(Circulation. 1995;92:1393-1398.)
© 1995 American Heart Association, Inc.
Articles |
Interstitial Collagenase (MMP-1) Expression in Human Carotid Atherosclerosis
From the Departments of Surgery (T.H., A.W.C.), Medicine (K.D.O.), and Pathology (M.F., C.E.A.), University of Washington, Seattle; the Department of Medicine, Washington University School of Medicine at the Jewish Hospital, St Louis, Mo (H.G.W.); and the Department of Medical Biochemistry, University of Tampere (Finland) Medical School (S.T.N.).
Correspondence to Alexander W. Clowes, MD, Professor, Department of Surgery, RF-25, University of Washington, Seattle, WA 98195. E-mail clowes@u.washington.edu.
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Abstract |
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Background In human atherosclerosis, most clinical events occur when plaque integrity is compromised and hemorrhage and thrombosis result. One mechanism for this might be the release by plaque cells of matrix-degrading proteases, such as interstitial collagenase (matrix metalloproteinase-1, MMP-1), which degrades two major plaque structural proteins, types I and III collagen. This study was undertaken to determine whether MMP-1 is expressed in human atherosclerotic plaques.
Methods and Results To determine the cellular source and location of MMP-1 in human carotid atherosclerotic lesions, in situ hybridization and immunohistochemistry were performed on 20 endarterectomy specimens. Six nonatherosclerotic carotid arteries also were studied. Intense MMP-1 expression (mRNA and protein) was detected in a subset of plaque macrophages located at the borders of the lipid cores adjacent to fibrous caps and shoulder regions. Subsets of plaque smooth muscle cells and endothelial cells also expressed MMP-1. There was a strong correlation between the percentage of the lipid core occupied by hemorrhage and the percentage of the lipid core perimeter positive for MMP-1 (r=.823, P=.0001). MMP-1 was not detected in any cell type in nonatherosclerotic carotid arteries.
Conclusions This study demonstrates that MMP-1 is expressed by several cell types in human carotid atherosclerosis and that there is a correlation between the expression of the protease and histopathological evidence of plaque instability. Since MMP-1 may degrade the major structural collagens of the plaque, expression of the protease by macrophages in regions critical to plaque integrity could contribute to plaque expansion, rupture, and hemorrhage.
Key Words: atherosclerosis • collagenase
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Advanced human atherosclerotic plaques are characterized by a lipid core covered by a fibrous cap composed of smooth muscle cells (SMCs) and extracellular matrix and may obstruct blood flow by protruding into the arterial lumen.1 These lesions have chronic inflammatory infiltrates of macrophages and T lymphocytes. In the majority of human plaques, microvasculature arising primarily from the capillaries of the adventitial vasa vasorum infiltrates into the plaque base.2 3 Plaque instability, manifesting as ulceration of the fibrous cap, plaque rupture, or intraplaque hemorrhage, is largely responsible for the complications of atherosclerosis.4 Instability is characteristic of plaques with a high content of extracellular lipid and an excess of macrophages in the cap.5 6 Sites of rupture, particularly in the margins of atherosclerotic plaque fibrous caps, are rich in macrophages.7 8 9 Release of proteolytic enzymes, in particular matrix metalloproteinases (MMPs), by these cells has been suggested as a mechanism of cap erosion.4 5 6 8 Inflammatory cytokines secreted by macrophages also might induce the release of matrix-degrading proteases from neighboring SMCs and endothelial cells.
MMPs are a family of enzymes that, as a group, can degrade a wide variety of extracellular matrix components. They have been implicated in normal tissue remodeling as well as in inflammatory processes, tumor invasion, and wound healing.10 MMPs are expressed in vitro by a variety of vascular cells, including macrophages, SMCs, and endothelial cells.11 12 13 In atherosclerotic plaques, macrophage-derived foam cells and also some SMCs have been shown to express stromelysin (MMP-3),14 which degrades principally proteoglycan core protein, laminin, and basement membranes.
Interstitial collagenases are the only metalloproteinases that can cleave native collagen types I and III,11 which are major structural components of the fibrous plaque cap.15 The major human interstitial collagenase, MMP-1, is secreted by a variety of mesenchymal and epithelial cell types.11 MMP-1 might play a significant role in fibrous plaque disruption by contributing to the degradation of interstitial collagens and thinning of the fibrous cap.16 It is not known whether MMP-1 is expressed in atherosclerotic lesions or whether it might participate in the pathogenesis of plaque instability. The purpose of this study was to determine, by in situ hybridization and immunohistochemistry, the location and cellular source of MMP-1 in human carotid atherosclerotic plaques and the relation of MMP-1 expression to histopathological evidence of plaque instability.
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Methods |
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Human Carotid Tissue
Carotid endarterectomy specimens were obtained from 20 consecutive patients (14 men and 6 women; mean age, 71 years; range, 50 to 83 years) treated by endarterectomy for occlusive carotid disease with a >75% occlusion of the common carotid artery. Half of the patients were symptomatic on the ipsilateral side of the carotid sample: 9 had evidence of transient ischemic attack or ocular symptoms, and 1 had had a stroke. The patients were from the University of Washington and the Seattle Veterans' Affairs Medical Centers. As controls, six carotid arteries were obtained from organ donors. Consent was obtained for research use of all carotid specimens. Samples were fixed in 10% neutral buffered formalin and decalcified with formic acid. After being embedded in paraffin, the carotid specimens were cross-sectioned along the entire length at 1-mm intervals. Transverse sections 8 µm thick were cut and used for in situ hybridization and immunohistochemistry.
The control carotid arteries had only diffuse intimal thickening without inflammatory cell infiltrate, as judged by light-microscopic examination of hematoxylin-eosin–stained sections. The presence of extracellular lipid deposition could not be excluded with histological stains for lipid, since any lipid present in these sections would have been extracted during deparaffinization.
In Situ Hybridization
Sections were deparaffinized and
rehydrated in graded alcohols,
rinsed in 0.5xSSC, and incubated with 50 µg/mL proteinase K (Sigma
Chemical Co) for 40 minutes at 37°C. The slides then were washed
briefly in 0.5xSSC and prehybridized in 100 mL of hybridization buffer
(50% formamide, 0.3 mol/L NaCl, 20 mmol/L Tris, pH 8.0, 5 mmol/L EDTA,
1x Denhardt's solution, 10% dextran sulfate, and 10 mmol/L
dithiothreitol). The prehybridization was performed in airtight boxes
containing blotting paper saturated with 50% formamide and 4xSSC on
the bottom at 55°C for 2 hours. 35S-labeled riboprobes
were generated as described previously17 from a 0.55-kb
human MMP-1 cDNA cloned into Bluescript vector (Stratagene) and
linearized with BamHI for antisense transcriptions and with
Sac II for sense transcriptions.18 Riboprobes
were added to the prehybridized slides in 25 µL of fresh
hybridization solution at 3.5x105 cpm per slide.
Hybridization was continued overnight at 55°C. The slides then were
rinsed three times in 0.5xSSC and immersed in RNase A solution (20
mg/mL in 0.5 mol/L NaCl and 10 mmol/L Tris, pH 8.0) for 30 minutes at
37°C. The slides were rinsed in 2xSSC and washed for 2 hours in
0.1xSSC and 0.5% Tween 20 at 37°C. After rinsing in 2xSSC, the
slides were dipped in Kodak NTB-2 nuclear track emulsion and exposed at
4°C for 14 days. Positive controls for the MMP-1 antisense riboprobe
included human skin burn wounds.19 Control hybridizations
performed with a sense riboprobe for MMP-1 produced nonspecific
background signal only (data not shown).
Immunohistochemistry
Immunohistochemical staining was
performed as described
previously3 by the immunoperoxidase method with
3,3'-diaminobenzidine plus nickel chloride as a chromogen. Cell types
were recognized by the following antibodies: human macrophages
by the mouse monoclonal antibody HAM-56 (titer, 1:1000) (Dako
Corp),20 SMCs by anti–smooth muscle 
-actin
(titer, 1:1000) (Dako),21 and endothelial
cells by the lectin Ulex europaeus I (Vector Laboratories
Inc).22 MMP-1 protein was localized with rabbit polyclonal
antiserum to human MMP-1 (1:4000),23 24 which was
generated to pure interstitial collagenase
produced by U937 cells.25 This antiserum has been shown to
recognize human MMP-1 and does not cross-react with any other human
MMP.26 Slides were counterstained with hematoxylin. Human
skin burn wounds were used as positive control tissue for MMP-1
immunohistochemistry.19 Negative controls included
substitution of normal rabbit serum for MMP-1 antiserum or mouse IgG
for monoclonal antibodies as well as omission of the primary antibody,
antiserum, or lectin. Double-label immunohistochemistry was
performed as described previously.3 Briefly, the slides
were incubated with the MMP-1 antibody diluted in PBS plus 1% BSA
overnight at 4°C. After being washed, sections were incubated with
gold-labeled goat anti-rabbit IgG (Amersham) diluted in PBS
(1/40) plus 1% BSA and 0.1% gelatin for 1 hour at room temperature.
Sections were washed, and the gold was visualized with an IntenSE M
silver enhancement kit (Amersham). The sections then were incubated
sequentially with (1) anti–-smooth muscle actin or HAM 56, (2)
biotinylated horse anti-mouse IgG (Vector), and (3)
avidin-biotin-alkaline phosphatase complex (Vector). The
alkaline phosphatase was developed with a red substrate kit (Vector),
and the slides were counterstained with methyl green. Negative controls
included substitution of normal rabbit serum for the MMP-1 antiserum
and substitution of normal mouse IgG for the anti–-smooth
muscle actin or HAM-56.
Measurement of Lipid Core Parameters
Transverse sections from
three different levels of each of the
20 carotid endarterectomy specimens were
deparaffinized in xylene and rehydrated in graded alcohols. Sections
were immunostained with the MMP-1 antiserum, counterstained
with methyl green, and projected onto a computerized digitizing pad
with a camera lucida to measure the total lipid core perimeter and the
portion of the perimeter occupied by cells staining for MMP-1. Adjacent
hematoxylin-eosin–stained sections were digitized for lipid
core area and areas in the core representing old
hemorrhage, ie, areas of thrombus and areas with fragments of
red blood cells. Areas with fragments of red blood cells were further
verified because they stained positively with the Ulex
europaeus lectin, which binds to a receptor on red blood cell as
well as endothelial cell membranes.22
Regions with intact red blood cells were not included in the
hemorrhage area, since these most likely
represented recent hemorrhage induced by surgical
manipulation at the time of endarterectomy. Five
plaques were fully analyzed at 1-mm intervals to determine that
only three sections around the area of maximal plaque thickness were
necessary to evaluate MMP-1 expression.
Statistics
The results are expressed as mean±SD.
Least-squares linear
regression analysis was performed with the STATVIEW 512+ program
(BrainPower Inc). Values of P<.05 were
considered statistically significant.
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Results |
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Histopathology
All the carotid endarterectomy specimens had a substantial fibrous cap overlying a lipid core. Calcification was identified in 12 of 20 plaques (60%). The lipid cores had widely varying degrees of old intraplaque hemorrhage, ranging from 2% to 73% of core volume (35±21%). Fibrous cap rupture was infrequent, since the zone of hemorrhage connected with the arterial lumen in only 4 of 20 plaques (20%). The lipid core size, as measured in two-dimensional histological sections, varied from 1 to 28 mm2 (10±7 mm2).
Localization of Collagenase Expression in Carotid
Arteries by In Situ Hybridization and
Immunohistochemistry
In situ hybridization and immunohistochemistry
demonstrated that
MMP-1 mRNA and protein were particularly prominent at the outer edge of
lipid cores in regions containing a high density of macrophages
(Fig 1
). In many carotid lesions, MMP-1 expression also
was present in the shoulder regions (Fig 1) as well as beneath
the
fibrous cap (Fig 2).
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To confirm the presence of MMP-1
protein in subsets of
macrophages and SMCs, double-label immunohistochemistry was
performed with the MMP-1 antiserum together with either the
macrophage marker (HAM-56) or the smooth muscle marker
(anti–-actin). The black reaction product identifying MMP-1
protein and the red reaction product of the macrophage
marker (HAM-56) are colocalized to a subpopulation of foam cells at the
interface of the lipid core and the fibrous cap (thin arrow, Fig
3A). Some regions of SMCs in the fibrous cap showed
positive staining with the MMP-1 antibody (thin arrow, Fig 3B)
and some
did not (Fig 2D
). Similar positive MMP-1 staining also was
found in
subsets of SMCs in areas of intimal thickening adjacent to plaques in
all endarterectomy specimens.
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Microvessels were detected frequently
near the intima-media border.
The majority of the microvessels did not stain for MMP-1 (data not
shown), but positive immunostaining for this protease
was present in some endothelial cells in small
microvessels in the plaque shoulder regions (Fig 4A).
Adjacent sections stained with Ulex lectin confirmed the
localization of MMP-1 to the endothelium (Fig 4B).
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Although MMP-1 was detected immunohistochemically in
macrophages, SMCs, and endothelial cells, as
identified by double-label immunohistochemistry performed with the
MMP-1 antiserum and, respectively, the HAM-56, -actin, and
Ulex markers, the possibility that occasional unlabeled
mesenchymal cells such as fibroblasts also might express MMP-1 could
not be excluded.
MMP-1 mRNA and protein were found in a similar pattern
in each of the
20 diseased carotid arteries examined but were not detected in the
plaque periphery at distances of >0.5 mm from the lipid core. In
contrast, in 6 carotid arteries removed from organ transplant
donor cadavers, areas with diffuse nonatherosclerotic intimal
thickening (representing the normal morphology of adult
human arteries) did not stain for MMP-1 (Fig 4C).
Comparison of Histopathological and Clinical Data With MMP-1
Expression
Sections obtained from five endarterectomy
specimens at 1-mm intervals beginning at the common carotid artery and
extending distally to the internal carotid artery were analyzed
to determine the relative amounts of MMP-1 expression (percent of lipid
core perimeter occupied by MMP-1–positive cells). The mean value of
MMP-1 expression for a set of three sections taken at the site of
maximal plaque mass was found to be representative of
plaque MMP-1 expression, since it fell within the 95% CI for the mean
of all levels analyzed in the five specimens. In specimens with
more than one discrete plaque, only one plaque was chosen for
analysis.
There was a direct linear correlation between the percentage
of the
lipid core occupied by hemorrhage and the percentage of the
lipid core perimeter positive for MMP-1 (r=.823,
P=.0001) (Fig 5). Frequently, we observed
MMP-1–positive macrophages at the outer edges of lipid cores
away from areas of hemorrhage. The correlation of MMP-1 with
lipid core size failed to reach statistical significance
(r=.4, P=.066), but the percentage of lipid
core
occupied by hemorrhage did correlate with core size
(r=.50, P=.024). There was no correlation of
MMP-1 with plaque rupture (r=.25, P=.29) or
symptoms (r=.10, P=.66).
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Discussion |
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This study demonstrates that in human carotid arteries, the matrix-degrading enzyme MMP-1 is expressed in advanced atherosclerotic plaques but not in nonatherosclerotic intima. This enzyme, which degrades types I and III collagen, could contribute to plaque expansion, disruption, and thrombosis. The source of MMP-1 is a population of vascular wall cells, in particular a subset of plaque macrophages.
In vitro, macrophages, SMCs, and endothelial cells have been shown to release a number of matrix-degrading proteases, including MMP-1.11 12 13 Macrophage-derived foam cells and also some SMCs in atherosclerotic plaques have been shown to express stromelysin (MMP-3),14 which degrades principally proteoglycan core protein but not types I and III collagen.27 MMP-1 would be required for the degradation of these two matrix proteins,11 and it has been shown that fibrous caps from unstable plaques have collagen fiber disruption.16 The present study shows that MMP-1 mRNA and protein are expressed primarily by a subset of plaque macrophages located at regions critical to plaque integrity. Thus, the secretion of this protease by macrophages might contribute to plaque instability. MMP-1 protein was associated with macrophages, SMCs, and microvascular endothelial cells both at the boundary between the fibrous cap and the lipid core and in the shoulder region of the plaque. The location of the protease supports the conclusion that it might play a role in fibrous cap disruption.
MMP-1 expression was confined to the atherosclerotic plaques and was
not found in control arteries with diffuse intimal thickening, as
judged by light-microscopic examination of
hematoxylin-eosin–stained, paraffin-embedded sections.
This observation raises the possibility that factors present only
in the plaque regulate the expression of MMP-1. MMP-1 expression in
vascular cells can be stimulated by many growth factors and
cytokines, including interleukin-1, tumor necrosis factor-,
and platelet-derived growth
factor.13 28 29 The
expression of MMP-1 is controlled at the transcriptional level by the
activating protein-1 family of transactivating factors.30
The upregulation of MMPs by cytokines may be important, since
platelet-derived growth factor,31
interleukin-1,32 and tumor necrosis
factor-33 have been detected in vascular lesions. In
addition to being regulated transcriptionally, all metalloproteinases
are secreted as latent proenzymes that require activation that is often
proteolytic.34 Plasmin and stromelysin together
activate MMP-1 in
vitro,35 36 37 38 and both of
these
molecules are present in the atherosclerotic
plaque.14 39 The presence of organizing thrombus in
some
carotid plaques suggests the presence of sufficient amounts of plasmin
to activate latent MMP-1. On the other hand, intramural
hemorrhage also might contain other plasma components, such as
2-macroglobulin, a potent inhibitor of
MMP-1.40 The tissue inhibitors of
metalloproteinases expressed constitutively by vascular wall cells
further modulate MMP activity.10 13 Thus, MMP-1
activity
in carotid atherosclerotic plaques probably is regulated by a number of
factors and cannot be correlated directly with the presence of MMP-1
mRNA or protein. However, the strong association of MMP-1 protein with
hemorrhage demonstrated in the present study is
consistent with the possibility that MMP-1 contributes to
instability of human carotid plaques.
This study demonstrates a direct linear relation between hemorrhage in the lipid core of the plaque and MMP-1 expression by cells at the lipid core perimeter. Intraplaque hemorrhage in carotid atherosclerotic plaques has been reported in many studies.41 42 The 20 atherosclerotic carotid endarterectomy specimens examined in this study also had a much higher prevalence of hemorrhage than has been reported in carotid arteries examined at autopsy, probably because all 20 patients had a recent increase in the percent diameter stenosis of the carotid segment removed and half had ipsilateral symptoms, either transient ischemic attack or ocular symptoms, consistent with recent plaque disruption. It is important to note that recent hemorrhage, which was identified histologically by the presence of intact red blood cells and which probably was an artifact induced by surgical manipulation, was not included as hemorrhage in our analyses.
In the present study, intraplaque hemorrhages of different histological ages were observed frequently within the lipid core of an individual lesion. Furthermore, although hemorrhage was present in a strikingly large proportion of the plaques, it did not correlate with fibrous cap rupture. The hemorrhages were only occasionally connected with the lumen and therefore might have originated from other sources, such as ruptured intimal microvessels,3 39 rather than from fibrous cap disruption.42 These results suggest that increased proteolysis in the neighborhood of the microvessels in concert with mechanical shearing forces could lead to intermittent microvascular hemorrhage. This process could be quite dynamic, since atherosclerotic plaques may grow larger and narrow the carotid lumen at a rapid rate.43 In addition, a proteolytically weakened fibrous cap might be more susceptible to mechanical disruption from the increased shear stress present at plaque shoulders.44 Thus, increased MMP-1 expression could contribute to both plaque expansion and fibrous cap disruption.
In conclusion, this study demonstrates that several cell types may express MMP-1 in human carotid atherosclerosis but not in histologically normal carotid intima. The expression of this protease by vascular cells could contribute to plaque instability. The increased expression of MMP-1 by macrophages in regions of the plaque identified by others as being critical to plaque integrity has been linked in this study to intraplaque hemorrhage and may represent a pathological event in the progression of complicated atherosclerotic lesions.
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Acknowledgments |
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This study was supported by grants HL-18645, HL-42270, and HL-47151 from the National Institutes of Health. Dr O'Brien was supported in part by a Clinical Investigator Development Award (HL-02788) from the NIH. Dr Nikkari was supported in part by a grant from the Alfred Kordelin Foundation. The authors thank Kelly Hudkins and Randy Small for excellent help with immunohistochemistry and Robert Bergelin for assistance with the statistical analyses.
Received December 21, 1994; revision received March 2, 1995; accepted March 5, 1995.
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G. A. R. Doyle, R. A. Pierce, and W. C. Parks Transcriptional Induction of Collagenase-1 in Differentiated Monocyte-like (U937) Cells is Regulated by AP-1 and an Upstream C/EBP-beta Site J. Biol. Chem., May 2, 1997; 272(18): 11840 - 11849. [Abstract] [Full Text] [PDF]
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W. D. Coats, P. Whittaker, D. T. Cheung, J. W. Currier, B. Han, and D. P. Faxon Collagen Content Is Significantly Lower in Restenotic Versus Nonrestenotic Vessels After Balloon Angioplasty in the Atherosclerotic Rabbit Model Circulation, March 4, 1997; 95(5): 1293 - 1300. [Abstract] [Full Text]
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R. Forough, N. Koyama, D. Hasenstab, H. Lea, M. Clowes, S. T. Nikkari, and A. W. Clowes Overexpression of Tissue Inhibitor of Matrix Metalloproteinase-1 Inhibits Vascular Smooth Muscle Cell Functions In Vitro and In Vivo Circ. Res., October 1, 1996; 79(4): 812 - 820. [Abstract] [Full Text]
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S. Ye, P. Eriksson, A. Hamsten, M. Kurkinen, S. E. Humphries, and A. M. Henney Progression of Coronary Atherosclerosis Is Associated with a Common Genetic Variant of the Human Stromelysin-1 Promoter Which Results in Reduced Gene Expression J. Biol. Chem., May 31, 1996; 271(22): 13055 - 13060. [Abstract] [Full Text] [PDF]
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M. W. Feinberg, M. K. Jain, F. Werner, N. E. S. Sibinga, P. Wiesel, H. Wang, J. N. Topper, M. A. Perrella, and M.-E. Lee Transforming Growth Factor-beta 1 Inhibits Cytokine-mediated Induction of Human Metalloelastase in Macrophages J. Biol. Chem., August 11, 2000; 275(33): 25766 - 25773. [Abstract] [Full Text] [PDF]
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A. a. Belaaouaj, A. Li, T.-C. Wun, H. G. Welgus, and S. D. Shapiro Matrix Metalloproteinases Cleave Tissue Factor Pathway Inhibitor. EFFECTS ON COAGULATION J. Biol. Chem., August 25, 2000; 275(35): 27123 - 27128. [Abstract] [Full Text] [PDF]
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S. Li, L. H. Chow, and J. G. Pickering Cell Surface-bound Collagenase-1 and Focal Substrate Degradation Stimulate the Rear Release of Motile Vascular Smooth Muscle Cells J. Biol. Chem., November 3, 2000; 275(45): 35384 - 35392. [Abstract] [Full Text] [PDF]
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X. Fu, S. Y. Kassim, W. C. Parks, and J. W. Heinecke Hypochlorous Acid Oxygenates the Cysteine Switch Domain of Pro-matrilysin (MMP-7). A MECHANISM FOR MATRIX METALLOPROTEINASE ACTIVATION AND ATHEROSCLEROTIC PLAQUE RUPTURE BY MYELOPEROXIDASE J. Biol. Chem., October 26, 2001; 276(44): 41279 - 41287. [Abstract] [Full Text] [PDF]
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