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© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Troglitazone Inhibits Formation of Early Atherosclerotic Lesions in Diabetic and Nondiabetic Low Density Lipoprotein Receptor–Deficient Mice
From the Division of Endocrinology, Diabetes, and Hypertension (A.R.C., W.P.M., U.K., S.J., S.W., G.N., W.A.H., R.E.L.), Department of Medicine, UCLA School of Medicine, Los Angeles, Calif; the Molecular Biology Institute (W.A.H., R.E.L.), Los Angeles, Calif; the Department of Medicine/Cardiology (U.K.), Virchow-Klinikum, Humboldt University, and the German Heart Institute (U.K.), Berlin, Germany; and the Department of Medicine (W.P.), UCSD, La Jolla, Calif.
Correspondence to Ronald E. Law, PhD, University of California, Los Angeles, Division of Endocrinology, Diabetes, and Hypertension, 900 Veteran Ave, Suite 24-130, Box 957073, Los Angeles, CA 90095. E-mail rlaw{at}mednet.ucla.edu
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Abstract |
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Abstract—Peroxisome proliferator–activated receptor-
(PPAR) is a
ligand-activated nuclear receptor expressed in all of the major
cell types found in atherosclerotic lesions:
monocytes/macrophages, endothelial cells, and
smooth muscle cells. In vitro, PPAR ligands inhibit cell
proliferation and migration, 2 processes critical for vascular lesion
formation. In contrast to these putative antiatherogenic activities,
PPAR has been shown in vitro to upregulate the CD36 scavenger
receptor, which could promote foam cell formation. Thus, it is unclear
what impact PPAR activation will have on the development and
progression of atherosclerosis. This issue is important
because thiazolidinediones, which are ligands for PPAR, have
recently been approved for the treatment of type 2 diabetes, a state of
accelerated atherosclerosis. We report herein that the
PPAR ligand, troglitazone, inhibited lesion formation in male low
density lipoprotein receptor–deficient mice fed either a high-fat
diet, which also induces type 2 diabetes, or a high-fructose diet.
Troglitazone decreased the accumulation of macrophages in
intimal xanthomas, consistent with our in vitro observation
that troglitazone and another thiazolidinedione, rosiglitazone,
inhibited monocyte chemoattractant protein-1–directed
transendothelial migration of monocytes. Although
troglitazone had some beneficial effects on metabolic risk
factors (in particular, a reduction of insulin levels in the diabetic
model), none of the systemic cardiovascular risk
factors was consistently improved in either model. These
observations suggest that the inhibition of early atherosclerotic
lesion formation by troglitazone may result, at least in part, from
direct effects of PPAR activation in the artery
wall.
Key Words: atherosclerosis • diabetes mellitus • pharmacology
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Introduction |
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Peroxisome proliferator–activated receptor-
(PPAR), a nuclear
receptor, is expressed in all major cell types participating in
vascular injury: endothelial cells (ECs),
macrophages, and vascular smooth muscle cells
(VSMCs).1 2 3 4 5 6
Activation of this receptor in vitro inhibits inflammatory processes,
including cytokine production and expression of NO
synthase.2 In early clinical
investigations, ligands of PPAR, such as thiazolidinediones (TZDs),
have also been reported to improve
endothelium-dependent vasodilation, suggesting that
PPAR activation enhances NO production and protects against
vascular injury.7 8
Activation of PPAR also inhibits 2 other processes critical for
vascular lesion formation, cell proliferation, and migration.
3,5,6,9,10 In vivo, 2 TZDs, troglitazone
(TRO) and pioglitazone, significantly reduced arterial
neointimal hyperplasia after endothelial
injury in
rats.11 12 13
In such balloon-catheterized arteries, neointima formation
essentially reflects increased migration and proliferation of VSMCs, a
major contributor to the growth of atherosclerotic lesions. TRO also inhibited
neointima formation in stents placed in the
coronary arteries of patients with type 2
diabetes.14
We and others have recently demonstrated that PPAR
activation by TZDs and
15-deoxy-
12 14 -prostaglandin
J2 inhibits EC expression of vascular cell
adhesion molecule-1, which mediates monocyte adherence to the
endothelial
surface.4 15 Because
inflammation, dysregulated growth, and migration of monocytes and VSMCs
play an important role in the development of
atherosclerosis, we hypothesized that PPAR
activation in cells of the vasculature would inhibit the
atherosclerotic process. On the other hand, TZDs also stimulate
conversion of macrophages into foam cells; therefore,
ligand-dependent activation of PPAR has been postulated to promote
atherosclerosis.16
The impact of TZDs on atherosclerosis is a critical issue. TZDs improve insulin-mediated glucose uptake and are used extensively in the treatment of insulin resistance and type 2 diabetes mellitus.17 Coronary artery disease mortality is increased 2- to 4-fold in type 2 diabetes.18 Atherosclerosis is the major cause of demise in people with diabetes; therefore, it is important to determine the action of any antidiabetic drug on the atherosclerotic process.
To determine whether PPAR activation has proatherogenic
or antiatherogenic effects, we administered TRO to male LDL
receptor–deficient
(LDLR-/-)
mice fed either a high-fat or a high-fructose atherogenic diet. Both
models develop substantial hypercholesterolemia
and macrophage-laden lesions, designated intimal xanthomata,
which do not normally progress to mature atherosclerotic
plaques.19 In addition, the
high-fat diet induces hyperglycemia and
hyperinsulinemia in the
LDLR-/-
mouse, making it also a model of type 2
diabetes.20 21 In
contrast, fructose does not increase glucose or insulin in this
model21 and, therefore, was
useful because the effects of TZDs on atherosclerosis
could be studied in the absence of improvements in insulin
action.
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Methods |
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Transendothelial Monocyte Migration
THP-1 cells (5x104), a human monocytic leukemia cell line, were added to a human aortic EC monolayer covering a gelatin-coated 8-µm porous membrane and incubated for 30 minutes at 37°C to facilitate their attachment. Cells were then pretreated with the indicated ligands or vehicle (dimethyl sulfoxide) for 30 minutes at 37°C. Migration was induced by the addition of monocyte chemoattractant protein-1 (MCP-1, 50 ng/mL) to the lower compartment. After 90 minutes, nonmigrating THP-1 cells and human aortic ECs were removed with a cotton tip, and the membranes were fixed and stained with the Quik-Diff Stain Set (DADE, Miami, Fla) to identify migrated cells. The number of migrated cells was determined per x320 high-power field. Experiments were performed in duplicate and were repeated at least 3 times.
Western Blots
Western immunoblots were performed as
previously described.10
Membranes were incubated with rabbit polyclonal antibodies (1:1000
dilution, New England Biolabs) that recognize either (1) total
extracellular signal–regulated kinase (ERK) or (2) ERK
phosphorylated on threonine 202 and tyrosine
204.
Animals and Diets
Male
LDLR-/-
mice were obtained (C57BL/6J-Ldlrtm1Her,
stock No. 002207, Jackson Laboratory, Bar Harbor, Me) and were
group-housed under a 12-hour light and 12-hour dark regimen. All animal
protocols were approved by the UCLA Animal Research Committee and
complied with all federal, state, and institutional regulations. At 3
months of age, the mice were randomly assigned to 1 of 5 dietary
regimens: (1) chow (Harlan Teklad 8604), (2) high-fat complex
carbohydrate (Research Diets), (3) high-fat complex carbohydrate with
4 g TRO/kg of food, (4) high fructose (Research Diets), or (5)
high fructose with 4 g TRO/kg of food. The high-fat diet consisted
of 21% fat, 20% protein, 50% carbohydrate, and 0.15%
cholesterol. Our high-fat diet differed from those commonly
used to study atherogenesis in
LDLR-/-
mice in that the majority of the nonfat energy came from complex
carbohydrate sources instead of sucrose. The high-fructose diet
contained 4% fat, 16% protein, 71% fructose, and 0.15%
cholesterol. Sources of fat in the diets were corn oil (1%
in all diets) and anhydrous milk fat (3% in the fructose diets and
20% in the high fat diets). Mice and feed were weighed weekly, and the
rate of consumption of drug was computed. The mice were fed for a
period of 12 weeks.
Metabolic Measurements
Blood samples from the retro-orbital sinus were
obtained from the mice before the beginning of treatment and every
month thereafter and from the abdominal vena cava at euthanasia. Mice
were fasted overnight before the collection of the blood samples.
Plasma glucose was measured by glucose oxidase reaction (Beckman
Glucose Analyzer 2, Beckman Instruments). Plasma lipids were
measured by the UCLA Lipid Analysis Laboratory. Plasma insulin
was determined by ELISA. Blood pressures were obtained by using an
indirect tail-cuff method with a controlled temperature chamber (IITC,
Inc) by a technician blinded to the treatment
groups.
Vessel Preparation and Image
Analysis
Mice were euthanized and perfused with 7.5% sucrose
in 4% paraformaldehyde. Aortas were dissected out,
split longitudinally, pinned flat in a dissection pan, and stained with
Sudan IV to detect lipids and determine lesion area. Images were
captured by use of a Sony 3-CCD video camera and analyzed by a
single technician who was blinded to the study protocol and used
ImagePro image analysis software. The extent of lesion
formation is expressed as the percentage of the total aortic surface
area covered by lesions.
Cross Sections: Determination of Intimal
Macrophage Content
The largest lesions from the aortic arch were excised
and embedded in paraffin. The avidin-biotin-peroxidase complex
technique for immunostaining was used.
Macrophages were stained by using monoclonal antibody to CD68
(titer 1:100, KP1 clone, M0814, Dako Corp). Nonimmune serum was used as
a control. Primary antibody incubations were performed in 1% BSA/2%
goat serum containing PBS for 60 minutes. Biotinylated rabbit
anti-mouse (Dako) was applied; incubation with a
streptavidin-peroxidase complex followed. Peroxidase activity was
detected with the use of diaminobenzidine tetrahydrochloride as a
chromogen. Slides were then counterstained with hematoxylin. Images of
the stained sections were analyzed by using the software
described above. After tracing the intimal area to be measured with a
cursor, 5 pixels of color, which defined the anti-CD68 stain, were
sampled by the operator. The area encompassed by the pixels, which was
not contiguous, in the color range for anti-CD68 was then computed
automatically by the software. This approach has been successfully used
by Shi et al22 to quantify
lesional macrophages in a mouse model of transplant
arteriosclerosis.
Statistical Analysis
Statistical analysis was performed by using
2-factorial ANOVA with Student-Newman-Keuls to determine the
differences between individual group
means.
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Results |
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TRO Inhibits Monocyte Migration
VSMC migration and proliferation play an important atherogenic role in the progression of fatty streaks toward more advanced atherosclerotic lesions, such as transitional lesions and classical atheromas. We have previously shown that PPAR
ligands inhibit ERK mitogen-activated protein kinase
(MAPK)-dependent migration of
VSMCs.10 11
However, in the earliest stages of atherosclerotic lesions, recruitment
of adherent monocytes through their migration into the
subendothelium and their phenotypic transformation to
macrophages and foam cells play a far greater role than VSMCs
in humans and in murine
models.23
To investigate whether TRO-mediated PPAR activation
affects monocyte recruitment and to further explore its mechanism, we
carried out a series of in vitro experiments before our in vivo
studies. MCP-1 is an important in vivo migration factor promoting the
subendothelial accumulation of monocytes. TRO inhibited
MCP-1–directed transmigration of THP-1 monocytes by 32.7±6.5% at 2.5
µmol/L and by 61.4±6.7% at 10 µmol/L
(Figure 1
). TRO contains a vitamin E moiety that may confer
an antioxidant activity that can inhibit monocyte recruitment and
endothelial expression of adhesion molecules. However,
rosiglitazone (RSG), another PPAR ligand that lacks antioxidant
activity, also inhibited monocyte transmigration, albeit with a lesser
potency than TRO
(Figure 1). Inhibition of monocyte transmigration by TRO,
therefore, is likely to be mediated at least in part through
PPAR.
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MCP-1 rapidly induced ERK activation, reaching a peak at 5
minutes, which was blocked by PD98059, an inhibitor of MAPK
ERK kinase (MEK, an upstream kinase), which phosphorylates
and activates ERK
(Figure 2). PD98059 attenuated MCP-1–directed transmigration
by 84.8±4.8%. In combination, these data suggest that activation of
PPAR in monocytes may inhibit their migration by interfering with
ERK-MAPK signaling, although the precise mechanism remains to be
determined.
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TRO Inhibits Intimal Macrophage
Accumulation and Lesion Formation in Male
LDLR-/-
Mice
LDLR-/-
mice that were fed a regular chow diet develop few lesions across the
surface of the aorta. Male 3-month-old
LDLR-/-
mice were placed on either a high-fat or high-fructose diet to induce
atherosclerosis.
LDLR-/-
males were used in the present study because they develop
hyperglycemia and become diabetic on a high-fat diet but remain
normoglycemic when fed a high-fructose diet. Moreover, males develop
twice the level of surface lesions as do
females,24 and their use
obviates the potentially confounding influence of the vascular
protection in females afforded by estrogen. Comparison of the impact of
TRO on atherogenesis in these 2 dietary models was undertaken to
distinguish any activity of PPAR to normalize metabolic
abnormalities accompanying diabetes that contribute to
high-fat–induced xanthomata formation from any direct effects on the
vasculature. To assess the impact of TRO on aortic lesions, 1 high-fat
diet group and 1 high-fructose diet group received TRO at 400 mg/kg
body wt per day from drugs pelleted into the atherogenic diets. This
dose of TRO was chosen because we previously demonstrated its efficacy
in inhibiting intimal hyperplasia in rats after balloon
injury.11
The en face method, which makes use of computer-assisted
analysis of color images of Sudan IV–stained lipid-containing
material in the entire aorta, was used to determine the percentage of
surface area affected by
lesions.24 Male
LDLR-/-
mice on normal chow for 3 months had <0.20% lesions
(Figure 3A). The high-fat diet increased the amount of
surface lesions after 3 months to 3.90±0.16% (n=8,
Figure 3B). TRO inhibited the high-fat–induced lesions by
30% (2.76±0.36% of the aortic surface, n=8,
P<0.02;
Figure 3C). Similar to Merat et
al,21 we noted that the
high-fructose diet was more atherogenic than the high-fat diet, causing
8.42±0.94% lesions (n=17,
Figure 3D). TRO reduced lesions in fructose-fed
LDLR-/-
males by 42% (4.90±0.65%, n=14,
P<0.01;
Figure 3E). Quantitative results are summarized in
Figure 4.
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TRO-treated male
LDLR-/-
mice fed either the high-fat or high-fructose diet for 3 months
developed lesions that contained substantially fewer CD68-staining
macrophages
(Figure 5A through 5D). Lesions induced by a high-fat diet
contained 39.1±6.8% macrophages (percent of cross-sectional
intimal area) compared with 13.3±4.9%
(P<0.01) in mice administered
TRO
(Figure 5E). Similar results were obtained for males fed the
high-fructose diet, where TRO decreased macrophage accumulation
from 40.4±3.5% to 17.1±1.7%
(P<0.01,
Figure 5E). The lesions in the TRO-fed animals tended to be
smaller in volume than those in males not fed TRO. The relative
macrophage content in the larger lesions (not treated with TRO)
exceeded the content in the smaller lesions (treated with TRO) by 140%
to 200%. The reduction in macrophage accumulation in the
lesions of TRO-treated animals is unlikely to be the result of their
being an earlier lesion stage, because the relative macrophage
content is known to be greatest in the smaller (ie, early-stage)
lesions.
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Effect of TRO on Metabolic
Parameters
All metabolic measurements determined on
blood samples drawn before treatment were similar in all groups
(Tables 1 and 2). In accordance with previous studies on male
LDLR-/-
mice, we found that a high-fat diet induced
diabetes20 21
(Table 1). Glucose levels progressively increased throughout
the study, reaching a maximum of 285 mg/dL at 3 months compared with
148 mg/dL for mice on normal chow. The fat-fed males were also
hyperinsulinemic (1198±149 versus 664±113 pg/mL on
normal chow), consistent with the development of early-stage
type II diabetes. Although TRO did not decrease hyperglycemia in
high-fat–fed male mice, TRO administration completely normalized their
plasma insulin levels. In marked contrast, mice on a high-fructose diet
had normal fasting plasma glucose and insulin levels, which were not
altered by TRO.
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LDLR-/-
males developed severe hypercholesterolemia on
either the high-fat or high-fructose diet, achieving levels 3- to
4-fold greater than those in animals maintained on regular chow
(Table 2
). TRO lowered total plasma cholesterol
by 27% in males on the high-fructose diet but had no effect on the
high-fat–fed mice. Triglycerides were elevated in the
high-fat–fed males but not in the high-fructose group; TRO did not
alter triglycerides in either model. HDL
cholesterol (HDLC) decreased with both of the diets,
compared with normal chow, as frequently
reported.3 TRO further lowered
the HDLC in the high-fat–fed males but increased it in the
high-fructose–fed group. Plasma free fatty acid levels increased in
males on the high-fat diet but not in those on the high-fructose diet;
TRO decreased free fatty acid levels in both
models.
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Discussion |
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The most significant finding of the present study is that TRO inhibited lesion formation in a type 2 diabetic mouse model and a nondiabetic LDLR-/- mouse model of intimal xanthomata. Mice fed the high-fat diet developed extensive hypercholesterolemia that was not affected by TRO. These mice also gained substantial weight and showed an increase in circulating free fatty acid levels, which probably contributed to their insulin resistance, hyperinsulinemia, and fasting hyperglycemia.25 The increase in triglycerides and decrease in HDLC are consistent with insulin resistance. TRO decreased circulating insulin but did not affect glucose in this model. The same has been reported in humans with type 2 diabetes, of whom 20% treated with TRO showed no improvement in glucose control, but all demonstrated improved insulin sensitivity.26 In contrast to the response in humans, TRO did not alter triglycerides and further decreased HDLC. Mice fed the high-fructose diet also developed severe hypercholesterolemia but did not gain weight or develop hyperinsulinemia or elevations in free fatty acids or triglycerides. In this model, TRO decreased the free fatty acids, increased HDLC, and decreased total cholesterol.
Despite the difference in metabolic responses
between the diabetic and nondiabetic animals, both
hypercholesterolemic models responded to TRO with
decreased lesion formation. These results suggest that TRO has direct
vascular effects, separate from its metabolic effects, that
decrease the atherosclerotic process. Alternatively, the
antiatherogenic effects of TRO in the 2 different models might involve
the collection of distinct metabolic processes. For
example, hemodynamic effects of TRO related to its
reported activity to lower blood pressure in animal models and in
humans could also impact pathophysiological
processes in high-fat– and high-fructose–fed
LDLR-/-
mice.27 28 29 30
All major cell types contributing to this vascular lesion formation
express PPAR, which provides a mechanism for the direct effect of
thiazolidinedione ligands in the vessel
wall.3 5 6 9
Data from in vitro experiments had suggested mechanisms by which
activation of PPAR could either accelerate or attenuate the
atherosclerotic
process.2 3 4 5 6 9 10 16
The present study provides conclusive evidence that ligand-induced
PPAR activation by TRO reduces intimal xanthomata in murine
models.
TRO had several systemic effects that may have contributed to its attenuation of intimal xanthomata. In the diabetic high-fat–fed mouse, TRO lowered insulin and glucose levels and decreased HDLC (which is thought to promote atherogenesis). In the fructose-fed model, TRO decreased total cholesterol and increased HDLC. Our finding that TRO was more potent in suppressing lesion formation in the fructose-fed model compared with the high-fat–fed mice could be due to the observed 27% reduction in total cholesterol. A common effect of TRO in the high-fat–fed and high-fructose–fed LDLR-/- models is its suppression of circulating free fatty acid levels. However, increased circulating free fatty acids have not been shown to be an independent risk factor for atherosclerosis.
Inflammation in the vascular wall has clearly emerged as a
major culprit in the development of
atherosclerosis.31
Damage to the endothelium and the subsequent
recruitment and transendothelial migration of monocytes
constitute critical early cellular responses during
atherogenesis.31
Transmigration of monocytes into the subendothelial
space is strongly stimulated by the chemokine MCP-1, which is expressed
and secreted by ECs and VSMCs. The essential role of MCP-1 in
atherogenesis is underscored by a recent study demonstrating that
crossing MCP-1–deficient mice into
LDLR-/-
mice attenuated lesion formation by
>80%.32 Our group and
others have shown that TRO and other PPAR ligands inhibit growth
factor–directed ERK-MAPK–dependent VSMC
migration.5 10 11
Cell migration requires de novo gene transcription that is
consistent with PPAR acting in the nucleus to inhibit this
process.10 In particular,
activation of PPAR can inhibit ERK-MAPK signaling to the
nucleus.11 33
Because MCP-1–directed migration of monocytes is ERK-MAPK dependent,
interference with this pathway by TRO could contribute to the observed
reduction in intimal xanthomata and lesional macrophages in
treated
LDLR-/-
mice.
TRO and another PPAR ligand, RSG, which does not contain
an 
-tocopherol moiety, inhibited MCP-1–directed
migration of human monocytes in vitro. TRO also consistently
decreased intimal macrophage accumulation in the diabetic and
nondiabetic mice. These findings support the concept that inhibition of
monocyte attachment and migration in the vessel by TRO may be one of
the mechanisms contributing to the reduction of atherogenesis. Although
it cannot be ruled out that the reduction of intimal monocytes in part
reflected the reduced lesion size induced by TRO treatment, this is
unlikely to be the sole explanation, because the relative intimal
monocyte/macrophage content is known to be greatest in the
early stages (smaller lesions) of atherosclerosis. In
any case, the antiatherosclerotic activity of TRO-induced PPAR
activation clearly prevailed over its hypothesized promotion of foam
cell formation via increased expression of the scavenger receptor
CD36.16
Unlike other PPAR ligands, TRO has an
-tocopherol (vitamin E) moiety that theoretically could
contribute to its antiatherogenic activity through antioxidant
effects.34 Vitamin E has been
shown to suppress atherosclerosis in the apoE knockout
model, which develops advanced atherosclerotic
lesions.35 36
Whether the dose of vitamin E provided by TRO in the present study
is enough to impact lesion formation is doubtful. At 400 mg/kg TRO per
day,
LDLR-/-
mice received the equivalent of 8 IU of vitamin E, a dose much lower
than that reported to affect atherosclerosis or to
significantly protect LDL against
oxidation.35 36 37 38
Another line of evidence for the assumption that the effect of TRO on
lesion formation was not, to a significant degree, dependent on
antioxidant effects is provided by a parallel study demonstrating that
2 other PPAR ligands, RSG and GW7845,which do not contain the
-tocopherol moiety, inhibited atherogenesis in the
aortic root of male
LDLR-/-
mice fed a high-fat, cholesterol-enriched
diet.39 In addition, the
recent Heart Outcomes Prevention Evaluation (HOPE) clinical trial in
humans did not show an effect of vitamin E on coronary artery
disease events or
mortality.40
In summary, given the absence of consistent major
metabolic changes present in diabetic and nondiabetic
mice, it is likely that TRO at least in part decreases early
atherosclerotic lesion formation through direct vascular effects. In
human subjects with diabetes, who have a high risk for coronary
disease, TRO improves insulin resistance and other proatherogenic
metabolic parameters, which may improve
cardiovascular risk. It is possible that some of the
vascular effects observed in our murine models may also be present
in humans. Although Li et
al39 and our data demonstrate
that PPAR ligands suppress early atherosclerotic lesions, intimal
xanthomata do not inexorably progress to more advanced atherosclerotic
plaques; in fact, they often
regress.19 Therefore,
determining the effects of PPAR ligands on more advanced
atherosclerotic lesions may prove to be a stronger predictor of their
potential clinical benefit. Nonetheless, the present results
indicate that an investigation of potential antiatherogenic effects of
PPAR ligands is strongly
warranted.
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Acknowledgments |
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This work was supported by National Institutes of Health grant HL-58328 to Willa A. Hsueh. Shu Wakino was supported by a Mary K. Iacocca Fellowship in Diabetes. Ulrich Kintscher was supported by a Gonda (Goldschmeid) Fellowship in Diabetes.
Received August 10, 2000; accepted December 1, 2000.
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