(Circulation. 1999;99:3103-3109.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Membrane Type 1 Matrix Metalloproteinase Expression in Human Atherosclerotic Plaques
Evidence for Activation by Proinflammatory Mediators
Presented at the 47th annual scientific sessions of the American College of Cardiology, Atlanta, Ga, March 29–April 1, 1998; and published in abstract form (J Am Coll Cardiol. 1998;31:419A).
From the Atherosclerosis Research Center, Burns and Allen Research Institute, Division of Cardiology and Department of Medicine, Cedars-Sinai Medical Center (T.B.R., X.-P.X., S.J., S.M., X.-O.X, N.-N.C., S.K., B.S., P.K.S.), Los Angeles, Calif, and the Departments of Pathology and Laboratory Medicine (M.C.F.), UCLA School of Medicine, Los Angeles, Calif.
Correspondence to Dr T.B. Rajavashisth or Dr P.K. Shah, Atherosclerosis Research Center, Division of Cardiology, Room 5347, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail rajavashisth@cshs.org or shahp{at}cshs.org
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Abstract |
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Background—Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques, where in their active form, they may contribute to vascular remodeling and plaque disruption. In this study, we tested the hypothesis that membrane type 1 MMP (MT1-MMP), a novel transmembrane MMP that activates pro-MMP-2 (gelatinase A), is expressed in human atherosclerotic plaques and that its expression is regulated by proinflammatory molecules.
Methods and Results—MT1-MMP expression was examined in normal and
atherosclerotic human arteries by immunocytochemistry with specific
antibodies. MT1-MMP expression in human saphenous vein–derived smooth
muscle cells (SMCs) maintained in tissue culture was determined under
basal conditions and in response to proinflammatory molecules
(interleukin [IL]-1
, tumor necrosis factor [TNF]-, and
oxidized LDL [ox-LDL]) by use of Northern blot and ribonuclease
protection assays for mRNA, Western blot and immunoprecipitation for
protein, and gelatin zymography for catalytic activity. Medial SMCs of
normal vessel wall expressed MT1-MMP. In atherosclerotic arteries,
MT1-MMP expression was noted within the complex atheroma
colocalizing with SMCs and macrophages (M
). Cultured SMCs
constitutively expressed MT1-MMP mRNA and protein, which increased 2-
to 4-fold over control in a time-dependent manner within 4 to 8 hours
of exposure to IL-1, TNF-, and ox-LDL (thiobarbituric
acid–reactive substances, 13.4 nmol/mg LDL protein), whereas native
LDL had no effect. Flow cytometry revealed MT1-MMP expression by human
monocyte-derived M, which increased 3.8-fold over baseline within 6
hours after exposure to 10 ng/mL TNF-.
Conclusions—This study demonstrates that MT1-MMP, an
activator of pro-MMP-2, is expressed by SMCs and M in
human atherosclerotic plaques. Furthermore, proinflammatory molecules
upregulate MT1-MMP expression in vascular SMCs and M. Thus,
activation of SMCs and M by proinflammatory molecules may influence
extracellular matrix remodeling in atherosclerosis by
regulating MT1-MMP expression.
Key Words: metalloproteinases • cells • proteins • lipoproteins
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Matrix metalloproteinases (MMPs) are a family of structurally related proteases that are capable of degrading virtually all components of the extracellular matrix (ECM).1 2 A number of MMPs are expressed by smooth muscle cells (SMCs) and macrophages (M
) in atherosclerotic and injured vessels,
where they may participate in vascular remodeling, SMC migration,
neointima formation, and plaque
disruption.3 4 5 6 7 8 9 10 11 12 The MMPs are secreted as zymogens,
requiring activation by limited proteolysis, and their activity is
inhibited by naturally occurring inhibitors called tissue
inhibitors of MMPs (TIMPs).1 2 Unlike other
secreted MMPs, MMP-2 activation does not occur through proteolysis by
serine proteases but rather through a cell-surface–associated MMP
activator, although thrombin and
integrin-Vß3 may also
activate pro-MMP-2.13 14 Several membrane-bound
MMPs have recently been identified with membrane type 1 MMP (MT1-MMP)
or MMP-14, representing the prototypical form of
membrane-bound activator of pro-MMP-2.15 16
Expression of MT1-MMP in human atherosclerotic plaques has not been
reported. In the present study, we tested the hypothesis that MT1-MMP is expressed in human atherosclerotic plaque and that proinflammatory molecules regulate its expression in vitro.
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Methods |
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Materials
Purified mouse monoclonal antibodies to human MT1-MMP, MMP-2, and TIMP-2 were purchased from Oncogene Research Products. Peroxidase-conjugated rabbit anti-mouse IgG was obtained from Zymed Laboratories. SMC marker HHF35, M
marker CD68 (PG-M1), and mouse
nonspecific IgG (used as a negative control) were purchased from Dako.
Goat IgG used to block nonspecific binding in the flow cytometric
analysis was purchased from Santa Cruz Biotechnology.
Phycoerythrin (PE)-conjugated anti-mouse goat IgG was purchased
from Caltag Laboratories. All tissue culture media and supplements were
purchased from GIBCO-BRL. Fetal calf serum (FCS) was from Hyclone
Laboratories. Human cytokine tumor necrosis factor (TNF)-
and interleukin (IL)-1 or -ß were purchased from R&D Systems.
Purified human native and oxidized (Ox) LDL were kindly provided by Dr
Judith Berliner, UCLA (Los Angeles, Calif). Radioisotopes were
purchased from either New England Nuclear or Amersham.
Immunocytochemical Staining
Sections of normal and atherosclerotic arteries were subjected
to immunohistochemical staining for MT1-MMP and MMP-2. Staining for
SMCs and M were performed with cell-type–specific antibodies. A
human lung adenocarcinoma specimen, which has previously been shown to
express MT1-MMP,15 was used as a positive control. Tissue
specimens were deparaffinized with xylene followed by immersion in
graded ethanol. They were washed 3 times for 5 minutes each in
PBS and blocked with 3% rabbit serum in PBS for 30 minutes.
Specimens were then exposed to primary antibody against MT1-MMP (5
µg/mL) overnight at 4°C. Controls included nonspecific IgG as
negative control (5 µg/mL) instead of primary antibody and use of PBS
instead of secondary antibody. After they were washed in PBS, specimens
were incubated with biotinylated rabbit anti-mouse IgG for 30 minutes
in a humidified chamber at room temperature. Specimens were then washed
with PBS and stained with horseradish peroxidase-conjugated
streptavidin for 30 minutes. Specimens were finally incubated with
substrate solution for 1 to 15 minutes and counterstained with dilute
hematoxylin. Atherosclerotic plaques were immunostained
with human TIMP-2–specific antibody by use of a similar technique.
Isolation and Culture of Human Vascular SMCs and
Monocyte-Derived M
SMCs were isolated from human saphenous vein with type II
collagenase, as previously described.17 Cells
after 3 passages were used throughout the experiments and were studied
at confluence in all treatment conditions. Preparation and
characterization of ox-LDL were performed essentially as described
previously.18 19 Cells were treated with cytokines
(10 ng/mL) or ox-LDL (100 µg/mL), as previously
described.18 19 20 All reagents in our tissue culture
studies were verified for the absence of endotoxin by a commercially
available assay kit (BioWhittaker) that has a sensitivity detection
level of 1 pg/mL. The final concentration of endotoxin in lipoprotein
preparations was <20 pg/mL of the culture medium used.
Peripheral blood monocytes were isolated as described
previously.20 Monocyte-derived M were cultured in RPMI
1640 containing 10% FCS, 100 U/mL penicillin, 100 µg/mL
streptomycin, and 0.25 µg/mL amphotericin B for 5 days and then
starved in the culture medium without FCS but with 0.1% low endotoxin
BSA (Sigma). Experiments were performed in the starvation medium with
or without TNF- (10 ng/mL).
Northern Blotting and Ribonuclease Protection Assays
Total cellular RNA was isolated by lysis of SMCs in guanidinium
isothiocyanate, phenol-chloroform extraction, and ethanol
precipitation.21 Each RNA preparation (20 µg) was
denatured and electrophoresed through a 1.2% formaldehyde agarose gel,
after which each preparation was blotted onto nylon filters and
subjected to ultraviolet (UV) cross-linking. Filters were hybridized
with isolated and radiolabeled MT1-MMP–specific cDNA
probe.18 The blots were washed, autoradiographed, and then
rehybridized with a ß-actin cDNA probe as an internal control.
Quantitative results of the assays were obtained by densitometry of
autoradiograms. Ribonuclease protection assays on the
total RNA were performed with radiolabeled anti-sense MT1-MMP and
ß-actin sequences by use of a commercially available kit
(Ambion).
Immunoblotting
Extracts of partially purified plasma membrane fractions of SMCs
treated with IL-1, TNF-, or ox-LDL were isolated as described
previously.22 Briefly, SMCs were suspended in ice-cold
lysis buffer (0.1 mmol/L PMSF, 5 mmol/L EDTA, 5 mmol/L
EGTA, 100 mmol/L NaCl, and 5 mmol/L Tris-HCl; pH 7.4).
Mechanical disruption of the cells was performed by Polytron
homogenizer, and the lysates were centrifuged
at 40 000g for 30 minutes at 4°C. The crude pellet was
washed twice with ice-cold suspension buffer and then
centrifuged at 3000g for 10 minutes. The pellet was
discarded, and the supernatant was centrifuged again at
40 000g for 45 minutes at 4°C. The resulting pellet
containing the enriched membrane preparation was then resuspended at a
protein concentration of 2 mg/mL in a buffer containing HEPES, EGTA,
EDTA, and NaCl; snap-frozen, and stored at –70°C.
Proteins of SMC membranes (50 µg) and known molecular weight markers were separated by SDS-PAGE, transferred onto Western polyvinyl difluoride membranes, and incubated overnight at 4°C with blocking solution (5% skim milk in PBS). Purified mouse monoclonal antibodies (10 µg of IgG per mL) to human MT1-MMP were incubated with the blots overnight at 4°C in PBS buffer containing 0.1% Tween 20.23 The blots were washed twice with PBS buffer and then treated with rabbit anti-mouse antibody (1:4000 dilution) coupled to horseradish peroxidase. Immunodetection was accomplished with an enhanced chemiluminescence kit from Amersham.
Immunoprecipitation and Gelatin Zymography
MT1-MMP immunoprecipitation was performed in the presence of
protease inhibitor cocktail (Boehringer Mannheim),
as previously described.23 Equal amounts of extracts of
partially purified plasma membrane fractions of SMCs, untreated or
treated with IL-1 or ox-LDL, were incubated with purified mouse
monoclonal antibodies to either human MT1-MMP or an irrelevant protein.
Antigen-antibody complexes were precipitated with protein G and
A–coupled agarose beads (Oncogene Research Products) by
centrifugation. Equal amounts of the supernatants were
added to culture media harvested from human SMCs containing pro-MMP-2
and assayed for gelatinolytic activity essentially
as described previously.24 Proteins were electrophoresed
in the presence of SDS in discontinuous 10% SDS-PAGE containing 1
mg/mL gelatin (Novex). Gels were processed to renature the protein by
exchanging SDS to Triton X-100 (2 changes of 2.5% Triton X-100 for a
total of 30 minutes). Gels were subsequently incubated for 18 hours at
37°C in 50 mmol/L Tris-HCl, pH 7.4, containing 10 mmol/L
CaCl2 and 0.05% Brij 3 and stained with
colloidal brilliant blue G (Sigma), followed by destaining in 5%
methanol and 7% acetic acid.
Flow Cytometric Analysis of Cultured Human
Monocyte-Derived M
Human cultured M grown in absence or presence of TNF- were
harvested by treating the culture with cold PBS for 30 minutes and then
scraping the cells from the plastic. The cells were pelleted by
centrifugation and incubated with 20 µg of goat IgG
in PBS/0.1% sodium azide on ice for 10 minutes. Primary monoclonal
antibody (0.5 µg per sample to a total volume of 50 µL) was added
to cells, which were then incubated on ice for 30 minutes. After 2
washes with PBS containing 1% FCS/0.1% sodium azide, cells were
incubated with saturating concentrations of PE-conjugated goat
anti-mouse IgG for 30 minutes at 4°C for 10 minutes. After 2 more
washes, cells were fixed with 1% paraformaldehyde in
PBS. Analysis was performed with FACScan (Becton Dickinson).
Cell populations were gated according to forward and side scattering.
Results were plotted as intensity of fluorescence versus cell
number.
Data Analysis
Intensities of experimental bands from the RNA and protein
assays were measured by computer-assisted densitometry. Results are
expressed as mean±SEM. Statistical analyses were performed by
Student's t test to determine the significance of change in
the densitometric measurements. A significant difference was considered
for probability value 
0.05.
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Results |
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Localization of MT1-MMP in Normal and Atherosclerotic Human Arteries
Normal human coronary arteries showed abundant MT1-MMP immunoreactivity that colocalized with MMP-2 antigen staining within the medial SMC (Figure 1
; a, b, and c).
Human atherosclerotic plaques contained MT1-MMP and MMP-2 proteins in
the media underlying fibrous and lipid-rich regions (Figure 1;
d, e, and f). Both MT1-MMP and MMP-2 proteins were also detectable in
M of the fibrous plaques (Figure 1; g, h, and i). Mouse
nonspecific IgG used in place of primary antibody showed no background
or nonspecific staining (Figure 1j) in
atheromatous plaque. Human lung adenocarcinoma
specimens, which have previously been shown to express MT1-MMP, served
as a positive control, as shown in the inset of Figure 1j.
Lipid-rich plaques, as shown in Figure 1k, exhibited expression
of MT1-MMP that was mostly localized to M, as determined by counting
cells in defined areas under a light microscope. Lipid-rich plaques
also exhibited expression of MMP-2 (Figure 1i). In addition,
abundant TIMP-2 expression was observed in atherosclerotic plaques
(Figure 1; m and n).
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Augmented Expression of MT1-MMP mRNA in Stimulated SMCs
Northern blotting showed that SMCs contained a single mRNA species
of 4.5 kb (Figure 2), a size similar to
MT1-MMP mRNA observed in normal lung tissue and tumor
cells.15 These assays also revealed that exposure of
cultured SMCs to IL-1, TNF-, or ox-LDL resulted in the
accumulation of MT1-MMP mRNA (Figures 2, 3, and 4). Both IL-1
and ox-LDL caused a time-dependent progressive increase in steady-state
levels of MT1-MMP mRNA in stimulated SMCs. MT1-MMP mRNA levels
increased within 4 hours of exposure to IL-1, reached a peak level
of 
4-fold above control by 6 hours, and remained elevated for 
12
hours (Figure 3). The time course for the
induction of MT1-MMP mRNA in response to ox-LDL appeared similar to
IL-1-. MT1-MMP mRNA levels increased (2.5-fold), peaked at 8
hours, and remained elevated for 16 hours (Figure 4).
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Increased Expression of MT1-MMP Protein in Stimulated SMCs
To establish that SMCs expressed MT1-MMP mRNA translates into
immunoreactive protein, we performed SDS-PAGE coupled with
immunoblotting on the plasma membrane extracts of
unstimulated and stimulated SMCs. SMCs constitutively expressed a
membrane-associated protein that reacted with human MT1-MMP–specific
antibody (Figure 5). Plasma membrane
extracts derived from cells that had been stimulated with IL-1,
TNF-, or ox-LDL exhibited increased immunoreactive MT1-MMP. The
IL-1–mediated increase in MT1-MMP mRNA correlated with an 3-fold
increase in MT1-MMP protein levels in SMC membranes (Figure 5).
Treatment of cells with ox-LDL also increased (2-fold) the level of
MT1-MMP proteins in SMC membrane extracts.
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Stimulation of MT1-MMP Enzymatic Activity in SMCs
To examine whether increased levels of MT1-MMP mRNA and
immunoreactive protein correspond to augmented enzymatic activity, we
performed SDS-PAGE gelatin zymography on plasma membrane extracts of
SMCs stimulated with IL-1 or ox-LDL. Incubation of medium
conditioned by human SMCs that contained pro-MMP-2 with plasma membrane
extracts derived from cells that had been stimulated with IL-1 or
ox-LDL increased the proteolytic conversion of 72-kDa pro-MMP-2 to new
gelatinolytic bands of 70 and 68 kDa, corresponding
to the processed active MMP-2 (Figure 6). Stimulation of SMCs with
TNF- also significantly increased the levels of membrane-associated
MT1-MMP enzymatic activity (data not shown). Purified mouse monoclonal
antibody to human MT1-MMP immunoprecipitated a 64-kDa protein of the
size of MT1-MMP from the membrane extracts of unstimulated and
stimulated SMCs (data not shown). Membrane-bound pro-MMP-2 proteolytic
processing activity was reduced in membrane extracts after
immunodepletion of MT1-MMP with the specific antibody (Figure 6).
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Increased Expression of MT1-MMP Protein in Stimulated M
In the basal state, M expressed low amounts of MT1-MMP, with
14.3±3.9% of cells showing a positive event compared with the
background level of 4.7±2.4% of cells. Exposure to TNF- for 6
hours increased the number of positive cells to 41.4±0.3% of the cell
population (Figure 7).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we have demonstrated that MT1-MMP, a membrane-bound MMP that activates pro-MMP-2, is expressed in medial SMCs and to a lesser extent in adventitia of normal and atherosclerotic coronary arteries. This study also demonstrates MT1-MMP expression by SMCs and M
in lipid-rich atherosclerotic plaques. The
in vitro data from this study show that human saphenous vein–derived
SMCs constitutively express MT1-MMP along with pro-MMP-2 and that
proinflammatory molecules (IL-1, TNF-, and ox-LDL) augment
MT1-MMP expression, leading to increased activation of pro-MMP-2. This
suggests a functional interaction between MT1-MMP and MMP-2 in
SMC-mediated vascular remodeling in normal and atherosclerotic human
arteries.
Activation of SMCs and M by proinflammatory molecules generated in
response to atherogenic stimuli appears to occur during various stages
of atherosclerosis. Several recent studies indicate
that ox-LDL may promote this process.25 26 27 We found that
exposure of cultured SMCs to proinflammatory cytokines and
ox-LDL alters appreciably the steady-state levels of MT1-MMP mRNA. The
augmented MT1-MMP mRNA correlated with increased plasma
membrane-associated immunoreactive protein and catalytic function to
precursor MMP-2, as demonstrated by Western blotting and gelatin
zymography. These results provide a possible mechanism underlying the
previous findings showing that IL-1– or TNF-–stimulated human
saphenous vein SMCs produce significantly increased levels of active
MMP-2.24 The results of our studies raise the intriguing
possibility that ox-LDL, directly or by inducing activators
such as cytokines, may influence remodeling of the ECM in
atherosclerosis. Previous studies showing that reactive
oxygen species can promote activation of MMPs26 27 argue
in favor of the concept that proinflammatory cytokines or
ox-LDL mediate the activation of MT1-MMP by generating highly reactive
oxygen species. Additional studies are required to test these
possibilities.
MT1-MMP is a 64-kDa protein that contains a single transmembrane domain
with the catalytic site positioned on the exterior surface of the
cell.15 MT1-MMP belongs to a family of cell-bound proteins
that specifically activate pro-MMP-2, which, unlike other MMPs,
is not activated by plasmin and other serine
proteases.1 2 13 14 Pro-MMP-2 binds to MT1-MMP and becomes
activated through limited proteolysis by MT1-MMP. The
properties of MT1-MMP are consistent with the membrane
localization and inhibition profiles attributed previously to the cell
surface–associated MMP-2 activator.13 14 15 16 17
Membrane lysates of vascular SMCs induced the conversion of pro-MMP-2
to the fully activated (68 kDa) protein through the
intermediate 70-kDa form. This catalytic conversion corresponded to
IL-1–, TNF-–, or ox-LDL–induced levels of MT1-MMP mRNA and
immunoreactive protein. Additionally, the affinity-purified
anti–MT1-MMP antibody specifically blocked a substantial portion of
the membrane-associated proteolytic activity that catalyzed the
conversion of 72-kDa pro-MMP-2 to MMP-2. Because MT1-MMP belongs to a
family of enzymes including 4 members, the residual activity that
partially activates the conversion of pro-MMP-2 to MMP-2 after
immunodepletion of MT1-MMP in our assays may be due to other members of
the family or to related enzymes present in SMC membrane
extracts.
Recent studies have suggested a unique mechanism by which MT1-MMP
activates pro-MMP-2.28 29 MT1-MMP–induced
activation of pro-MMP-2 appears to involve the formation of a complex
with TIMP-2, which in turn can form a ternary complex of
MT1-MMP/TIMP-2/pro-MMP-2. In the present study, we have also
demonstrated immunohistochemical evidence for TIMP-2 expression in
M-rich regions of human atherosclerotic plaque. Galis et
al4 previously showed evidence of the presence of active
MMP-2 in human atheroma using in situ zymography. Thus, all
3 components of the ternary complex necessary for the generation of
active MMP-2 coexist in the atherosclerotic plaque. Additionally,
recent evidence suggests that MT1-MMP is also capable of directly
degrading ECM.30 The exact functional significance of
MT1-MMP expression in atherosclerotic plaque demonstrated in the
present study remains to be clarified. Our findings, however,
provide evidence that coexpression of MT1-MMP and MMP-2 in SMCs could
play a critical role in normal vascular homeostasis and may also
contribute to abnormal matrix turnover and remodeling in
atherosclerotic plaques. The presence of an activator of
pro-MMP-2 on the plasma membrane of SMCs or M may serve to localize
matrix degradation near the cell surface, permitting a focal and
controlled dissolution of ECM.
The results of our studies suggest that inflammatory activation of MT1-MMP may contribute to the enhanced local matrix degradation in atherosclerotic plaques. Experimental studies with MMP inhibitors have demonstrated inhibition of neointima formation in a double-injury–restenosis model in the pig, suggesting a potentially critical role for MMPs in vascular SMC migration and accumulation as well as collagen gene expression after vascular injury.11 Similarly, focal expression of several MMPs, including MMP-2, in rupture-prone regions of human atherosclerotic plaque, as well as the previously demonstrated ability to induce collagen breakdown in vitro and in vivo, provides support for the role of MMPs in plaque disruption and consequent acute coronary thrombosis.8 9 31 Preferential expression of MMP-2 and TIMP-2 has been demonstrated in areas of superficial plaque erosions and endothelial denudation, a process that accounts for 30% to 40% of coronary thrombi, suggesting the possible involvement of MMP-2 in basement membrane dissolution and endothelial desquamation in plaque erosion.32 An improved understanding of the factors that regulate the activity of MMPs in general and MMP-2 in particular should provide new directions for the development of novel therapeutic interventions to prevent atherosclerotic plaque growth, erosion, and rupture or restenosis after angioplasty.
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Acknowledgments |
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This research work was supported by funds from the National Heart, Lung, and Blood Institute (grants HL-51980 and HL-58555 to Dr Rajavashisth) and by a generous grant from the Grand Foundation of Los Angeles, Calif (Dr Shah). Dr Xu was supported by the Dunitz family fellowship award during this research. Dr Jovinge was supported by a fellowship from the Johann and Throne Holst and the Swedish Heart and Lung Foundations. We thank Dr Judith Berliner for providing native and oxidized LDL preparations, Alan Wagner and Leslie Drake for human monocyte-derived M
, and Sangeetika Tripathi for expert technical
assistance. The authors thank Maria Muszynski, DVM, of the Brigham and
Women's Hospital, Boston for help with human SMC cultures. Received August 12, 1998; revision received March 31, 1999; accepted March 31, 1999.
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