(Circulation. 1999;99:2503-2509.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Evidence for Increased Collagenolysis by Interstitial Collagenases-1 and -3 in Vulnerable Human Atheromatous Plaques
From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine (G.K.S., U.S., P.L.), and Department of Pathology (E.R., F.J.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Joint Diseases Laboratory (A.R.P.), Shriners Hospitals for Children, Division of Surgical Research, Department of Surgery, McGill University, Montreal, Quebec, Canada; and Department of Clinical Sciences (R.C.B.), Colorado State University, Fort Collins, Colo.
Correspondence to Peter Libby, MD, Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, LMRC #307, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
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Abstract |
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Background—Several recent studies attempted to classify plaques as those prone to cause clinical manifestations (vulnerable, atheromatous plaques) or those less frequently associated with acute thrombotic complication (stable, fibrous plaques). Defining the cellular and molecular mechanisms that underlie these morphological features remains a challenge. Because interstitial forms of collagen determine the biomechanical strength of the atherosclerotic lesion, this study investigated expression of the collagen-degrading matrix metalloproteinase (MMP) interstitial collagenase-3 (MMP-13) and the previously studied MMP-1 in human atheroma and used a novel technique to test the hypothesis that collagenolysis in atheromatous lesions exceeds that in fibrous human atherosclerotic lesions.
Methods and Results—Human carotid atherosclerotic plaques, similar in size, were separated by conventional morphological characteristics into fibrous (n=10) and atheromatous (n=10) lesions. Immunohistochemical and Western blot analysis demonstrated increased levels of MMP-1 and MMP-13 in atheromatous versus fibrous plaques. In addition, collagenase-cleaved type I collagen, demonstrated by a novel cleavage-specific antibody, colocalized with MMP-1– and MMP-13–positive macrophages. Macrophages, rather than endothelial or smooth muscle cells, expressed MMP-13 and MMP-1 on stimulation in vitro. Furthermore, Western blot analysis demonstrated loss of interstitial collagen type I and increased collagenolysis in atheromatous versus fibrous lesions. Finally, atheromatous plaques contained higher levels of proinflammatory cytokines, activators of MMPs.
Conclusions—This report demonstrates that atheromatous rather than fibrous plaques might be prone to rupture due to increased collagenolysis associated with macrophages, probably mediated by the interstitial collagenases MMP-1 and MMP-13.
Key Words: atherosclerosis • collagen • cells • enzymes
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Introduction |
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Pathoanatomic studies showed that human atheroma that rupture share certain common characteristics. So-called vulnerable plaques, referred to here as atheromatous, characteristically have a thin fibrous cap (FC), a prominent collection of lipid, and abundant macrophages (M
).1 2 3 4 In contrast, plaques with
more vascular smooth muscle cells (SMCs), a well-developed FC, and
lower M and lipid content, referred to here as fibrous, appear less
prone to disruption. The integrity of the FC of the plaque and hence its resistance to rupture depend greatly on its content of fibrillar interstitial collagen.5 6 Hence, much effort has focused on the study of proteinases that may degrade interstitial collagen.
Specialized pathways of degrading macromolecules of the extracellular matrix involve a group of proteolytic enzymes known as matrix metalloproteinases (MMP), including 3 interstitial collagenases, any of which could catalyze the initial proteolytic attack on fibrillar interstitial collagen. We and others have shown expression of interstitial collagenase-1 (MMP-1),7 8 9 the prototypical MMP, in human atheroma.7 10
At least 2 other interstitial collagenases exist in mammals. Collagenase-2, or MMP-8, is expressed by neutrophils, cells not commonly found in human atheroma. However, collagenase-3, or MMP-13, a major interstitial collagenase in rodents, can occur in human tissues characterized by chronic inflammation and extensive matrix remodeling.11 12 13 14 15 Because atherosclerotic lesions and particularly vulnerable plaques also exhibit signs of chronic inflammation and matrix remodeling, we hypothesized that MMP-13 might also localize in atheroma.
Interstitial collagenases mediate the initial step of collagen degradation by cleaving triple-helical fibrils of interstitial collagen types I, II, and III at a single site (Gly775-Leu/Ile776), resulting in the generation of three-quarter– and one-quarter–length fragments.14 These fragments then become accessible to other proteases, such as gelatinases and stromelysins, which together with collagenases further catabolize collagen.7 10 16 17 Previous studies have provided evidence for augmented gelatinolytic and caseinolytic activity in unselected human atheroma.9 16 However, to date, no direct experimental evidence demonstrates collagenolytic activity in the atherosclerotic plaque.
Therefore, we sought direct evidence for collagenolysis in human atheroma of various morphologies using a novel and more biochemically rigorous in situ technique than those previously used.
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Methods |
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Human Tissue
Surgical specimens of human carotid plaques from endarterectomies (n=20) as well as nonatherosclerotic arteries (carotids from autopsies [n=6] and aortas from cardiac transplantation donors [n=5]) were obtained by protocols approved by the Human Investigation Review Committee at the Brigham and Women's Hospital. We used well-established criteria of plaque vulnerability.6 18 Plaques with a minimal FC thickness
0.8 mm and an immunohistochemically determined positive area
10% for SMCs and 
10% for M and lipid content were designated
as fibrous. In contrast, lesions with minimal FC thickness 0.3
mm, 10% positive area for SMC, and 20% positive area for M and
lipid content were designated as atheromatous
(Table
; Figure 1).
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The tissue samples were divided into 2 macroscopically identical portions. One half was embedded in OCT compound for morphological analysis, and the other half was snap-frozen for biochemical study.
Immunocytochemistry
Serial cryostat sections (6 µm) were fixed in acetone
(-20°C, 5 minutes), air-dried, and stained by the
avidin-biotin-peroxidase method. Tissue sections were treated with
0.3% hydrogen peroxide to inhibit endogenous peroxidase
activity and incubated with primary antibodies diluted in PBS
supplemented with 4% of the species-appropriate normal serum. The
subsequent processing was performed according to the manufacturer's
recommendations (Universal Dako LSAB kit, peroxidase; Dako Co). The
reaction was visualized with 3-amino-9-ethyl carbazole as substrate
(AEC; Sigma Chemical Co). Sections were counterstained with Gill's
hematoxylin solution (Sigma).
Cell types were identified with monoclonal anti-muscle actin HHF-35
(Enzo Diagnostics), monoclonal anti-human CD68 (M), or
CD31 (endothelial cells [ECs]) (DAKO Corp)
antibodies.
Polyclonal rabbit anti-human MMP-1 (a gift of Dr M.W. Lark and Merck Research Laboratories) and MMP-13 (Triple Point Biologics) antibodies were used for immunohistochemistry and Western blot analysis. Adjacent sections treated with nonimmune IgG served as controls for antibody specificity.
Sites of collagenase-cleaved interstitial type I collagen were detected by staining with a polyclonal rabbit antibody reactive to the carboxy-terminal COL2–3/4Cshort neoepitope generated by cleavage of native human collagen by either human collagenases MMP-1, MMP-8, or MMP-13.17 The antibody showed no immunoreactivity to native or denatured human type I or III collagens.
For double immunofluorescent staining for collagenase-cleaved and intact type I collagen, frozen sections were incubated for 90 minutes with rabbit anti-human COL2–3/4Cshort antibody, followed by biotinylated secondary goat anti-rabbit antibody (45 minutes; Vector Laboratories), and finally FITC-conjugated streptavidin (30 minutes; Amersham Corp). Subsequently, specimens were treated with an avidin-biotin blocking kit (Vector Laboratories) and washed and stained with mouse anti-human type I collagen antibody overnight at 4°C, biotinylated secondary horse anti-mouse antibody, and streptavidin conjugated with Texas red (Amersham Corp). Nuclei were stained with bisbenzimide (Calbiochem).
Staining of Collagens Type I and III by Picrosirius Red
Frozen sections were incubated for 90 minutes in 0.1% Sirius
red F3BA (Polyscience Inc) in saturated picric acid. After rinsing
twice in 0.01N HCl and in distilled water, sections were briefly
dehydrated with 70% ethanol and put under coverslips. Staining with
Sirius red was analyzed by polarization
microscopy.19
Quantitative Analysis for Histology and
Immunohistochemistry
Analysis of immunohistochemistry for M, SMCs, MMP-1,
MMP-13, and cleaved collagen and Sirius red and oil red O staining were
performed with a personal computer–based quantitative 24-bit Optimas
5.2 color image analysis system. The percentage of the total
area with positive color for each section was recorded.
Cell Culture
Human saphenous vein SMCs and ECs were isolated and cultured in
DMEM or M199 (BioWhittaker), respectively, supplemented with 10% fetal
bovine serum (Hyclone). Cells were rendered quiescent by culture in
serum-free insulin/transferrin medium (SMCs)20 or M199
supplemented with 0.1% BSA (ECs) 24 hours before stimulation.
Monocytes were isolated from leukopacs of healthy donors by counterflow centrifugation and plated into 6-well culture plates (Nunc, Inc), as described previously.21
Western Blot Analysis
Frozen tissue samples from 5 nonatherosclerotic arteries and 6
fibrous and 7 atheromatous carotid plaques were
homogenized (Ultra-turrax T 25,
IKA-Labortechnik) lysed (0.3 mg of tissue per 1 mL of lysis buffer),
and clarified by centrifugation (16 000g,
15 minutes) as described previously.7 Fifty
micrograms of total protein of tissue extracts, 10x ECs and SMCs or
2.5x M culture supernatants (Centricon 3 devices, Amicon), were
separated by 12% SDS-PAGE under reducing conditions and blotted onto
polyvinylidene difluoride membranes (Millipore) with a semidry
blotting apparatus (3.0 mA/cm2, 30
minutes; Bio-Rad). Blots were blocked overnight, and primary antibodies
(1:1000 polyclonal rabbit anti-human MMP-1 and
COL2–3/4Cshort; 1:5000 polyclonal rabbit
anti-human MMP-13; 1:1000 monoclonal mouse anti-human collagen type I,
interleukin [IL]-1ß [Upstate Biotechnology Inc], tumor necrosis
factor [TNF]-
[Endogen], and interferon [IFN]-
[Genzyme])
and secondary antibodies (goat anti-rabbit or anti-mouse [1:10,000])
were diluted in 5% nonfat milk/PBS/0.1% Tween 20. Specificity
of the rabbit anti-human MMP-1 and -13 antibodies was confirmed by use
of antibodies preincubated (1 hour, 37°C) with the respective
recombinant antigen (Chemicon and Triple Point Biological). Blots were
developed by chemiluminescence (NEN). Densitometric analysis
was performed with NIH Image software.
In Situ Hybridization
In situ hybridization was performed according to the
instructions of the manufacturer (Hyb-Probe, Shandon/Lipshaw) with a
mixture of FITC-labeled MMP-13-specific (5'-TAC GTA GGT CCC CAG GAC CGA
CGG AAG GAG-3'; 5'-AAC AAC GAC GCG TAC TCA AGC CGG TGA GGA-3'; 5'-TGC
TAC CGT AAC GAC TGT ACT AGA-3'; 5'-TAC TAC TAT GAT TGG TAT AAT ACC
TAT-3') or random oligomers.
Statistical Analysis
Data are presented as mean±SD and were compared between
fibrous and atheromatous plaques by an unpaired Student
t test. A value of P0.05 was considered
significant.
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Results |
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Collagenase-3 (MMP-13) colocalized with MMP-1 in human atheroma (Figure 2A
),
appeared most abundant in M, and localized mostly in the shoulder
region of the plaques as well as in areas surrounding the lipid core.
By quantitative image analysis, levels of MMP-1 as well as
MMP-13 in atheromatous plaques (21.4±3.4% and
20.4±2.7%, respectively) significantly (P<0.001;
n=10/group) exceeded those in fibrous plaques (5.9±2.1% and
2.8±0.9%, respectively), corresponding to the content of M (Figure 2B). Nonatherosclerotic arteries contained neither MMP-1 or
MMP-13 protein (data not shown). In accordance with these findings,
normal arteries did not contain MMP-13 mRNA in contrast with human
atherosclerotic plaques (Figure 3), as
detected by in situ hybridization. Within the lesions, MMP-13 gene
transcripts localized most prominently in areas described above as
positive for the immunoreactive protein. MMP-13 mRNA was detected in
luminal ECs, SMCs of the fibrous cap, and clusters of M. In situ
hybridization analysis with the respective negative control
yielded no signal (data not shown).
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Western blot analysis of tissue extracts for MMP-1 and MMP-13
provided biochemical corroboration of the results obtained by
immunohistochemistry (Figure 4).
Densitometric analysis showed a 2.7±1.3-fold
(P<0.001) greater level of MMP-1 and a 5.4±2.6-fold higher
level of MMP-13 in extracts of atheromatous (n=7)
compared with fibrous (n=6) plaques. Nonatherosclerotic arteries
(control) contained little or no immunodetectable MMP-1 or MMP-13.
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Although MMP-13 protein appeared most abundant in M, ECs and SMCs
within atheroma also contained MMP-13 protein and mRNA
(Figures 2A
and 3). To determine the relative capacities
of these atheroma-associated cell types to express MMP-13
(as well as MMP-1), we analyzed the media of
homogeneous cell cultures by Western blotting (Figure 5). Unstimulated SMCs and ECs barely
expressed MMP-13 (data not shown), but after stimulation with PMA 50
ng/mL (Figure 5) as well as IL-1ß 10 ng/mL or TNF- 50 ng/mL
(data not shown), these cells elaborated MMP-13 that migrated with
bands seen in extracts of atheromatous plaques. In
vitro, as in situ, M expressed more MMP-13 (as well as MMP-1) than
did SMCs or ECs. Indeed, 4 times less protein load in the M lanes
yielded much stronger signals (
20-fold by densitometric
analysis) than those derived from vascular cells (Figure 5). Even unstimulated M cultured for 10 days released MMP-13
constitutively (data not shown).
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Because the presence of immunoreactive MMPs does not necessarily
correspond to the active enzyme, we sought direct evidence for
collagenase activity by immunostaining for
the neoepitope of type I collagen fibrils generated uniquely by
collagenase cleavage.17 Nonatherosclerotic
human arteries do not express this epitope (data not shown). However,
human atherosclerotic plaques contained cleaved
interstitial type I collagen, as demonstrated by
immunostaining for this neoepitope (Figure 6A). Cleaved collagen characteristically
localized on the margins of intact interstitial type I
collagen, as demonstrated by double immunofluorescent labeling.
Importantly, areas of cleaved collagen colocalize with MMP-1– and
MMP-13–positive M. Color image analysis showed a
substantial increase of neoepitope in atheromatous
(22.8±7.9%; n=7) versus fibrous (3.3±2.2%; n=6; P<0.05)
plaques (Figure 6B). This finding corresponded to a reduced type
I collagen–positive area in atheromatous compared with
fibrous lesions (35.3±10.3% versus 67.9±11.9%;
P<0.001). Accordingly, Western blot experiments of tissue
extracts showed increased amounts of cleaved collagen in
atheromatous versus fibrous plaques (Figure 6C).
Densitometry of immunoreactive bands showed that fibrous lesions (n=6)
contained 2.4±1.1-fold more cleaved collagen than normal control
tissue (n=5). Some samples of normal arteries and fibrous plaques,
however, contained no immunodetectable cleaved collagen (Figure 6C), which accounts for the large standard error. In contrast to
fibrous lesions, all atheromatous plaques
analyzed (n=7) showed increased cleaved collagen, averaging
4.9±1.8-fold greater amount than in normal tissue. Interestingly,
measurement of type I collagen by Western blotting showed a reciprocal
decrease. The amount of intact collagen type I in fibrous plaques
(86.9±4.7%; n=6) did not differ significantly from that in normal
arteries, whereas atheromatous plaques showed a
52.2±8.9% (P<0.001; n=7) decrease of immunoreactive
intact collagen type I, corroborating the results obtained by Sirius
red birefringence in situ (Figure 6B).
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Finally, IL-1ß, TNF-, and IFN-, potential mediators of MMP
expression, were not detected in normal arteries but were expressed in
atherosclerotic lesions (Fig. 7). Interestingly,
atheromatous plaques contained not only more
pro–IL-1ß but even more importantly, more of the biologically active
17-kDa form versus fibrous lesions.
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Discussion |
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The integrity of the collagenous skeleton critically determines the lability of an atheromatous plaque to rupture.5 The collagen content of plaques depends on the balance between synthesis and breakdown. Collagen biosynthesis is difficult to assess in intact humans; however, SMCs, the major source of arterial interstitial collagen, are less frequent in atheromatous than fibrous plaques22 23 (Table
). Moreover, vulnerable regions
of human atherosclerotic plaques exhibit reduced procollagen gene
expression.24 With regard to collagen catabolism, interstitial collagenases catalyze the critical initial rate-limiting step in collagen breakdown.7 10 16 17 The tightly wound triple helix of interstitial collagen fibrils resists degradation by most proteinases. The actions of interstitial collagenases yield characteristic fragments 75% and 25% of the span of the intact collagen molecule,14 which are further degraded by collagenases and other members of the MMP family.7 10 16 17
Using an antibody raised against the C-terminal peptide neoepitope of
the three-quarter fragment that selectively recognizes cleaved forms of
type I collagen (as well as type II),17 we provide direct
evidence for increased collagenolysis in situ in
atheromatous plaques. Specificity of the antibody, as
established previously,17 was further supported by our
Western blot analysis, which yielded a single immunoreactive
protein of the expected molecular weight for the three-quarter
piece of collagenase-cleaved type I collagen within
extracts of human atheroma (Figure 6).
The present study also provides new information regarding the
spectrum of proteinases potentially involved in collagen catabolism in
atheroma. MMP-13, an interstitial
collagenase recently described in certain carcinomas and
extravascular sites of chronic inflammation,11 15
colocalizes with the "classic" interstitial
collagenase MMP-1 that was described previously by us and
others7 8 9 in human atheroma. Western blot
analysis of tissue extracts from atheromatous
plaques, as well as stimulated cultured human M and vascular cells
(ECs and SMCs), showed immunoreactive bands corresponding in molecular
weight to the zymogen and active forms of the collagenases
MMP-1 and MMP-13.25 26 27 Immunohistochemistry and Western
blot analysis pointed to M as the major source of these
collagenases. This observation agrees well with the finding
that cultured human M express collagenolytic activity28
and our previous demonstration of de novo synthesis and release of
MMP-1 by lipid-laden M isolated from experimental rabbit
atheroma.29 Expression of MMP-13 in addition
to MMP-1 and the presence of nonmetalloenzymes30 capable
of degrading extracellular matrix components suggest that strategies to
control proteolysis therapeutically may require a broad rather than
narrow spectrum of inhibitors.
Careful clinical-pathological correlations have led to the
concept that plaque morphology determines its propensity to provoke
acute manifestations. The dichotomization of plaques into "stable"
versus "vulnerable," although doubtless oversimplified, has proved
a useful framework for a better understanding of the pathophysiology of
the thrombotic complications of atheroma. The present
observations provide support for the established morphological,
anatomic classification at the molecular level. Our biochemical studies
on plaque extracts (although limited to extremes of a broad spectrum)
show that classification of plaques a priori on the basis of
morphology alone can predict their content of relevant proteinases and
their potential activators. The cytokines that we
found to be elevated in atheromatous plaques (IL-1ß,
TNF-, and IFN-) have been shown to induce expression of
MMPs.31 32 Therefore, one strategy to limit matrix
degradation would involve targeting inflammatory stimuli proximal to
protease gene expression rather than the multiple enzymes
themselves.
Vulnerable plaques characteristically contain relatively few SMCs
in relation to M18 23 33 34 (Table). The low
content of SMCs in atheromatous plaques can result from
impaired growth or even death of SMCs and may contribute to plaque
vulnerability, because SMCs synthesize interstitial
collagen. One of the cytokines (IFN-) found to be
overexpressed in atheromatous plaques in the
present study can cause cytostasis of SMCs.35 36 A
combination of 3 of the proinflammatory cytokines we found
overexpressed in atheromatous lesions (IL-1ß plus
TNF- plus IFN-; Figure 6) can promote death of SMCs
by apoptosis.37
The notion that augmented collagenolysis can precipitate rupture
of atherosclerotic plaques still requires direct proof. However,
several recent in vivo studies support the concept that unchecked
proteolytic activity can lead to dilatation of the aorta38
or rupture of aortic aneurysms in experimental
animals.39 In the case of human
atherosclerosis, we lack the type of direct evidence
provided by gene transfer or germ-line mutation that is currently
possible in experimental animals. However, the present unambiguous
demonstration of enhanced cleavage of collagen by
collagenases associated with an increase in the presence of
M-derived active forms of the interstitial
collagenases MMP-1 and MMP-13 in human atherosclerotic
plaques provides strong support for the role of M-mediated
collagenolysis in matrix degradation, remodeling, and plaque rupture
and hence in clinical complications of human atherosclerotic
plaques.
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Acknowledgments |
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This work was supported by a grant from the National Heart, Lung, and Blood Institute to Dr Libby (HL-34636) and was performed during the tenure of a Paul Dudley White fellowship (Dr Schönbeck) from the American Heart Association, Massachusetts Affiliate. We thank our colleagues Dr M.W. Muszcynski, E. Shvartz, and M. Herman for their skillful assistance.
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Footnotes |
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Drs Sukhova and Schönbeck contributed equally to this work.
Received November 9, 1998; revision received February 4, 1999; accepted February 16, 1999.
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34. Libby P, Geng YJ, Aikawa M, Schoenbeck U, Mach F, Clinton SK, Sukhova GK, Lee RT. Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol. 1996;7:330–335.[Medline] [Order article via Infotrieve]
35.
Hansson GK, Jonasson L, Holm J, Clowes MM, Clowes AW.
Gamma-interferon regulates vascular smooth muscle proliferation and Ia
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36. Warner SJ, Friedman GB, Libby P. Immune interferon inhibits proliferation and induces 2'-5'-oligoadenylate synthetase gene expression in human vascular smooth muscle cells. J Clin Invest. 1989;83:1174–1182.
37.
Geng YJ, Wu Q, Muszynski M, Hansson GK, Libby P.
Apoptosis of vascular smooth muscle cells induced by in vitro
stimulation with interferon-, tumor necrosis factor-, and
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38. Carmeliet P, Moons L, Lijnen R, Baes M, Lemaitre V, Tipping P, Drew A, Eeckhout Y, Shapiro S, Lupu F, Collen D. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet. 1997;17:439–444.[Medline] [Order article via Infotrieve]
39.
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U. Schonbeck and P. Libby Inflammation, Immunity, and HMG-CoA Reductase Inhibitors: Statins as Antiinflammatory Agents? Circulation, June 1, 2004; 109(21_suppl_1): II-18 - II-26. [Abstract] [Full Text] [PDF]
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S. Beyzade, S. Zhang, Y.-k. Wong, I. N. M. Day, P. Eriksson, and S. Ye Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2130 - 2137. [Abstract] [Full Text] [PDF]
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C. M. Dollery, C. A. Owen, G. K. Sukhova, A. Krettek, S. D. Shapiro, and P. Libby Neutrophil Elastase in Human Atherosclerotic Plaques: Production by Macrophages Circulation, June 10, 2003; 107(22): 2829 - 2836. [Abstract] [Full Text] [PDF]
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Z. Luan, A. J. Chase, and A. C. Newby Statins Inhibit Secretion of Metalloproteinases-1, -2, -3, and -9 From Vascular Smooth Muscle Cells and Macrophages Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 769 - 775. [Abstract] [Full Text] [PDF]
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A. Krettek, G. K. Sukhova, and P. Libby Elastogenesis in Human Arterial Disease: A Role for Macrophages in Disordered Elastin Synthesis Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 582 - 587. [Abstract] [Full Text] [PDF]
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 J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]
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M. W. Manning, L. A. Cassis, and A. Daugherty Differential Effects of Doxycycline, a Broad-Spectrum Matrix Metalloproteinase Inhibitor, on Angiotensin II-Induced Atherosclerosis and Abdominal Aortic Aneurysms Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 483 - 488. [Abstract] [Full Text] [PDF]
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B. R. Kwak, N. Veillard, G. Pelli, F. Mulhaupt, R. W. James, M. Chanson, and F. Mach Reduced Connexin43 Expression Inhibits Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, February 25, 2003; 107(7): 1033 - 1039. [Abstract] [Full Text] [PDF]
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D. K. Das Cardioprotection With High-Density Lipoproteins: Fact or Fiction? Circ. Res., February 21, 2003; 92(3): 258 - 260. [Full Text] [PDF]
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P. K. Shah Mechanisms of plaque vulnerability and rupture J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 15S - 22S. [Abstract] [Full Text] [PDF]
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V. Lemaitre, P. D. Soloway, and J. D'Armiento Increased Medial Degradation With Pseudo-Aneurysm Formation in Apolipoprotein E-Knockout Mice Deficient in Tissue Inhibitor of Metalloproteinases-1 Circulation, January 21, 2003; 107(2): 333 - 338. [Abstract] [Full Text] [PDF]
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B. Axisa, I. M. Loftus, A. R. Naylor, S. Goodall, L. Jones, P. R.F. Bell, M. M. Thompson, and C. Napoli Prospective, Randomized, Double-Blind Trial Investigating the Effect of Doxycycline on Matrix Metalloproteinase Expression Within Atherosclerotic Carotid Plaques * Editorial Comment Stroke, December 1, 2002; 33(12): 2858 - 2864. [Abstract] [Full Text] [PDF]
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 J. S. Forrester Prevention of Plaque Rupture: A New Paradigm of Therapy Ann Intern Med, November 19, 2002; 137(10): 823 - 833. [Abstract] [Full Text] [PDF]
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 M.T. Henry, K. McMahon, A.J. Mackarel, K. Prikk, T. Sorsa, P. Maisi, R. Sepper, M.X. FitzGerald, and C.M. O'Connor Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF Eur. Respir. J., November 1, 2002; 20(5): 1220 - 1227. [Abstract] [Full Text] [PDF]
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 C. Zaragoza, E. Soria, E. Lopez, D. Browning, M. Balbin, C. Lopez-Otin, and S. Lamas Activation of the Mitogen Activated Protein Kinase Extracellular Signal-Regulated Kinase 1 and 2 by the Nitric Oxide-cGMP-cGMP-Dependent Protein Kinase Axis Regulates the Expression of Matrix Metalloproteinase 13 in Vascular Endothelial Cells Mol. Pharmacol., October 1, 2002; 62(4): 927 - 935. [Abstract] [Full Text] [PDF]
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G. Ghilardi, M. L. Biondi, M. DeMonti, O. Turri, E. Guagnellini, and R. Scorza Matrix Metalloproteinase-1 and Matrix Metalloproteinase-3 Gene Promoter Polymorphisms Are Associated With Carotid Artery Stenosis Stroke, October 1, 2002; 33(10): 2408 - 2412. [Abstract] [Full Text] [PDF]
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T. Cyrus, S. Sung, L. Zhao, C. D. Funk, S. Tang, and D. Pratico Effect of Low-Dose Aspirin on Vascular Inflammation, Plaque Stability, and Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, September 3, 2002; 106(10): 1282 - 1287. [Abstract] [Full Text] [PDF]
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G. K. Sukhova, J. K. Williams, and P. Libby Statins Reduce Inflammation in Atheroma of Nonhuman Primates Independent of Effects on Serum Cholesterol Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): 1452 - 1458. [Abstract] [Full Text] [PDF]
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U. Schonbeck, G. K. Sukhova, N. Gerdes, and P. Libby TH2 Predominant Immune Responses Prevail in Human Abdominal Aortic Aneurysm Am. J. Pathol., August 1, 2002; 161(2): 499 - 506. [Abstract] [Full Text] [PDF]
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 C. Muckian, A. Fitzgerald, A. O'Neill, A. O'Byrne, D. J. Fitzgerald, and D. C. Shields Genetic variability in the extracellular matrix as a determinant of cardiovascular risk: association of type III collagen COL3A1 polymorphisms with coronary artery disease Blood, July 30, 2002; 100(4): 1220 - 1223. [Abstract] [Full Text] [PDF]
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S. Hussain, J. W. Assender, M. Bond, L.-F. Wong, D. Murphy, and A. C. Newby Activation of Protein Kinase Czeta Is Essential for Cytokine-induced Metalloproteinase-1, -3, and -9 Secretion from Rabbit Smooth Muscle Cells and Inhibits Proliferation J. Biol. Chem., July 19, 2002; 277(30): 27345 - 27352. [Abstract] [Full Text] [PDF]
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C. Buono, C. E. Come, J. L. Witztum, G. F. Maguire, P. W. Connelly, M. Carroll, and A. H. Lichtman Influence of C3 Deficiency on Atherosclerosis Circulation, June 25, 2002; 105(25): 3025 - 3031. [Abstract] [Full Text] [PDF]
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J. A. Ardans, A. P. Economou, J. M. Martinson Jr., M. Zhou, and L. M. Wahl Oxidized low-density and high-density lipoproteins regulate the production of matrix metalloproteinase-1 and -9 by activated monocytes J. Leukoc. Biol., June 1, 2002; 71(6): 1012 - 1018. [Abstract] [Full Text] [PDF]
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I. Loftus and M. Thompson The role of matrix metalloproteinases in vascular disease Vascular Medicine, May 1, 2002; 7(2): 117 - 133. [Abstract] [PDF]
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A. J. Chase, M. Bond, M. F. Crook, and A. C. Newby Role of Nuclear Factor-{kappa}B Activation in Metalloproteinase-1, -3, and -9 Secretion by Human Macrophages In Vitro and Rabbit Foam Cells Produced In Vivo Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 765 - 771. [Abstract] [Full Text] [PDF]
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M. D. Rekhter How to evaluate plaque vulnerability in animal models of atherosclerosis? Cardiovasc Res, April 1, 2002; 54(1): 36 - 41. [Abstract] [Full Text] [PDF]
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P. Libby and M. Aikawa Vitamin C, Collagen, and Cracks in the Plaque Circulation, March 26, 2002; 105(12): 1396 - 1398. [Full Text] [PDF]
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Z. S. Galis and J. J. Khatri Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis: The Good, the Bad, and the Ugly Circ. Res., February 22, 2002; 90(3): 251 - 262. [Abstract] [Full Text] [PDF]
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 N. Gerdes, G. K. Sukhova, P. Libby, R. S. Reynolds, J. L. Young, and U. Schonbeck Expression of Interleukin (IL)-18 and Functional IL-18 Receptor on Human Vascular Endothelial Cells, Smooth Muscle Cells, and Macrophages: Implications for Atherogenesis J. Exp. Med., January 22, 2002; 195(2): 245 - 257. [Abstract] [Full Text] [PDF]
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