(Circulation. 2000;101:235.)
© 2000 American Heart Association, Inc.
Brief Rapid Communications |
Activators
From the Department of Internal Medicine (V.P., H.D.W., J.T.W., E.T.H.Y.) and Institute of Molecular Medicine for the Prevention of Human Diseases (E.T.H.Y.), University of Texas Health Science Center, and Texas Heart Institute (V.P., J.T.W., E.T.H.Y.), St Lukes Episcopal Hospital, Houston.
Correspondence to Edward T.H. Yeh, MD, Department of Internal Medicine, 6431 Fannin, Suite 4200, UT-Houston HSC, Houston, TX 77030.
| Abstract |
|---|
|
|
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(PPAR
) is expressed in
atherosclerotic plaques and in endothelial cells. The
possible effects of PPAR
activators on
endothelial activation and inflammatory response within
the plaque are currently unknown.
Methods and ResultsWe tested the hypothesis that PPAR
activators inhibit vascular cell adhesion molecule (VCAM-1)
and intercellular adhesion molecule (ICAM-1) expression in cultured
endothelial cells (evaluated by flow cytometry) and
homing of monocyte/macrophages to atherosclerotic plaques in
vivo. In endothelial cells, the PPAR
agonists
troglitazone at 100 µmol/L and
15-deoxy-
12,14-prostaglandin
J2 (15d-PGJ2) at 20 µmol/L markedly attenuated the
tumor necrosis factorinduced expression of VCAM-1 and ICAM-1. A
significant inhibition of VCAM-1 expression was also evident at 5 and
10 µmol/L 15d-PGJ2 and 20 µmol/L troglitazone. Expression
of E-selectin and PECAM-1 was not altered. To confirm the biological
relevance of these results, we assessed the effects of troglitazone on
monocyte/macrophage homing to atherosclerotic plaques in
apoE-deficient mice. A 7-day treatment with troglitazone (400 mg/kg)
significantly reduced monocyte/macrophage homing to
atherosclerotic plaques (236±77 versus 177±43 macrophages,
P=0.03); an even more striking inhibition was found at
3200 mg/kg troglitazone (344±76 versus 172±83 macrophages,
P=0.005).
ConclusionsPPAR
activators inhibit expression of
VCAM-1 and ICAM-1 in activated endothelial
cells and significantly reduce monocyte/macrophage homing to
atherosclerotic plaques. These findings suggest that PPAR
activators, currently used in treatment of type II
diabetes, may have beneficial effects in modulating inflammatory
response in atherosclerosis.
Key Words: cell adhesion molecules receptors atherosclerosis
| Introduction |
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|
|
|---|
(PPAR
)
may have a role in the pathogenesis of
atherosclerosis.1 PPAR
is a nuclear
receptor highly expressed in several tissues, including adipose tissue,
monocytes/macrophages, and smooth muscle cells.2
In atherosclerotic plaques, PPAR
is expressed by
macrophage/foam cells, and activation of this receptor can
inhibit macrophage activation.3 4 Although PPAR
is also expressed by endothelial cells,5
the possible effects of PPAR
activators in
atherosclerotic plaques are currently unknown.
Expression of adhesion molecules by endothelial cells
and adhesion of leukocytes to endothelial cells is an
essential step in atherogenesis.6 7 We have recently
shown, in an animal model of atherosclerosis, that
monocyte/macrophage homing to atherosclerotic plaques depends
on the expression of the adhesion molecules vascular cell adhesion
molecule (VCAM-1) and intercellular adhesion molecule
(ICAM-1).8 The aim of our study was to assess the effects
of PPAR
activators on the expression of adhesion
molecules on activated endothelial cells and on
monocyte/macrophage homing to atherosclerotic plaques in
vivo.
| Methods |
|---|
|
|
|---|
Mouse RAW 264.7 cells were grown in DMEM with 10% FBS, 2 mmol/L L-glutamine, and 1% penicillin/streptomycin.
Detection of Adhesion Molecules
HUVECs were pretreated with the PPAR
agonists troglitazone
(Parke-Davis), ciglitazone (Biomol),
15-deoxy-
12,14-prostaglandin
J2 (15d-PGJ2, from Calbiochem); with the PPAR
agonist fenofibrate (Sigma); or with vehicle (0.1% DMSO) at the
concentrations indicated. After 2 hours, the cells were incubated with
tumor necrosis factor (TNF)-
at 10 ng/mL for 12 hours. Cells were
detached with 10 mmol/L EDTA in PBS (without trypsin) and stained
with R-phycoerythrinlabeled monoclonal antibodies
(Pharmingen) against VCAM-1 (CD106), ICAM-1 (CD54), or PECAM-1 (CD31)
with FITC-labeled monoclonal antibodies (R and D)
against E-selectin (CD62E) or with the appropriate isotype IgG
(phycoerythrin or FITC) as control. Fluorescence
intensity of 9000 cells for each sample was quantified by a
FACSCalibur analyzer (Becton-Dickinson). All experiments
were performed in triplicate.
Monocyte/Macrophage Homing to Atherosclerotic
Plaques
Monocyte/macrophage homing to the atherosclerotic
plaques in vivo was assessed according to a previously published
protocol,8 modified to use a RAW murine macrophage
cell line rather than activated peritoneal macrophages.
RAW 267.4 cells were incubated for 75 minutes with 2-µm
fluorescent microspheres (Molecular Probes). Cells were
then injected into the tail vein of apoE knockout mice
(10x106 cells per mouse).8 The mice
were euthanized after 48 hours. Labeled cells adhering to or
present inside the atheromatous plaque were
quantified in 200 serial sections covering the first 1 mm of the
ascending aorta. To validate RAW cells as monocyte/macrophage
surrogates in our animal model, we performed an inhibition experiment
by pretreating apoE-deficient mice with monoclonal antibody against
integrin-
4 (R1-2, from Pharmingen) 6 hours before injection with RAW
cells.
Mice (6 to 8 in each group) were randomized to troglitazone administered by gavage (0.5-mL suspension in water 2 times per day) or to vehicle for 7 days before monocyte/macrophage injection and for the following 2 days. Two different doses of troglitazone (400 mg · kg-1 · d-1 or 3200 mg · kg-1 · d-1) were tested in 2 studies.
Statistics
Results are expressed as mean±SD. Monocyte/macrophage
homing was analyzed with the Mann-Whitney U test to
take into account the small sample size. A value of P<0.05
(2-tailed) was considered significant.
| Results |
|---|
|
|
|---|
10 ng/mL for 12 hours significantly increased the expression of ICAM-1
(A and B), VCAM-1 (C and D), and E-selectin (E and F), with no change
in the expression of PECAM-1 (G and H). Pretreatment with troglitazone
at 100 µmol/L and with 15d-PGJ2 20 µmol/L decreased the
expression of both ICAM-1 (A and B) and VCAM-1 (C and D) almost to
baseline levels. In addition, ciglitazone 100 µmol/L (L)
decreased expression of VCAM-1 (but not ICAM-1), with an even stronger
effect at 200 µmol/L (M). A significant reduction of VCAM-1
expression was also evident with 20 µmol/L of troglitazone (O)
and with 5 or 10 µmol/L of 15d-PGJ2 (P and Q), although these
doses did not significantly change expression of ICAM-1 (data not
shown). Expression of E-selectin (E and F) or PECAM-1 (G and H) was not
changed.
|
The PPAR
agonist fenofibrate at 100 µmol/L was associated
with a slight reduction of VCAM-1 expression after TNF-
stimulation
(J) but did not change the expression of ICAM-1 (I) or E-selectin (data
not shown). Other prostaglandins
(PGE2 20 µmol/L and
PGF2
20 µmol/L) did not change
expression of adhesion molecules (data not shown).
Monocyte/Macrophage Homing
Labeled RAW cells migrated to atherosclerotic plaque, and
anti-
4 antibodies markedly inhibited this phenomenon (Figure 2
). Pretreatment with troglitazone at 400
mg · kg-1 ·
d-1 for 7 days reduced homing of labeled
monocyte/macrophages to atherosclerotic plaques in the aortic
root significantly, by 25% (P=0.03, Figure 2
).
High-dose troglitazone (3200 mg ·
kg-1 · d-1) was
associated with a 50% reduction of monocyte/macrophage homing
(P=0.005). Troglitazone treatment did not change serum
levels of total cholesterol, triglycerides, or
glucose.
|
| Discussion |
|---|
|
|
|---|
activators
markedly decrease expression of adhesion molecules in activated
human endothelial cells. Short-term treatment with the
PPAR
activator troglitazone also significantly inhibits
macrophage homing to atherosclerotic plaques.
PPAR
is expressed in atherosclerotic plaques, and activation of
PPAR
inhibits macrophage activation.3 4 The
antidiabetic drugs thiazolidinediones are specific
activators of PPAR
, whereas the natural agonists are
still largely unknown. However, natural polyunsaturated fatty acids can
activate PPAR
, and 15d-PGJ2 is the most specific
(KD=2.5
µmol/L).10
PPAR
is expressed by human endothelial cells,
including HUVECs.5 Activation of this receptor can inhibit
endothelial cell proliferation and may modulate PAI-1
expression,5 11 reduce endothelin-1
production,12 and induce
apoptosis,13 in particular in serum-free
conditions. Activation of PPAR
results in inhibition of the AP-1 and
NF-
B pathways3 12 that regulate the expression of
adhesion molecules by activated endothelial
cells. We found that several PPAR
activators inhibit
expression of ICAM-1 and VCAM-1 in activated HUVECs. However,
as in several previous studies,3 4 the response to
troglitazone and ciglitazone occurred at concentrations higher than
their binding affinity for PPAR
, whereas the effects of 15d-PGJ2
were in a concentration range compatible with its
KD. The reasons for this discrepancy are
unclear, and activation of additional pathways cannot be excluded.
However, in a recent study using endothelial cells in
conditions similar to our experiments (with complete medium including
serum), only high concentrations (100 µmol/L) of ciglitazone
could activate a PPAR reporter.13 Thus, it
appears that high concentrations of thiazolidinediones are necessary to
activate the PPAR
receptor in our experimental
conditions.
Although high concentrations of troglitazone and 15d-PGJ2 (but not of
ciglitazone) may also activate PPAR
, this is unlikely to
explain our results, because 5 µmol/L 15d-PGJ2 and 100
µmol/L ciglitazone are not associated with any PPAR
activation.14
Marx et al15 recently reported that PPAR
activators reduced expression of VCAM-1 (but not ICAM-1 and
E-selectin) by activated human saphenous vein
endothelial cells.15 The same study did
not find any significant effect of PPAR
agonists (troglitazone or
15d-PGJ2 10 µmol/L) on the expression of adhesion molecules.
Differences in the study design (2-hour pretreatment in our study
versus 24-hour) may explain their negative results, because we found
that inhibition of VCAM-1 expression by PPAR
agonists was much less
evident with 24-hour pretreatment than with a 2-hour pretreatment (data
not shown).
We reported previously that in apoE-deficient mice, homing of
activated peritoneal macrophages to atherosclerotic
plaques is reduced by pretreatment with monoclonal antibodies against
ICAM-1 and
4 integrin (the natural ligand for VCAM-1).8
We modified this model to use a mouse macrophage cell line (RAW
267.4) that does not express significant levels of
PPAR
.3 Troglitazone treatment significantly inhibits
monocyte/macrophage homing, with a 50% reduction at the
highest dose. However, 400 mg · kg-1
· d-1 of troglitazone, a dose used in mouse
models of diabetes,16 is also associated with a
significant reduction in monocyte/macrophage accumulation.
Similarly, troglitazone inhibits neointimal hyperplasia in
rats.17 Troglitazone also has antioxidant effects, and the
beneficial effects observed in our experiments may not be due only to
PPAR
activation.
PPAR
activators are used in treatment of type II
diabetes, and in a preliminary study, treatment with troglitazone was
found to reduce carotid intimal-medial thickness, a marker of early
stages of atherosclerosis.18 However,
atherosclerosis is a composite phenomenon involving
many different molecular pathways, and further studies are needed to
assess the effects of PPAR
activators on the progression
of atherosclerosis.
| Footnotes |
|---|
Received September 16, 1999; revision received November 15, 1999; accepted November 18, 1999.
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activation in human endothelial cells
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activators inhibit
cytokine-induced vascular cell adhesion molecule-1
expression in human endothelial cells.
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