(Circulation. 2000;101:1311.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Expression and Function of PPAR
in Rat and Human Vascular Smooth Muscle Cells
From the Department of Medicine (R.E.L., S.G., X.-P.X., S.J., Y.K., L.D., W.P.M., W.A.H.); the Division of Endocrinology, Diabetes, and Hypertension (R.E.L., S.G., X.-P.X., Y.K., W.P.M., W.A.H.); the Division of Cardiology (S.J., L.D.); and the Department of Pathology and Laboratory Medicine (M.C.F.), University of California at Los Angeles School of Medicine.
Correspondence to Ronald E. Law, PhD, UCLA, Warren Hall, Second Floor, Suite 24-130, 900 Veteran Ave, Los Angeles, CA 90095.
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Abstract |
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Background—Peroxisome proliferator–activated receptor-
(PPAR) is
activated by fatty acids, eicosanoids, and insulin-sensitizing
thiazolidinediones (TZDs). The TZD troglitazone (TRO) inhibits vascular
smooth muscle cell (VSMC) proliferation and migration in vitro and in
postinjury intimal hyperplasia.
Methods and Results—Rat and human VSMCs express mRNA and nuclear
receptors for PPAR1. Three PPAR ligands, the TZDs TRO and
rosiglitazone and the prostanoid
15-deoxy-
12,14-prostaglandin J2 (15d-PGJ2),
all inhibited VSMC proliferation and migration. PPAR is upregulated
in rat neointima at 7 days and 14 days after balloon injury
and is also present in early human atheroma and
precursor lesions.
Conclusions—Pharmacological activation of PPAR expressed in
VSMCs inhibits their proliferation and migration, potentially limiting
restenosis and atherosclerosis. These receptors
are upregulated during vascular injury.
Key Words: atherosclerosis • restenosis • growth substances • migration • thiazolidinediones
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Introduction |
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TopAbstractIntroductionResultsDiscussionMethodsReferences |
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Peroxisome proliferator–activated receptor-
(PPAR) is a member of the nuclear receptor superfamily of
ligand-activated transcription factors. PPAR expression is
abundant in adipose tissue, where it promotes adipocyte differentiation
and regulates expression of genes involved in fatty acid
metabolism.1 Various fatty acids and
eicosanoids are likely physiological ligands for
PPAR.2 3 4 Thiazolidinediones (TZDs) are oral
antidiabetic compounds that enhance sensitivity to the
metabolic effects of insulin and that bind with high
affinity to PPAR.5 In humans and animals with insulin
resistance and type 2 diabetes, TZDs ameliorate hyperglycemia,
hyperinsulinemia, and
hypertriglyceridemia.6 7 8
We previously reported that troglitazone (TRO) suppressed
neointima formation in rat aorta after
endothelial injury, most likely as a result of direct
vascular action to inhibit vascular smooth muscle cell (VSMC) growth
and migration.9 However, our initial studies did not
address whether the vascular effects of TRO were mediated through
PPAR, which at that time was thought to be highly restricted to
adipose tissue. Recent studies have identified PPAR in a variety of
nonadipose tissues: skeletal muscle,10 11
heart,11 kidney proximal tubules,12
colon,13 bone marrow stromal cells,14
neutrophils,14 macrophages,15 16 17 18 19 20 and
breast carcinoma,21 which implicates novel functions for
this receptor distinct from its well-characterized
metabolic activity. TRO, however, is distinguishable from
other TZD PPAR ligands because it also contains a vitamin E moiety,
which is also known to inhibit VSMC growth and intimal
hyperplasia.22 The vascular effects of TRO, therefore,
could be independent of PPAR.
The expression and function of PPAR in VSMCs is somewhat
controversial. In human VSMCs, Staels et al23 observed
faint expression of PPAR that was not involved in the negative
regulation of cytokine-induced interleukin-6 and
cyclooxygenase-2 expression, this effect being
mediated by PPAR
. In contrast, a recent study reported that human
VSMCs express PPAR, which inhibited matrix metalloproteinase
expression and cell migration.24 Therefore, we examined
the expression and function of PPAR in rat and human VSMCs, focusing
on VSMC growth and migration.
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Results |
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PPAR
Ligands Inhibit bFGF-Induced DNA Synthesis in Rat and
Human VSMCsThe TZD PPAR
ligands TRO and RSG, and
15-deoxy-12,14-prostaglandin J2
(15d-PGJ2), a non-TZD PPAR ligand, all inhibited basic fibroblast
growth factor (bFGF)-induced DNA synthesis in rat VSMCs (Figure 1
< pick;3702f1;0;;;ZPICKFOOT;F1>). At concentrations of 5
µmol/L, rosiglitazone (RSG) and TRO inhibited DNA synthesis by
65% and 58%, respectively. 15d-PGJ2 was a far more potent
inhibitor of VSMC DNA synthesis, reducing
[3H]thymidine incorporation by 64.2±7% and
95±3.4% at 0.1 and 1 µmol/L, respectively.
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In human coronary artery VSMCs (CASMCs), all tested PPAR
ligands inhibited bFGF-stimulated DNA synthesis (Figure 2). RSG and 15d-PGJ2 were more potent
than TRO. Even at 0.1 µmol/L, RSG and 15d-PGJ2 caused a
statistically significant inhibition of CASMC proliferation
(25.5±5.5% and 42.8±5.8%, respectively). Inhibition of 
50% was
observed at concentrations >0.5 µmol/L for 15d-PGJ2 or >1
µmol/L for RSG. TRO exhibited weaker antiproliferative activity with
a maximum effect of 45.5±4.7% inhibition observed at 10
µmol/L.
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TRO and RSG had no effect on VSMC viability at 10 µmol/L, but 5 µmol/L 15d-PGJ2 for 48 hours induced significant cell death.
PPAR Ligands Inhibit PDGF-Directed Migration in Rat and
Human VSMCs
Platelet-derived growth factor (PDGF) is one of the most
potent in vitro chemoattractants for VSMCs. TRO, RSG, and 15d-PGJ2 all
blocked PDGF-directed VSMC migration (Figure 3). PDGF induced a 5.6-fold increase in
the number of rat VSMCs that migrated through the gelatin-coated
membrane. TRO and RSG inhibited PDGF-directed migration in a
dose-dependent manner at concentrations of 0.1 to 10
µmol/L. A modest but statistically significant effect was observed at
0.1 µmol/L: At 1 µmol/L for RSG and at 5
µmol/L for TRO, migration was inhibited by >50%. At 10
µmol/L, RSG totally abolished PDGF-directed migration.
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In contrast to its strong antiproliferative activity, 15d-PGJ2 was only
a slightly more potent inhibitor of PDGF-directed migration
than TRO or RSG. The concentrations of TRO, RSG, and 15d-PGJ2 required
to inhibit PDGF-directed migration by 50% were 2.4 µmol/L,
0.3 µmol/L, and 0.2 µmol/L, respectively. TRO, RSG, and
15d-PGJ2 also inhibited PDGF-directed migration of human CASMCs with
very similar dose-response curves (Figure 4).
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Rat and Human VSMCs Express PPAR mRNA
The PPAR gene produces 2 major mRNA species through alternative
promoter usage.11 Adipose tissues express both isoforms,
but PPAR1 expression is much higher than PPAR2 in nonadipose
tissues.10 11 Using a sensitive RNase protection assay
(RPA) (Figure 5), we observed only faint
expression of PPAR1 mRNA in mouse 3T3-L1 preadipocyte cells,
whereas significant upregulation of both PPAR1 and -2 mRNAs
occurred during their in vitro differentiation to
adipocytes.3 VSMCs from rat aorta and human VSMCs from
umbilical artery, coronary artery, and aorta expressed PPAR1
mRNA exclusively, as evidenced by the single protected band of 258
(human) or 185 (rat) bases. Although rat aortic tissue contained
PPAR1 and -2, the presence of PPAR2 mRNA in aorta and its
absence in cultured VSMCs are most likely due to contaminating
adventitial fat. Human umbilical vein endothelial cells
also prominently expressed PPAR1 but not -2 mRNA.
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Expression and Subcellular Localization of PPAR in Rat and
Human VSMCs
To detect PPAR protein in VSMCs, we performed Western
immunoblotting using a murine monoclonal antibody to
human recombinant PPAR (Glaxo Wellcome) previously shown to
recognize 2 bands of 56 and 52 kDa, corresponding to PPAR2 and
-1, respectively, in 3T3-L1 adipocyte nuclear extracts (Figure 6).25 Receptor levels were
low in nuclear extracts of undifferentiated 3T3-L1 preadipocytes.
Cultured aortic and human coronary artery VSMCs expressed only
PPAR1, which was present almost exclusively in the nuclear
fraction (Figure 6). Nuclear extracts from rat and human VSMCs
contain a protein with a molecular weight greater than that of PPAR2
that is probably not PPAR2, because these cells do not express
detectable mRNA for this isoform by RPA (see Figure 5
).
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Whole-tissue extracts from normal rat aortas contained PPAR1 and
-2 protein, consistent with the pattern of PPAR mRNA
expression detected by RPA (Figure 5).
PPAR Expression in Human Vascular Lesions and Rat
Neointima
In human atherosclerotic lesions, PPAR is expressed in
macrophages and to a lesser extent in VSMCs.19 20
To validate the quality of PPAR antibodies used for
immunohistochemical analysis, we first examined human
coronary arteries for receptor expression. Immunoreactive
PPAR colocalizes with macrophages visualized by staining of
parallel sections of a type II atherosclerotic lesion (Figure 7)26 with the
macrophage-specific antibody anti-CD68. In a type I
lesion exhibiting adaptive intimal thickening, faint expression of
PPAR is seen both in neointimal regions devoid of
CD68-positive cells and in the underlying media in VSMCs, as
demonstrated in serial sections stained with antibody against
-smooth muscle actin. Similar results were obtained with either of
the 2 commercial antibodies to stain 2 additional type I and type II
lesions from separate biopsies.
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In neointima formed after balloon injury of rat aortas,
faint expression of PPAR is observed in the media of uninjured
vessels (Figure 8). Neointima
that developed at 7 and 14 days after balloon injury displayed intense
staining for immunoreactive PPAR, which suggests that this receptor
is upregulated in response to vascular injury. VSMCs were the major
cell type present in rat neointima, as shown by its
strong positive staining for -smooth muscle actin and the absence of
staining for the macrophage marker ED1. Immunoreactive PPAR
did not localize specifically to the nucleus of neointimal
or medial VSMCs, because staining of the cytoplasm was observed. We do
not know whether VSMCs in arterial vessels actually contain
PPAR in their cytoplasm or whether this is an artifact of tissue
fixation.
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To confirm that the immunoreactive signal detected in rat
neointima was bona fide PPAR, we used nuclear extracts
from differentiated 3T3-L1 adipocytes to preabsorb PPAR antibodies
before their use in immunostaining. Addition of 50 µg
of nuclear extracts of differentiated 3T3-L1 adipocytes, which contain
high levels of PPAR1 and -2 compared with undifferentiated 3T3-L1
cells (see Figure 6), markedly attenuated staining in both the
neointima and media (Figure 9), whereas extracts from
undifferentiated 3T3-L1 preadipocytes had little effect. Thus, the
immunoreactivity observed in these tissues corresponds to PPAR
protein.
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Discussion |
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PPAR
mRNA and protein have previously been identified in rat
aortic and human saphenous vein VSMCs.24 27 In human
aortic VSMCs, Staels et al23 found extremely low levels of
PPAR mRNA relative to PPAR message detected by RPA. However, the
pattern of PPAR isoform expression was not described. Using an RPA
that permits the detection of both isoforms, we found that PPAR1
mRNA is easily detectable in cultured rat aortic VSMCs, in whole aortas
from uninjured animals, and in human VSMCs. PPAR1 expression was
substantially higher in VSMCs from human coronary artery and
umbilical artery than in cells from aortas. None of these cells
expressed detectable PPAR2 mRNA.
Cultured VSMCs from rat aortas and human coronary arteries
expressed only PPAR1 protein, consistent with their pattern
of mRNA isoform expression. Rat aortic tissue contained receptors for
both PPAR1 and -2, consistent with the presence of both
mRNA species in that tissue. Levels of PPAR1 protein in rat aortic
and human coronary arterial VSMCs appeared to be
substantial, because they express levels similar to those of
differentiated 3T3-L1 adipocytes, a major in vitro model for studying
PPAR function. Our data are also consistent with previous
studies showing that PPAR is present in rat aortic and human
saphenous vein VSMCs.24 27
Inhibition of VSMC growth and migration in vitro occurred at low
micromolar concentrations of PPAR ligands, which are achievable in
the circulation of humans or animals given TRO for insulin
sensitization.28 TRO and RSG had comparable activities to
inhibit VSMC growth and migration. This finding is somewhat surprising,
because other studies have shown RSG to be 5- to 20-fold more
efficacious than TRO in binding to PPAR and in increasing
transcriptional activity of PPAR,2 stimulating
insulin-mediated glucose transport,4 lowering
hyperglycemia in ob/ob diabetic mice,4 and inducing
adipocyte differentiation.3 The roughly equal potencies
between TRO and RSG for inhibiting VSMC proliferation and migration may
be the result of TRO being a bifunctional molecule having both a TZD
and -tocopherol (vitamin E) moiety.
Tocopherol inhibits VSMC proliferation and
macrophage migration.22 29 TRO has also recently
been shown to inhibit cholesterol synthesis through a
mechanism independent of its vitamin E or PPAR ligand
properties.30 The vascular effects of TRO, therefore, may
be complex, with its activity mediated partially through
-tocopherol and/or other PPAR-independent mechanisms
and partially through PPAR. RSG lacks -tocopherol and
is a more "pure" PPAR ligand. Its vascular effects are likely to
be mediated exclusively through PPAR. The non-TZD PPAR ligand
15d-PGJ2 displayed the strongest antiproliferative and antimigration
activity in VSMCs. RSG is 20-fold more potent than 15d-PGJ2 in
activating PPAR as a transcription factor in transient transfection
experiments and in inducing differentiation of 3T3-L1 cells into
adipocytes.2 3 The biological effects of 15d-PGJ2,
however, are complex because of its potential to activate
prostaglandin receptors. RSG, therefore, may provide the
clearest evidence for PPAR-mediated effects. The vascular effects of
RSG we observed importantly distinguish this study from that of Marx et
al,24 which used only TRO and 15d-PGJ2 to inhibit human
VSMC migration.
The molecular basis for the inhibition of VSMC growth and migration by
PPAR remains to be elucidated. PPAR-mediated inhibition of
transcription factor function (ie, transrepression) critical for these
processes is probably involved. We previously observed that TRO
inhibited the activity of ELK-1, an ets-family transcription
factor, after mitogenic stimulation of VSMCs by
bFGF.9 Transrepression of ELK-1, and possibly other
transcription factors, by TRO may be the underlying mechanism for its
inhibition of VSMC growth and migration and hence intimal
hyperplasia.9 This hypothesis is supported by studies in
macrophages in which PPAR also negatively regulates gene
expression.16 17 Iijima et al27 observed that
TRO and 15d-PGJ2 poorly activate (<1-fold induction)
endogenous PPAR in rat VSMCs, a finding we reproduced
(unpublished data). By comparison, PPAR present in 3T3-L1
adipocytes or overexpressed by transfection in CV-1 renal fibroblasts
show a 5- to 100-fold increase in transcription factor activity in
response to RSG, TRO, or 15d-PGJ2.2 3 5 These data suggest
that transcriptional activation by PPAR may have a different
pharmacology than transrepression by these receptors and is dependent
on the cell type.
To date, only 2 previous studies have described the expression of
PPAR in normal or diseased vasculature. Immunohistochemical
analysis of PPAR human atherosclerotic lesions revealed
strong expression in macrophages, with fainter expression
observed in VSMCs. VSMCs in the underlying media of lesions or in
unaffected areas of the coronary artery had nearly undetectable
levels of PPAR.19 20 In early human
atheroma (type II), we found that the highest levels of
PPAR colocalized with macrophages in the
neointima. VSMCs present in the neointima
and the underlying media stained positively for PPAR, but staining
was less than in macrophages. We also observed significant
staining for PPAR in human VSMCs present in regions of adaptive
intimal thickening in type I lesions that can be precursors to
atheromas.
Our study also provides new insight concerning the in vivo
expression of PPAR in the injured vasculature.
Neointimal VSMCs prominently upregulate PPAR protein
levels. Lesions that result from this model of vascular injury differ
from atheromas in several important aspects. First, intimal
hyperplasia after mechanical injury is a more acute response than
atherosclerosis, which develops over a longer period of
time. Second, VSMCs are the predominant cell type in balloon
injury–induced neointimal lesions, where we find little
infiltration of macrophages. In contrast, macrophages
are abundant in atherosclerotic lesions and play a major role in
driving atherogenesis.31 Therefore, upregulation of
PPAR and its activation by physiological
or pharmacological ligands in the damaged vasculature may be important
in limiting lesions dependent on VSMC activity.
The present data are in stark contrast to a recent report
emphasizing the role of PPAR and dismissing involvement of PPAR
in VSMC responses that promote restenosis and
atherosclerosis. In that study, Staels et
al,23 using a different antibody and not using nuclear
extracts, did not detect significant levels of PPAR in human aortic
VSMCs. Using RPA, we find that human aortic VSMCs express much lower
levels of PPAR mRNA than human coronary VSMCs. Either or
both of these differences may have resulted in our experimental
approach being more sensitive for detecting PPAR protein. We also
found that PPAR ligands had no effect on VSMC inflammatory
responses, whereas we find that PPAR ligands have antiproliferative
and antimigratory activity in VSMCs.
The present results have important implications for diabetes-associated vascular disease. In type 2 diabetes, the development of both atherosclerosis and restenosis is substantially accelerated.32 We and others have suggested that TZD may retard atherogenesis and restenosis through their inhibitory effects on VSMCs9 24 and macrophages17 19 20 in the damaged vasculature. TZDs, therefore, may provide a dual benefit for type 2 diabetes by ameliorating insulin resistance and its metabolic sequelae, as well as directly protecting the vasculature from injury.
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Methods |
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TopAbstractIntroductionResultsDiscussionMethodsReferences |
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Materials
TRO was kindly provided by Parke Davis; rosiglitazone was a generous gift from SmithKline Beecham. All other materials were purchased from commercial suppliers.
Cell Culture and Treatment With Growth Factors and PPAR
Ligands
Rat aortic VSMCs were prepared from thoracic aorta of 2- to
3-month-old Sprague-Dawley rats (Charles River) and assessed for purity
as previously described.13 Human vascular cells were
purchased from Clonetics and cultured as
recommended.Subconfluent VSMCs (passage 5 or less) were made
quiescent by serum starvation (0.4% FBS). PPAR ligands were added
30 minutes before growth factors. Independent preparations of VSMCs
were used for each experiment in the n value.
DNA Synthesis
Quiescent VSMCs were stimulated with 20 ng/mL basic fibroblast
growth factor (bFGF) in the presence or absence of PPAR ligands for
48 hours. During the final 6 hours of the incubation, cells were pulsed
with 1 µCi of [3H]thymidine/mL.
Trichloroacetic acid–precipitable
[3H]thymidine incorporation measurements are
the average of triplicate wells.
Migration
VSMC migration was examined in transwell cell culture
chambers with a gelatin-coated polycarbonate membrane with 8-µm pores
as previously published.9
RNase Protection Assay
RNase protection assays (RPAs) were performed with antisense RNA
probes prepared from PPAR cDNA (kindly provided by Dr J. Flier,
Harvard University, Boston, Mass) as described in Reference
11 . RPA detected protected bands of rat PPAR1, 185
bases, rat PPAR2, 273 bases, human PPAR1, 258 bases, human
PPAR2, 348 bases, rat GAPDH, 97 bases, and human GAPDH, 96
bases.
Immunoblotting
Protein extracts from aortas were prepared by removal of
adventitial fat, homogenization after
quick-freezing in liquid nitrogen, and centrifugation
to remove debris.
Nuclear and cytosolic fractions from cultured VSMCs were prepared by
the method of Dignam et al.33 Equal amounts of proteins
(25 to 50 µg) were electrophoresed and transferred to nitrocellulose
membranes. Membranes were incubated with anti-PPAR antibodies,
either a murine monoclonal (Glaxo-Wellcome) or rabbit polyclonal
(Biomol or Santa Cruz) at a concentration of 1:1000 for 2 hours in 0.2
mol/L Tris-HCl pH 7.5, 0.5 mol/L NaCl buffer containing 5% fat-free
milk powder and 0.1% Tween 20. Blots were washed and incubated for
another hour with a goat anti-rabbit horseradish peroxidase–conjugated
antibody 1:500 before development with ECL Detection (Amersham).
Balloon Injury and Immunodetection of PPAR in Rat and Human
Vascular Lesions
Balloon-catheter injury was induced in male Sprague-Dawley
rats.9 At 0, 2, 7, and 14 days after injury, aortas were
removed, cut into cross-sectional segments, and embedded in
paraffin.
Surgical specimens of human coronary artery lesions embedded in paraffin were obtained as approved by the Human Investigational Review Board at UCLA. Lesions were classified on the basis of their histological composition and structure in accordance with the report from the American Heart Association Committee on Vascular Lesions.26
Sections were preincubated with a blocking buffer (PBS containing 5%
BSA) for 60 minutes at room temperature. After incubation with
polyclonal rabbit anti-PPAR (rabbit polyclonal), smooth muscle
-actin (mouse monoclonal), rat macrophage marker ED1 (mouse
monoclonal, Serotec), or human macrophage marker CD68 (goat
polyclonal, Santa Cruz) in PBS containing 1% BSA for 60 minutes,
biotinylated antibodies (Zymed) for 30 minutes, and
streptavidin-peroxidase for 20 minutes, peroxidase activity was
detected with an AEC kit (Zymed). Slides were counterstained with
Mayer’s acid hematoxylin for 3 minutes.
Statistics
ANOVAs were performed and differences between means were
determined by Student-Newman-Keuls test.Values of
P<0.05 were considered statistically significant. Data are
expressed as mean±SEM.
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Acknowledgments |
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This study was supported by NIH grant HL-58328-03 to W.A.H., Deutsche Forschungsgemeinschaftgrant DFG GO 800/1-1 to S.G., and ADA support to R.E.L. We thank Janie Teran and Dolores Mendoza for their assistance in preparing the manuscript.
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Footnotes |
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The Methods section of this article can be found at http://www.circulationaha.org
Received February 26, 1999; revision received September 22, 1999; accepted October 8, 1999.
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References |
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|---|
1. Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998;47:507–514.[Abstract]
2. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995;83:803–812.[Medline] [Order article via Infotrieve]
3. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 1995;83:813–819.[Medline] [Order article via Infotrieve]
4. Berger J, Bailey P, Biswas C, Cullinan CA, Doebber TW, Hayes NS, Saperstein R, Smith RG, Leibowitz MD. Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology. 1996;137:4189–4195.[Abstract]
5.
Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison
WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high
affinity ligand for peroxisome proliferator-activated receptor
gamma (PPAR gamma). J Biol Chem. 1995;270:12953–12956.
6.
Maggs DG, Buchanan TA, Burant CF, Cline G,
Gumbiner B, Hsueh WA, Inzucchi S, Kelley D, Nolan J, Olefsky JM,
Polonsky KS, Silver D, Valiquett TR, Shulman GI. Metabolic
effects of troglitazone monotherapy in type 2 diabetes mellitus: a
randomized, double-blind, placebo-controlled trial. Ann Intern
Med. 1998;128:176–185.
7.
Inzucchi SE, Maggs DG, Spollett GR, Page SL,
Rife FS, Walton V, Shulman GI. Efficacy and metabolic
effects of metformin and troglitazone in type II diabetes mellitus.
N Engl J Med. 1998;338:867–872.
8. Mukherjee R, Davies PJ, Crombie DL, Bischoff ED, Cesario RM, Jow L, Hamann LG, Boehm MF, Mondon CE, Nadzan AM, Paterniti JR Jr, Heyman RA. Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. Nature. 1997;386:407–410.[Medline] [Order article via Infotrieve]
9. Law RE, Meehan WP, Xi XP, Graf K, Wuthrich DA, Coats W, Faxon D, Hsueh WA. Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J Clin Invest. 1996;98:1897–1905.[Medline] [Order article via Infotrieve]
10. Park KS, Ciaraldi TP, Abrams-Carter L, Mudaliar S, Nikoulina SE, Henry RR. PPAR-gamma gene expression is elevated in skeletal muscle of obese and type II diabetic subjects. Diabetes. 1997;46:1230–1234.[Abstract]
11. Vidal-Puig AJ, Considine RV, Jimenez-Linan M, Werman A, Pories WJ, Caro JF, Flier JS. Peroxisome proliferator-activated receptor gene expression in human tissues: effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest. 1997;99:2416–2422.[Medline] [Order article via Infotrieve]
12.
Guan Y, Zhang Y, Davis L, Breyer MD. Expression
of peroxisome proliferator-activated receptors in urinary tract
of rabbits and humans. Am J Physiol. 1997;273:F1013–F1022.
13. Mansen A, Guardiola-Diaz H, Rafter J, Branting C, Gustafsson JA. Expression of the peroxisome proliferator-activated receptor (PPAR) in the mouse colonic mucosa. Biochem Biophys Res Commun. 1996;222:844–851.[Medline] [Order article via Infotrieve]
14. Greene ME, Blumberg B, McBride OW, Yi HF, Kronquist K, Kwan K, Hsieh L, Greene G, Nimer SD. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Exp. 1995;4:281–299.
15.
Nagy L, Tontonoz P, Alvarez JGA, Chen H, Evans
RM. Oxidized LDL regulates macrophage gene expression through
ligand activation of PPAR. Cell. 1998;93:229–240.[Medline]
[Order article via Infotrieve]
16. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998;391:82–86.[Medline] [Order article via Infotrieve]
17. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82.[Medline] [Order article via Infotrieve]
18. Tontonoz P, Nagy L, Alvarez JGA, Thomazy VA, Evans RM. PPAR promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell. 1998;93:241–252.[Medline] [Order article via Infotrieve]
19.
Marx N, Sukhova G, Murphy C, Libby P, Plutzky J.
Macrophages in human atheroma contain PPARgamma:
differentiation-dependent peroxisomal proliferator-activated
receptor gamma (PPARgamma) expression and reduction of MMP-9 activity
through PPARgamma activation in mononuclear phagocytes in vitro.
Am J Pathol. 1998;153:17–23.
20.
Ricote M, Huang J, Fajas L, Li A, Welch J, Najib
J, Witztum JL, Auwerx J, Palinski W, Glass CK. Expression of the
peroxisome proliferator-activated receptor gamma (PPARgamma) in
human atherosclerosis and regulation in
macrophages by colony stimulating factors and oxidized low
density lipoprotein. Proc Natl Acad Sci U S A. 1998;95:7614–7619.
21.
Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin
KJ, Zhang M, Fletcher C, Singer S, Spiegelman BM. Terminal
differentiation of human breast cancer through PPAR. Mol
Cell. 1998;1:465–470.[Medline]
[Order article via Infotrieve]
22. Lafont AM, Chai YC, Cornhill JF, Whitlow PL, Howe PH, Chisolm GM. Effect of alpha-tocopherol on restenosis after angioplasty in a model of experimental atherosclerosis. J Clin Invest. 1995;95:1018–1025.
23. Staels B, Koenig W, Habib A, Merval R, Lebret M, Torra IP, Delerive P, Fadel A, Chinetti G, Fruchart JC, Najib J, Maclouf J, Tedgui A. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature. 1998;393:790–793.[Medline] [Order article via Infotrieve]
24.
Marx N, Schonbeck U, Lazar MA, Libby P, Plutzky
J. Peroxisome proliferator-activated receptor gamma
activators inhibit gene expression and migration in human
vascular smooth muscle cells. Circ Res. 1998;83:1097–1103.
25.
Xing H, Northrop JP, Grove JR, Kilpatrick KE, Su JL,
Ringold GM. TNF alpha-mediated inhibition and reversal of adipocyte
differentiation is accompanied by suppressed expression of PPARgamma
without effects on Pref-1 expression. Endocrinology. 1997;138:2776–2783.
26.
Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S,
Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A
definition of advanced types of atherosclerotic lesions and a
histological classification of
atherosclerosis: a report from the Committee on
Vascular Lesions of the Council on
Arteriosclerosis, American Heart Association.
Arterioscler Thromb Vasc Biol. 1995;15:1512–1531.
27. Iijima K, Yoshizumi M, Ako J, Eto M, Kim S, Hashimoto M, Sugimoto N, Liang YQ, Sudoh N, Toba K, Ouchi Y. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in rat aortic smooth muscle cells. Biochem Biophys Res Commun. 1998;247:353–356.[Medline] [Order article via Infotrieve]
28. Loi CM, Randinitis EJ, Vassos AB, Kazierad DJ, Koup JR, Sedman AJ. Lack of effect of type II diabetes on the pharmacokinetics of troglitazone in a multiple-dose study. J Clin Pharmacol. 1997;37:1114–1120.[Abstract]
29. Trach CC, Wulfroth PM, Severs NJ, Robenek H. Influence of native and modified lipoproteins on migration of mouse peritoneal macrophages and the effect of the antioxidants vitamin E and probucol. Eur J Cell Biol. 1996;71:199–205.[Medline] [Order article via Infotrieve]
30. Wang M, Wise SC, Leff T, Su TZ. Troglitazone, an antidiabetic agent, inhibits cholesterol biosynthesis through a mechanism independent of peroxisome proliferator-activated receptor-gamma. Diabetes. 1999;48:254–260.[Abstract]
31. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]
32. Stern MP. Diabetes and cardiovascular disease: the "common soil" hypothesis. Diabetes. 1995;44:369–374.[Abstract]
33.
Dignam JD, Lebovitz RM, Roeder RG. Accurate
transcription initiation by RNA polymerase II in a soluble extract from
isolated mammalian nuclei. Nucleic Acids Res. 1983;11:1475–1489.
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 P. Meerarani, G. Reiterer, M. Toborek, and B. Hennig Zinc Modulates PPAR{gamma} Signaling and Activation of Porcine Endothelial Cells J. Nutr., October 1, 2003; 133(10): 3058 - 3064. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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 |
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|
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|
|
|
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|
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
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J. Zhang, M. Fu, X. Zhu, Y. Xiao, Y. Mou, H. Zheng, M. A. Akinbami, Q. Wang, and Y. E. Chen Peroxisome Proliferator-activated Receptor delta Is Up-regulated during Vascular Lesion Formation and Promotes Post-confluent Cell Proliferation in Vascular Smooth Muscle Cells J. Biol. Chem., March 22, 2002; 277(13): 11505 - 11512. [Abstract] [Full Text] [PDF]
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N. Frey and E. N. Olson Modulating Cardiac Hypertrophy by Manipulating Myocardial Lipid Metabolism? Circulation, March 12, 2002; 105(10): 1152 - 1154. [Full Text] [PDF]
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 B. Molavi, N. Rasouli, and J. L. Mehta Peroxisome Proliferator-Activated Receptor Ligands as Antiatherogenic Agents: Panacea or Another Pandora's Box? Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2002; 7(1): 1 - 8. [Abstract] [PDF]
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S. Arima, K. Kohagura, K. Takeuchi, Y. Taniyama, A. Sugawara, Y. Ikeda, M. Abe, K. Omata, and S. Ito Biphasic Vasodilator Action of Troglitazone on the Renal Microcirculation J. Am. Soc. Nephrol., February 1, 2002; 13(2): 342 - 349. [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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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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D. P. Kelly The Pleiotropic Nature of the Vascular PPAR Gene Regulatory Pathway Circ. Res., November 23, 2001; 89(11): 935 - 937. [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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 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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 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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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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 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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A. R. Collins, W. P. Meehan, U. Kintscher, S. Jackson, S. Wakino, G. Noh, W. Palinski, W. A. Hsueh, and R. E. Law Troglitazone Inhibits Formation of Early Atherosclerotic Lesions in Diabetic and Nondiabetic Low Density Lipoprotein Receptor-Deficient Mice Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 365 - 371. [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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S. B. Nicholas, Y. Kawano, S. Wakino, A. R. Collins, and W. A. Hsueh Expression and Function of Peroxisome Proliferator-Activated Receptor-{{gamma}} in Mesangial Cells Hypertension, February 1, 2001; 37(2): 722 - 727. [Abstract] [Full Text] [PDF]
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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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 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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K. Takeda, T. Ichiki, T. Tokunou, N. Iino, and A. Takeshita 15-Deoxy-Delta 12,14-prostaglandin J2 and Thiazolidinediones Activate the MEK/ERK Pathway through Phosphatidylinositol 3-Kinase in Vascular Smooth Muscle Cells J. Biol. Chem., December 21, 2001; 276(52): 48950 - 48955. [Abstract] [Full Text] [PDF]
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S. Wakino, U. Kintscher, S. Kim, F. Yin, W. A. Hsueh, and R. E. Law Peroxisome Proliferator-activated Receptor gamma Ligands Inhibit Retinoblastoma Phosphorylation and G1right-arrow S Transition in Vascular Smooth Muscle Cells J. Biol. Chem., July 14, 2000; 275(29): 22435 - 22441. [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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M. Asakawa, H. Takano, T. Nagai, H. Uozumi, H. Hasegawa, N. Kubota, T. Saito, Y. Masuda, T. Kadowaki, and I. Komuro Peroxisome Proliferator-Activated Receptor {gamma} Plays a Critical Role in Inhibition of Cardiac Hypertrophy In Vitro and In Vivo Circulation, March 12, 2002; 105(10): 1240 - 1246. [Abstract] [Full Text] [PDF]
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