD2 synthetase, an enzyme produced primarily
by macrophages and other antigen-presenting cells.33
Thus,
15 d-PGJ2, acting through PPAR, may be an important
regulator of macrophage function. Troglitazone, a synthetic PPAR
activator, is currently in clinical use as an antidiabetic
agent.34,36
The implications of its effects on inhibiting
macrophage MMP-9 matrix degradation merit further consideration in a
clinical context.
A very recent report showed that the PPAR activator 15
d-PGJ2 inhibits expression of an MMP-9 promoter luciferase
construct when transfected into U937 cells.25
Our findings
support a critical role for PPAR in atherosclerosis, demonstrating
its presence in monocytes/macrophages of human atheroma and increased
expression during differentiation in vitro. Furthermore, the
present study of MMP-9 gelatinolytic activity illustrates directly the
functional relevance of PPAR in these cells. These results establish
a rationale for further study of PPAR in monocyte/macrophage
biology, particularly in the context of atherosclerosis.
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Acknowledgements |
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Footnotes |
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Supported by Deutsche Forschungsgemeinschaft Grant MA 2047/1-1 (to NM) and National Institutes of Health Grants HL 03107 and P50HL56985 (to JP), and P50HL56985 and R37HL34636 (to PL).
Accepted for publication April 2, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1ß selectively induce expression of 92-kd gelatinase by human macrophages. J Immunol 1996, 157:4159-4165[Abstract]
2, a lipid-activated transcription factor. Cell 1994, 79:1147-1156[Medline]
. Cell 1995, 83:803-812[Medline]
and promotes adipocyte differentiation. Cell 1995, 83:813-819[Medline]
. J Biol Chem 1995, 270:12953-12956 agonism and the antihyperglycemic activity of thiazolidinediones. J Med Chem 1996, 39:665-668[Medline]
and . Proc Natl Acad Sci USA 1997, 94:4318-4323 cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expression 1995, 4:281-299[Medline]
agonists inhibit production of monocyte inflammatory cytokines. Nature 1998, 391:82-86[Medline]
is a negative regulator of macrophage activation. Nature 1998, 391:79-82[Medline]
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N. Hennuyer, A. Tailleux, G. Torpier, H. Mezdour, J.-C. Fruchart, B. Staels, and C. Fievet PPAR{alpha}, but not PPAR{gamma}, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1897 - 1902. [Abstract] [Full Text] [PDF]
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 A. Pfutzner, N. Marx, G. Lubben, M. Langenfeld, D. Walcher, T. Konrad, and T. Forst Improvement of Cardiovascular Risk Markers by Pioglitazone Is Independent From Glycemic Control: Results From the Pioneer Study J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1925 - 1931. [Abstract] [Full Text] [PDF]
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S Soumian, C Albrecht, A. Davies, and R. Gibbs ABCA1 and atherosclerosis Vascular Medicine, May 1, 2005; 10(2): 109 - 119. [Abstract] [PDF]
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 N. P. Kadoglou, S. S. Daskalopoulou, D. Perrea, and C. D. Liapis Matrix Metalloproteinases and Diabetic Vascular Complications Angiology, March 1, 2005; 56(2): 173 - 189. [Abstract] [PDF]
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 M. Abdelrahman, A. Sivarajah, and C. Thiemermann Beneficial effects of PPAR-{gamma} ligands in ischemia-reperfusion injury, inflammation and shock Cardiovasc Res, March 1, 2005; 65(4): 772 - 781. [Abstract] [Full Text] [PDF]
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C. J. Scotton, F. O. Martinez, M. J. Smelt, M. Sironi, M. Locati, A. Mantovani, and S. Sozzani Transcriptional Profiling Reveals Complex Regulation of the Monocyte IL-1{beta} System by IL-13 J. Immunol., January 15, 2005; 174(2): 834 - 845. [Abstract] [Full Text] [PDF]
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 S. C. Tyagi, W. Rodriguez, A. M. Patel, A. M. Roberts, J. C. Falcone, J. C. Passmore, J. T. Fleming, and I. G. Joshua Hyperhomocysteinemic Diabetic Cardiomyopathy: Oxidative Stress, Remodeling, and Endothelial-Myocyte Uncoupling Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2005; 10(1): 1 - 10. [Abstract] [PDF]
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 A. C. Newby Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture Physiol Rev, January 1, 2005; 85(1): 1 - 31. [Abstract] [Full Text] [PDF]
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S. Giri, R. Rattan, A. K. Singh, and I. Singh The 15-Deoxy-{delta}12,14-Prostaglandin J2 Inhibits the Inflammatory Response in Primary Rat Astrocytes via Down-Regulating Multiple Steps in Phosphatidylinositol 3-Kinase-Akt-NF-{kappa}B-p300 Pathway Independent of Peroxisome Proliferator-Activated Receptor {gamma} J. Immunol., October 15, 2004; 173(8): 5196 - 5208. [Abstract] [Full Text] [PDF]
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D. Walcher and N. Marx Insulin resistance and cardiovascular disease: the role of PPAR{gamma} activators beyond their anti-diabetic action Diabetes and Vascular Disease Research, October 1, 2004; 1(2): 76 - 81. [Abstract] [PDF]
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 X. Wang, J. Liang, T. Koike, H. Sun, T. Ichikawa, S. Kitajima, M. Morimoto, H. Shikama, T. Watanabe, Y. Sasaguri, et al. Overexpression of Human Matrix Metalloproteinase-12 Enhances the Development of Inflammatory Arthritis in Transgenic Rabbits Am. J. Pathol., October 1, 2004; 165(4): 1375 - 1383. [Abstract] [Full Text] [PDF]
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M. Francois, P. Richette, L. Tsagris, M. Raymondjean, M.-C. Fulchignoni-Lataud, C. Forest, J.-F. Savouret, and M.-T. Corvol Peroxisome Proliferator-activated Receptor-{gamma} Down-regulates Chondrocyte Matrix Metalloproteinase-1 via a Novel Composite Element J. Biol. Chem., July 2, 2004; 279(27): 28411 - 28418. [Abstract] [Full Text] [PDF]
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 M.A. Birrell, H.J. Patel, K. McCluskie, S. Wong, T. Leonard, M.H. Yacoub, and M.G. Belvisi PPAR-{gamma} agonists as therapy for diseases involving airway neutrophilia Eur. Respir. J., July 1, 2004; 24(1): 18 - 23. [Abstract] [Full Text] [PDF]
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 G. Reiterer, M. Toborek, and B. Hennig Peroxisome Proliferator Activated Receptors {alpha} and {gamma} Require Zinc for Their Anti-inflammatory Properties in Porcine Vascular Endothelial Cells J. Nutr., July 1, 2004; 134(7): 1711 - 1715. [Abstract] [Full Text]
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K. S. Meir and E. Leitersdorf Atherosclerosis in the Apolipoprotein E-Deficient Mouse: A Decade of Progress Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1006 - 1014. [Abstract] [Full Text] [PDF]
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N. Marx, H. Duez, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-Activated Receptors and Atherogenesis: Regulators of Gene Expression in Vascular Cells Circ. Res., May 14, 2004; 94(9): 1168 - 1178. [Abstract] [Full Text] [PDF]
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A. P. Kumar, F. J. Piedrafita, and W. F. Reynolds Peroxisome Proliferator-activated Receptor {gamma} Ligands Regulate Myeloperoxidase Expression in Macrophages by an Estrogen-dependent Mechanism Involving the -463GA Promoter Polymorphism J. Biol. Chem., February 27, 2004; 279(9): 8300 - 8315. [Abstract] [Full Text] [PDF]
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R. Corti, J. I. Osende, J. T. Fallon, V. Fuster, G. Mizsei, H. Jneid, S. D. Wright, W. F. Chaplin, and J. J. Badimon The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis: in vivo study by high-resolution magnetic resonance imaging J. Am. Coll. Cardiol., February 4, 2004; 43(3): 464 - 473. [Abstract] [Full Text] [PDF]
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W. A. Hsueh and D. Bruemmer Peroxisome Proliferator-Activated Receptor {gamma}: Implications for Cardiovascular Disease Hypertension, February 1, 2004; 43(2): 297 - 305. [Abstract] [Full Text] [PDF]
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H. Hammad, H. J. de Heer, T. Soullie, V. Angeli, F. Trottein, H. C. Hoogsteden, and B. N. Lambrecht Activation of Peroxisome Proliferator-Activated Receptor-{gamma} in Dendritic Cells Inhibits the Development of Eosinophilic Airway Inflammation in a Mouse Model of Asthma Am. J. Pathol., January 1, 2004; 164(1): 263 - 271. [Abstract] [Full Text] [PDF]
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H. Du, S. Schiavi, N. Wan, M. Levine, D. P. Witte, and G. A. Grabowski Reduction of Atherosclerotic Plaques by Lysosomal Acid Lipase Supplementation Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 147 - 154. [Abstract] [Full Text] [PDF]
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J. R. Worley, M. D. Baugh, D. A. Hughes, D. R. Edwards, A. Hogan, M. J. Sampson, and J. Gavrilovic Metalloproteinase Expression in PMA-stimulated THP-1 Cells: EFFECTS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-{gamma} (PPAR{gamma}) AGONISTS AND 9-CIS-RETINOIC ACID J. Biol. Chem., December 19, 2003; 278(51): 51340 - 51346. [Abstract] [Full Text] [PDF]
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J. S. Sidhu, D. Cowan, and J.-C. Kaski The effects of rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1757 - 1763. [Abstract] [Full Text] [PDF]
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B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF]
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T. F. Luscher, M. A. Creager, J. A. Beckman, and F. Cosentino Diabetes and Vascular Disease: Pathophysiology, Clinical Consequences, and Medical Therapy: Part II Circulation, September 30, 2003; 108(13): 1655 - 1661. [Full Text] [PDF]
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 M Hetzel, D Walcher, M Grub, H Bach, V Hombach, and N Marx Inhibition of MMP-9 expression by PPAR{gamma} activators in human bronchial epithelial cells Thorax, September 1, 2003; 58(9): 778 - 783. [Abstract] [Full Text] [PDF]
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 F. Liang, F. Wang, S. Zhang, and D. G. Gardner Peroxisome Proliferator Activated Receptor (PPAR){alpha} Agonists Inhibit Hypertrophy of Neonatal Rat Cardiac Myocytes Endocrinology, September 1, 2003; 144(9): 4187 - 4194. [Abstract] [Full Text] [PDF]
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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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N. Varo, D. Vicent, P. Libby, R. Nuzzo, A. L. Calle-Pascual, M. R. Bernal, A. Fernandez-Cruz, A. Veves, P. Jarolim, J. J. Varo, et al. Elevated Plasma Levels of the Atherogenic Mediator Soluble CD40 Ligand in Diabetic Patients: A Novel Target of Thiazolidinediones Circulation, June 3, 2003; 107(21): 2664 - 2669. [Abstract] [Full Text] [PDF]
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 M. Gurnell, D. B. Savage, V. K. K. Chatterjee, and S. O'Rahilly The Metabolic Syndrome: Peroxisome Proliferator-Activated Receptor {gamma} and Its Therapeutic Modulation J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2412 - 2421. [Abstract] [Full Text] [PDF]
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 G. Haraguchi, Y. Kobayashi, M. L. Brown, A. Tanaka, M. Isobe, S. H. Gianturco, and W. A. Bradley PPAR{alpha} and PPAR{gamma} activators suppress the monocyte-macrophage apoB-48 receptor J. Lipid Res., June 1, 2003; 44(6): 1224 - 1231. [Abstract] [Full Text] [PDF]
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V. Angeli, H. Hammad, B. Staels, M. Capron, B. N. Lambrecht, and F. Trottein Peroxisome Proliferator-Activated Receptor {gamma} Inhibits the Migration of Dendritic Cells: Consequences for the Immune Response J. Immunol., May 15, 2003; 170(10): 5295 - 5301. [Abstract] [Full Text] [PDF]
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 V. R. Aroda and R. R. Henry Thiazolidinediones: Potential Link Between Insulin Resistance and Cardiovascular Disease Diabetes Spectr, April 1, 2003; 16(2): 120 - 125. [Abstract] [Full Text] [PDF]
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 F. Zangeneh, Y. C. Kudva, and A. Basu Insulin Sensitizers Mayo Clin. Proc., April 1, 2003; 78(4): 471 - 479. [Abstract] [PDF]
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C.A. Argmann, C.G. Sawyez, C.J. McNeil, R.A. Hegele, and M.W. Huff Activation of Peroxisome Proliferator-Activated Receptor Gamma and Retinoid X Receptor Results in Net Depletion of Cellular Cholesteryl Esters in Macrophages Exposed to Oxidized Lipoproteins Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 475 - 482. [Abstract] [Full Text] [PDF]
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N. Marx, J. Froehlich, L. Siam, J. Ittner, G. Wierse, A. Schmidt, H. Scharnagl, V. Hombach, and W. Koenig Antidiabetic PPAR{gamma}-Activator Rosiglitazone Reduces MMP-9 Serum Levels in Type 2 Diabetic Patients With Coronary Artery Disease Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 283 - 288. [Abstract] [Full Text] [PDF]
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 H. S. Sood, M. J. Hunt, and S. C. Tyagi Peroxisome proliferator ameliorates endothelial dysfunction in a murine model of hyperhomocysteinemia Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L333 - L341. [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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 C. Kluft, R. Kleemann, and M.P.M. de Maat How best to counteract the enemies? By controlling inflammation in the coronary circulation Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G53 - G65. [Abstract] [PDF]
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 M. J. Hunt and S. C. Tyagi Peroxisome proliferators compete and ameliorate Hcy-mediated endocardial endothelial cell activation Am J Physiol Cell Physiol, October 1, 2002; 283(4): C1073 - C1079. [Abstract] [Full Text] [PDF]
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Y. Takata, Y. Kitami, Z.-H. Yang, M. Nakamura, T. Okura, and K. Hiwada Vascular Inflammation Is Negatively Autoregulated by Interaction Between CCAAT/Enhancer-Binding Protein-{delta} and Peroxisome Proliferator-Activated Receptor-{gamma} Circ. Res., September 6, 2002; 91(5): 427 - 433. [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. S. Elangbam, T. A. Brodie, H. Roger Brown, J. B. Nold, T. J. Raczniak, R. D. Tyler, R. M. Lightfoot, and H. G. Wall Vascular Effects of GI262570X (PPAR-{gamma} agonist) in the Brown Adipose Tissue of Han Wistar Rats: A Review of 1-month, 13-week, 27-week and 2-year Oral Toxicity Studies Toxicol Pathol, June 1, 2002; 30(4): 420 - 426. [Abstract] [PDF]
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F. Bureau, C. Desmet, D. Melotte, F. Jaspar, C. Volanti, A. Vanderplasschen, P.-P. Pastoret, J. Piette, and P. Lekeux A Proinflammatory Role for the Cyclopentenone Prostaglandins at Low Micromolar Concentrations: Oxidative Stress-Induced Extracellular Signal-Regulated Kinase Activation Without NF-{kappa}B Inhibition J. Immunol., May 15, 2002; 168(10): 5318 - 5325. [Abstract] [Full Text] [PDF]
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Q. N. Diep, M. El Mabrouk, J. S. Cohn, D. Endemann, F. Amiri, A. Virdis, M. F. Neves, and E. L. Schiffrin Structure, Endothelial Function, Cell Growth, and Inflammation in Blood Vessels of Angiotensin II-Infused Rats: Role of Peroxisome Proliferator-Activated Receptor-{gamma} Circulation, May 14, 2002; 105(19): 2296 - 2302. [Abstract] [Full Text] [PDF]
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 S. Cuzzocrea, N. S. Wayman, E. Mazzon, L. Dugo, R. Di Paola, I. Serraino, D. Britti, P. K. Chatterjee, A. P. Caputi, and C. Thiemermann The Cyclopentenone Prostaglandin 15-Deoxy-Delta 12,14-Prostaglandin J2 Attenuates the Development of Acute and Chronic Inflammation Mol. Pharmacol., May 1, 2002; 61(5): 997 - 1007. [Abstract] [Full Text] [PDF]
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O. Barbier, I. P. Torra, Y. Duguay, C. Blanquart, J.-C. Fruchart, C. Glineur, and B. Staels Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors in Lipid Metabolism and Atherosclerosis Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 717 - 726. [Abstract] [Full Text] [PDF]
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 C. M. Komar and T. E. Curry Jr Localization and Expression of Messenger RNAs for the Peroxisome Proliferator-Activated Receptors in Ovarian Tissue from Naturally Cycling and Pseudopregnant Rats Biol Reprod, May 1, 2002; 66(5): 1531 - 1539. [Abstract] [Full Text]
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 T. E. Akiyama, S. Sakai, G. Lambert, C. J. Nicol, K. Matsusue, S. Pimprale, Y.-H. Lee, M. Ricote, C. K. Glass, H. B. Brewer Jr., et al. Conditional Disruption of the Peroxisome Proliferator-Activated Receptor {gamma} Gene in Mice Results in Lowered Expression of ABCA1, ABCG1, and apoE in Macrophages and Reduced Cholesterol Efflux Mol. Cell. Biol., April 15, 2002; 22(8): 2607 - 2619. [Abstract] [Full Text] [PDF]
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A. V. Pontsler, A. St. Hilaire, G. K. Marathe, G. A. Zimmerman, and T. M. McIntyre Cyclooxygenase-2 Is Induced in Monocytes by Peroxisome Proliferator Activated Receptor gamma and Oxidized Alkyl Phospholipids from Oxidized Low Density Lipoprotein J. Biol. Chem., April 5, 2002; 277(15): 13029 - 13036. [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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R. L. Schild, W. T. Schaiff, M. G. Carlson, E. J. Cronbach, D. M. Nelson, and Y. Sadovsky The Activity of PPAR{gamma} in Primary Human Trophoblasts Is Enhanced by Oxidized Lipids J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1105 - 1110. [Abstract] [Full Text] [PDF]
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Y. Oyama, N. Akuzawa, R. Nagai, and M. Kurabayashi PPAR{gamma} Ligand Inhibits Osteopontin Gene Expression Through Interference With Binding of Nuclear Factors to A/T-Rich Sequence in THP-1 Cells Circ. Res., February 22, 2002; 90(3): 348 - 355. [Abstract] [Full Text] [PDF]
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B. R. Kwak, S. Myit, F. Mulhaupt, N. Veillard, N. Rufer, E. Roosnek, and F. Mach PPAR{gamma} but not PPAR{alpha} Ligands Are Potent Repressors of Major Histocompatibility Complex Class II Induction in Atheroma-Associated Cells Circ. Res., February 22, 2002; 90(3): 356 - 362. [Abstract] [Full Text] [PDF]
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 D J Grainger and H W L Bethell High titres of serum antinuclear antibodies, mostly directed against nucleolar antigens, are associated with the presence of coronary atherosclerosis Ann Rheum Dis, February 1, 2002; 61(2): 110 - 114. [Abstract] [Full Text] [PDF]
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W. A. Hsueh and R. E. Law PPAR{gamma} and Atherosclerosis: Effects on Cell Growth and Movement Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1891 - 1895. [Abstract] [Full Text] [PDF]
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C. M. Komar, O. Braissant, W. Wahli, and T. E. Curry Jr. Expression and Localization of PPARs in the Rat Ovary During Follicular Development and the Periovulatory Period Endocrinology, November 1, 2001; 142(11): 4831 - 4838. [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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 J S Sidhu and J C Kaski Peroxisome proliferator activated receptor {gamma}: a potential therapeutic target in the management of ischaemic heart disease Heart, September 1, 2001; 86(3): 255 - 258. [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. Aljada, H. Ghanim, J. Friedman, R. Garg, P. Mohanty, and P. Dandona Troglitazone Reduces the Expression of PPAR{{gamma}} While Stimulating That of PPAR{{alpha}} in Mononuclear Cells in Obese Subjects J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3130 - 3133. [Abstract] [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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H. Ghanim, R. Garg, A. Aljada, P. Mohanty, Y. Kumbkarni, E. Assian, W. Hamouda, and P. Dandona Suppression of Nuclear Factor-{{kappa}}B and Stimulation of Inhibitor {{kappa}}B by Troglitazone: Evidence for an Anti-inflammatory Effect and a Potential Antiatherosclerotic Effect in the Obese J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1306 - 1312. [Abstract] [Full Text]
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 T. Claudel, M. D. Leibowitz, C. Fievet, A. Tailleux, B. Wagner, J. J. Repa, G. Torpier, J.-M. Lobaccaro, J. R. Paterniti, D. J. Mangelsdorf, et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor PNAS, February 15, 2001; (2001) 41609298. [Abstract] [Full Text]
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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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N. Marx, N. Mackman, U. Schonbeck, N. Yilmaz, V. Hombach, P. Libby, and J. Plutzky PPAR{{alpha}} Activators Inhibit Tissue Factor Expression and Activity in Human Monocytes Circulation, January 16, 2001; 103(2): 213 - 219. [Abstract] [Full Text] [PDF]
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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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U. Ikeda, M. Shimpo, Y. Murakami, and K. Shimada Peroxisome Proliferator-Activated Receptor-{gamma} Ligands Inhibit Nitric Oxide Synthesis in Vascular Smooth Muscle Cells Hypertension, June 1, 2000; 35(6): 1232 - 1236. [Abstract] [Full Text] [PDF]
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R. E. Law, S. Goetze, X.-P. Xi, S. Jackson, Y. Kawano, L. Demer, M. C. Fishbein, W. P. Meehan, and W. A. Hsueh Expression and Function of PPAR{gamma} in Rat and Human Vascular Smooth Muscle Cells Circulation, March 21, 2000; 101(11): 1311 - 1318. [Abstract] [Full Text] [PDF]
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A. Castrillo, M. J. M. Diaz-Guerra, S. Hortelano, P. Martin-Sanz, and L. Bosca Inhibition of Ikappa B Kinase and Ikappa B Phosphorylation by 15-Deoxy-Delta 12,14-Prostaglandin J2 in Activated Murine Macrophages Mol. Cell. Biol., March 1, 2000; 20(5): 1692 - 1698. [Abstract] [Full Text] [PDF]
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R. Thieringer, J. E. Fenyk-Melody, C. B. Le Grand, B. A. Shelton, P. A. Detmers, E. P. Somers, L. Carbin, D. E. Moller, S. D. Wright, and J. Berger Activation of Peroxisome Proliferator-Activated Receptor {gamma} Does Not Inhibit IL-6 or TNF-{alpha} Responses of Macrophages to Lipopolysaccharide In Vitro or In Vivo J. Immunol., January 15, 2000; 164(2): 1046 - 1054. [Abstract] [Full Text] [PDF]
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