(Circulation. 2001;103:2181.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Matrix-Dependent Mechanism of Neutrophil-Mediated Release and Activation of Matrix Metalloproteinase 9 in Myocardial Ischemia/Reperfusion
From the Section of Cardiovascular Sciences, DeBakey Heart Center, Department of Medicine, Methodist Hospital (M.L., K.W., C.K., A.J.E., A.R.B., L.M., M.E.); Immunology Research Laboratory and Research Center for AIDS and HIV Infections at the Houston Veterans Affairs Medical Center (M.D.B., R.D.R.); Speros P. Martel Laboratory of Leukocyte Biology at Texas Children’s Hospital (J.S.); and the Departments of Medicine, Microbiology and Immunology, and Pediatrics, Baylor College of Medicine (all authors), Houston, Tex.
Correspondence to Mark L. Entman, MD, Chief, Cardiovascular Sciences, Department of Medicine, One Baylor Plaza, MS F602, Houston, TX 77030. E-mail mentman{at}bcm.tmc.edu
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Abstract |
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Background—A key component of reperfusion of myocardial infarction is an immediate inflammatory response, which enhances tissue repair. Matrix turnover is crucial to tissue repair, and matrix metalloproteinases (MMPs) are key enzymes involved in matrix degradation. The hypothesis tested is that one inflammation-based effector of tissue repair is the secretion and activation of MMP-9 by infiltrating neutrophils.
Methods and Results—Cardiac lymph and tissue were assayed for latent and active MMP-2 and MMP-9 by zymography and immunochemistry. Dual-labeling immunofluorescence determined the cellular source of MMP-9 protein. Isolated canine neutrophils were incubated with preischemic and postischemic cardiac lymph in the presence and absence of collagen-fibronectin pads, and the supernatants were assayed for latent and active MMP-9. MMP-9 increased during the first hours of reperfusion in both lymph supernatants and myocardial extracts, and this increase was of neutrophil origin. MMP-9 in the cardiac lymph remained latent but was activatable. In contrast, MMP-9 in the myocardium was in both latent and active forms. In situ zymography demonstrated that activated MMP-9 surrounded the infiltrated neutrophils. When postischemic cardiac lymph was incubated with neutrophils in vitro, MMP-9 secretion and activation occurred only in the presence of a collagen-fibronectin substrate; preischemic cardiac lymph did not induce significant secretion or activation.
Conclusions—Infiltrating neutrophils are an early source of MMP-9 after reperfusion, and a portion of MMP-9 in the myocardium is active. Infiltrating neutrophils may localize MMP-9 activation by secreting MMP-9 and as a source of activating proteases.
Key Words: metalloproteinases • ischemia • reperfusion • blood cells
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Introduction |
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Recent studies have proposed an important role for early reperfusion in myocardial tissue repair, with substantial evidence suggesting that the advantage of early reperfusion relates to the associated robust, neutrophil-rich inflammatory reaction.1 2 3 4 5 6 7 8 One cellular response that might favor tissue repair is early resorption of denatured matrix proteins. Neutrophil-derived MMP-9 is stored in tertiary granules and released on chemotactic stimulation. The tertiary granules are the first to be degranulated, with the lowest levels of stimulation, followed by the secondary granules; the primary granules require the greatest level of stimulation.7
Suppression of the inflammatory reaction is associated with an increased incidence of ventricular aneurysm, cardiac rupture, and death,9 10 suggesting that inflammation might mediate a beneficial repair component. The present report demonstrates that neutrophil-derived MMP-9 is released in the myocardium within the first hour of reperfusion and is activated. Although other proteolytic mechanisms may be important, the data suggest that neutrophil-derived protease(s) found in the primary granule play a role in MMP-9 activation in the tissue via sequential degranulation.7 Thus, matrix degradation activity is focused in the area of inflammation and injury, where repair ensues.
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Methods |
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All animal procedures were conducted in accordance with guidelines published in the Guide for the Care and Use of Laboratory Animals (DHEW publication NIH 85-23, revised 1985, Office of Science and Health Reports, DRR/NIH, Bethesda, Md). All studies were approved by the Animal Research Committee at Baylor College of Medicine.
Ischemia/Reperfusion Protocol
The canine ischemia/reperfusion with lymph
duct cannulation protocol has been described in
detail.8 11 12 13 14 15
Briefly, healthy mongrel dogs (15 to 25 kg) of either sex were
surgically instrumented with a hydraulically activated
occluding device and Doppler flow probe on the circumflex
coronary artery, and the cardiac lymph duct was cannulated.
After 72 hours of recovery, coronary occlusion occurred for 1
hour, followed by various times of reperfusion. At 50 minutes of
occlusion, radiolabeled microspheres were injected into the
left atrium to quantify regional blood
flow.
Total Protein Extraction
Myocardial segments were frozen and stored in liquid
nitrogen until ready to use. Protein was extracted as
described,16 and total
protein levels were determined by Lowry
assay.17
Gelatin Zymography
Samples were loaded onto nondenaturing 10%
polyacrylamide gels containing 0.1% gelatin, electrophoresed,
renatured, and developed as described
previously.16 18 19
To determine activity levels, gels were scanned into Adobe Photoshop
4.0 (Adobe Systems, Inc) as black-and-white images and inverted, and
densitometry levels were determined by use of the Scion Image (Scion
Corp) gel plot 2 macro.
Histology
Cardiac tissue segments were fixed in 10% formalin
or 4% paraformaldehyde, embedded in paraffin, and
sectioned at 4 µm. Cells isolated from cardiac lymph were fixed in
1% paraformaldehyde, resuspended in 75% ethanol, and
divided into aliquots on slides.
Immunocytochemistry was performed on lymph cells with the ABC technique. For the sheep anti–human MMP-9 antibody, a sheep kit (Pierce) that contained a biotinylated donkey anti-sheep IgG was used. For the mouse anti–dog neutrophil antibody, a mouse kit (Vector) that contained a biotinylated goat anti-mouse IgG was used. To calculate the percentage of lymph cells that were positive, random fields were scanned into Adobe Photoshop, and a minimum of 500 cells for each time point were counted with Zeiss Image.
Immunofluorescence was used on myocardial tissue sections. Both sheep anti-human MMP-9 (the binding site) and mouse anti-dog neutrophil (SG8H6)4 antibodies were used at a 1:100 dilution. Negative controls included using no primary antibody and isotype-matched nonimmune IgG antibodies. A donkey anti-sheep IgG conjugated with Texas Red (Jackson Immunochemicals) was used for the sheep anti-human MMP-9 antibody. A goat anti-mouse IgG conjugated with Bodipy (Molecular Probes) was used for the mouse anti–dog neutrophil antibody. No bleed-over fluorescence was observed in control sections.
In situ zymography was used to determine localization of MMP-9 activity. A solution of 0.1 mg/mL gelatin–Oregon green (Molecular Probes) in 1x developing buffer (mmol/L: Tris base 50, HCl 40, NaCl 200, CaCl2 · 2H2O 5, and PMSF 50, and 0.2% [wt/vol] Brij 35) was placed onto 4-µm frozen sections. Adjacent serial sections also had 50 mmol/L EDTA or a 1:40 dilution of neutralizing mouse anti-human MMP-9 antibody (antibody 1, Calbiochem). These sections were incubated at 37°C for 3 hours, washed 3 times with water to remove unbound gelatin, and counterstained with the nuclear stain DAPI (Vector mounting media, Vector Laboratories). Because gelatinase activity resulted in the loss of quenching, the increase in activity was visualized as a linear increase in fluorescence.
Neutrophil Isolation and Stimulation
Neutrophils were isolated from peripheral
blood in citrate phosphate dextrose by dextran (Spectrum Chemicals)
sedimentation and separation through Ficoll-Hypaque gradients (Sigma).
The isolates were >95% viable by trypan blue dye exclusion and were
>95% neutrophils by Giemsa staining. After isolation, the neutrophils
were counted with a hemacytometer and resuspended in Dulbecco’s PBS
(containing 10 mmol/L glucose, 1 mmol/L
CaCl2, and 1 mmol/L
MgCl2) to 10x106
neutrophils/mL. The neutrophils were placed above the collagen inserts,
cardiac lymph was placed below, and the plates were incubated at 37°C
in 5% CO2 for 1 hour. The neutrophils (upper
fraction) were removed, centrifuged at
10 000g for 3 minutes to
remove neutrophils, and assayed for MMP-9 activity.
Statistical analysis was performed with Microsoft Excel and GraphPad InStat version 3.01 (GraphPad Software).
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Results |
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Latent MMP-9 Levels Increase in Lymph Supernatants During Reperfusion
By use of gelatin zymography, lymph supernatants at various times from 11 animals were examined for MMP-2 and MMP-9 levels (Figure 1
). To achieve specificity, the gels were incubated
in PMSF to eliminate non-MMP activity, negative control gels were
incubated with 20 mmol/L EDTA to inhibit MMP activity, and MMP-2
and MMP-9 standards were loaded to confirm molecular weight sizes. To
ensure that MMP enzymatic levels were in the linear range, initial gels
were loaded with 1, 2.5, 5, 7.5, 10, and 20 µg total protein. An
MMP-9 standard curve confirmed that the lytic band was MMP-9 and that
activity remained in the linear range. A representative
zymogram and its densitometry is shown in
Figure 1A. None of the animals had changes in MMP 2 during
the first day of reperfusion. From the 11 dogs examined, 60 time points
ranging from preocclusion to 12 hours of reperfusion were pooled into
preocclusion, occlusion, 1- to 5-hour reperfusion, and 6- to 12-hour
reperfusion groups and statistically analyzed
(Figure 1B). Of the 11 animals examined, 6 had increases in
latent MMP-9 levels after reperfusion during day 1. Incubation of the
lymph samples with
p-aminophenylmercuric acetate
resulted in MMP-9 activation, demonstrating that MMP-9 was latent but
activatable
(Figure 1C). On the basis of quantification of
microspheres, the 5 dogs that did not show increases in MMP-9
had normal flows in the myocardium downstream of the
occluding device, indicating that collateral circulation was sufficient
to compensate for the occlusion. These animals were classified as
shams. The increase in MMP-9 in the lymph supernatants corresponded to
a decrease in MMP-9 in the lymph cell fraction, suggesting that the
source of MMP-9 was the cells in the lymph (data not
shown).
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Neutrophils Are the Predominant Source of MMP-9
in the Lymph
To determine which cells are positive for MMP-9,
parallel time courses of lymph cells from 6 animals were
immunostained with a sheep anti–human MMP-9 antibody or a
mouse anti–dog neutrophil antibody. The percentage of cells that were
MMP-9–positive or were neutrophils was calculated.
Figure 2A shows a representative time course
from 1 of these animals. When the percentages of all 6 animals (47 time
points) are plotted against each other
(Figure 2B), there is a significant linear correlation
(r2=0.81,
P<0.001), suggesting that
neutrophils are the predominant source of MMP-9 found in the cardiac
lymph supernatants.
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Latent and Active MMP-9 Levels Increase in the
Myocardium During Reperfusion
By gelatin zymography, tissue extracts from 3 control
and 5 ischemic areas from each dog were examined for MMP-9.
Figure 3A shows a representative zymogram
from animals undergoing 1-hour ischemia and 5-hour reperfusion.
The densitometry results from 11 dogs undergoing 1-hour
ischemia/5-hour reperfusion are shown in
Figure 3B. For each dog, the densities from 3 control
sections and 5 ischemic sections were averaged. Control,
normal-flow sections did not have latent or active MMP-9 protein. The
ischemic sections again demonstrate variation in the level of
response, some of which is due to nonuniform reductions in flows. Of
the 11 reperfused dogs, 7 had increases in latent and active MMP-9
levels, and 4 did not. Neither the reperfused nor nonreperfused groups
had changes in MMP-2 levels
(Figure 3B). This increase in latent and active MMP-9 in the
ischemic/reperfused segments, compared with nonischemic
myocardium, was statistically significant. Nonreperfused
dogs with <20% collateral circulation showed no increased release or
activation of MMP-9. A representative zymogram from a
6-hour ischemia/0-hour reperfusion experiment is shown in
Figure 3C.
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Active MMP-9 Is Seen Where Neutrophils
Accumulate
To determine localization of the active MMP-9 within
the reperfused myocardium, frozen sections were incubated
with gelatin that is quenched with Oregon green, a fluorescent
label. An increase in gelatinase activity is therefore visualized as an
increase in fluorescence
(Figure 4). To achieve specificity, all sections were
incubated with PMSF to block endogenous serine protease
activity. Adjacent serial sections were tested for MMP-9 activity
(green fluorescence) as follows: (1) 1-hour
ischemia/5-hour reperfusion, (2) + EDTA, and (3) +
neutralizing MMP-9 antibody. The sections were counterstained with DAPI
(blue fluorescence) to depict nuclei.
Figure 5 demonstrates that MMP activity is inhibited by both
EDTA and neutralizing MMP-9 antibody. No MMP activity is seen in shams
or nonischemic control sections (data not shown).
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The data suggest that MMP-9 activation occurs in the area in
which neutrophils accumulate. To further demonstrate this association,
serial sections were stained for MMP-9 activity and neutrophils.
Figure 6 demonstrates that neutrophil infiltration
(SG8H6-stained cells) occurs in the region of MMP activity.
Figure 6A demonstrates MMP-9 activity with the quenched
gelatin overlay (green fluorescence indicates activity).
Figure 6B demonstrates a serial section stained for
neutrophils (the black-stained cells are neutrophils). A
computer-generated overlay of the neutrophil staining superimposed over
the MMP-9 activity
(Figure 6C) demonstrates that MMP-9 activation occurs
wherever there are infiltrating neutrophils.
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Postischemic but Not
Preischemic Lymph Stimulates the Release of MMP-9 and Its
Activator(s) From Neutrophils in the Presence of a
Collagen-Fibronectin Matrix
To examine the in vitro release and activation of
MMP-9, we studied neutrophils migrating into a collagen matrix in
response to preischemic and postischemic
cardiac lymph. Cardiac lymph was used for 2 reasons: (1) cardiac lymph
is an excellent sample of the macromolecular constituents of the
myocardium at any one time (1 minute lag
time)15 and (2) latent MMP-9
but not active MMP-9 was increased in the cardiac lymph on day 1 of
reperfusion (see above). Therefore, the ability of lymph to induce the
release of MMP-9 and its activator would demonstrate that,
as opposed to neutrophils suspended in the cardiac lymph, neutrophils
stimulated in a matrix environment have the ability to activate
MMP-9. The ability of postischemic cardiac lymph to induce
MMP-9 activation would also provide evidence against the possibility
that inhibitors in the lymph prevent
activation.
Neutrophils were placed above collagen and fibronectin
inserts, and 10%, 20%, or 40% dilution of cardiac lymph was placed
below the collagen and fibronectin inserts. Negative controls included
PBS. After a 1-hour incubation, the supernatants were collected,
centrifuged to remove the unadhered neutrophils, and assayed
for MMP-9. Preischemic and postischemic lymph
controls were also analyzed to confirm that the levels assayed
were neutrophil-derived. As shown in
Figure 7, postischemic cardiac lymph stimulated
the release and activation of MMP-9 from the neutrophils. This
activation was attended by release of the primary granule marker,
myeloperoxidase. The increase in latent and active MMP-9 was
statistically significant. Preischemic cardiac lymph
induced a small, statistically insignificant, increase in latent MMP-9
but no activation of MMP-9 and no release of myeloperoxidase. Saline
controls initiated no release or activation. In contrast, when
postischemic lymph was used to stimulate neutrophils in
suspension (n=6 experiments), there was no increase in either latent or
active MMP-9 or myeloperoxidase release (data not
shown).
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Discussion |
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MMP-9 Levels In Vivo
MMP-9 levels in cardiac lymph increase in the first hours of reperfusion, an increase that parallels neutrophil numbers and is accompanied by a loss of MMP-9 from neutrophils in the lymph sample. This suggests that MMP-9 in the lymph is secreted by neutrophils in the lymph rather than by neutrophils in the myocardium. As with the lymph, MMP-9 increases in the myocardium during the first hours of reperfusion, much earlier than reported previously in studies examining MMP-9 gene induction by in situ hybridization. Because MMP-9 protein is synthesized in the neutrophil early in its development and is stored in tertiary granules, very little mRNA for MMP-9 is seen in the neutrophil once it enters the circulation.20 21 In contrast to the MMP-9 in the lymph, MMP-9 is activated in the myocardium, as demonstrated by both gelatin zymography and in situ zymography. The neutrophil is also the source of early MMP-9 appearance in the myocardium. The data localize potential matrix-degrading capability to the area of injury and introduce the idea that the neutrophil may also be important in controlling MMP-9 activation. Because MMP-9 activity surrounds the neutrophil, it is possible that neutrophil proteases contribute to MMP-9 activation. The presence of more classic MMP activators, such as plasmin and, perhaps, proteases released from injured tissue, suggest that activation may have multiple components.
Conceptually, neutrophil-derived activation of MMP-9 has
potential biological advantages. Owen and
Campbell22 23
suggested that pericellular proteolysis during injury and repair would
be desirable to prevent more uncontrolled global proteolytic
degradation. At least in early reperfusion, MMP-9 activation could be
localized to the perineutrophil area and might be initiated by
neutrophils adhering to the extracellular matrix. Thus, neutrophils can
easily be activated by chemotactic factors to secrete MMP-9
from the tertiary
granules.20 21 24
Additional or greater stimulation is required for degranulation of
neutrophil primary granules, which contain the neutrophil proteases
that might activate MMP-9. A greater sensitivity to chemotactic
factors occurs when neutrophils are adherent, perhaps due to
cytoskeletal rearrangement, which is necessary for full degranulation
to
occur.25 26 27
This is compatible with the data in
Figure 7
, in which we demonstrate that
postischemic cardiac lymph would not initiate
neutrophil-derived activation of MMP-9 unless the cells were adherent
to a fibronectin/collagen matrix.
Functional Roles of MMP-9
The potential beneficial and potential deleterious
aspects of MMP-9 activity on myocardial injury and repair overlap to a
great extent. Potential deleterious effects of MMP-9 include
stimulating inappropriate extracellular matrix degradation, activating
inflammatory mediators, and/or increasing capillary
permeability.28 29 30
Potential beneficial effects of early MMP-9 activation include removing
matrix and necrotic myocytes, releasing growth factors and cell surface
receptors, remodeling the extracellular matrix for scar formation,
processing inflammatory mediators such as interleukin-1ß, and
influencing
angiogenesis.31 32 33 34 35 36 37 38 39 40 41 42 43
An increase in MMP-9 that occurs within hours after reperfusion could
serve a proactive function, with the overall result being an
accelerated healing. The more focused secretion and activation of MMP-9
proposed here might obviate the danger of inappropriate proteolytic
degradation. In a dog model of ischemia/reperfusion,
reperfusion at 6 hours did not affect the infarct size at 4 days or the
scar size at 6 weeks.44 The
reperfused infarcts at 2 weeks, however, had less expansion, more
granulation tissue, and more resorption of necrotic myocytes than
nonreperfused infarcts. The earlier progression of infarct shrinkage
during healing in the reperfused hearts was also associated with a
progressive decrease in the relative wall thickness, indicating a
decreased amount of compensatory hypertrophy.
MMP-9 activity that appears within the first day of reperfusion could also serve as a brake for later matrix degradation and wall thinning through the stimulation of TIMP synthesis in the first days of reperfusion. This would limit the amount of dilatation due to infarct expansion. If the initial dilation is moderate or severe, then compensatory hypertrophy of the spared myocardium is often progressive and can lead to heart failure and death.45 Thus, a mechanism to slow down or limit infarct expansion would also limit the hypertrophic response of the noninfarcted ventricle. Coordination of MMP-9 expression could clearly play a role in monitoring the timing, localization, and levels of matrix degradation to optimize events of remodeling.29 During the healing phase, damaged collagen must first be degraded and removed before necrotic myocytes can be resorbed and new collagen generated to form a scar. Reperfusion may control the timing of these steps by initiating matrix degradation and myocyte resorption and allowing new collagen deposition at a much earlier time course (within hours versus several days).
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Acknowledgments |
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This work was supported by an NIH training grant (1-T32-HL-07816-03) and an NIH program project grant (NHLBI P01-HL-42550). The authors wish to express their gratitude to Peggy Jackson, Etai Funk, Stephanie Butcher, and Evelyn Brown for expert technical assistance and to Sharon Malinowski and Concepcion Mata for editorial assistance.
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Footnotes |
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Guest Editor for this article was Peter Libby, MD, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Received August 3, 2000; revision received November 10, 2000; accepted November 30, 2000.
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K. Uemura, M. Li, T. Tsutsumi, T. Yamazaki, T. Kawada, A. Kamiya, M. Inagaki, K. Sunagawa, and M. Sugimachi Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2254 - H2261. [Abstract] [Full Text] [PDF]
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M. A. Cavasin, Z.-Y. Tao, A.-L. Yu, and X.-P. Yang Testosterone enhances early cardiac remodeling after myocardial infarction, causing rupture and degrading cardiac function Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2043 - H2050. [Abstract] [Full Text] [PDF]
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D. Vanhoutte, M. Schellings, Y. Pinto, and S. Heymans Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: A temporal and spatial window Cardiovasc Res, February 15, 2006; 69(3): 604 - 613. [Abstract] [Full Text] [PDF]
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M. L. Lindsey, G. P. Escobar, L. W. Dobrucki, D. K. Goshorn, S. Bouges, J. T. Mingoia, D. M. McClister Jr., H. Su, J. Gannon, C. MacGillivray, et al. Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H232 - H239. [Abstract] [Full Text] [PDF]
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G. Ertl and S. Frantz Healing after myocardial infarction Cardiovasc Res, April 1, 2005; 66(1): 22 - 32. [Abstract] [Full Text] [PDF]
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R. A. Garcia, K. L. Brown, R. S. Pavelec, K. V. Go, J. W. Covell, and F. J. Villarreal Abnormal cardiac wall motion and early matrix metalloproteinase activity Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1080 - H1087. [Abstract] [Full Text] [PDF]
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M. M. Lalu, E. Pasini, C. J. Schulze, M. Ferrari-Vivaldi, G. Ferrari-Vivaldi, T. Bachetti, and R. Schulz Ischaemia-reperfusion injury activates matrix metalloproteinases in the human heart Eur. Heart J., January 1, 2005; 26(1): 27 - 35. [Abstract] [Full Text] [PDF]
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W. M. Frederiks and O. R.F. Mook Metabolic Mapping of Proteinase Activity with Emphasis on In Situ Zymography of Gelatinases: Review and Protocols J. Histochem. Cytochem., June 1, 2004; 52(6): 711 - 722. [Abstract] [Full Text] [PDF]
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H. S. Rosario, S. W. Waldo, S. A. Becker, and G. W. Schmid-Schonbein Pancreatic Trypsin Increases Matrix Metalloproteinase-9 Accumulation and Activation during Acute Intestinal Ischemia-Reperfusion in the Rat Am. J. Pathol., May 1, 2004; 164(5): 1707 - 1716. [Abstract] [Full Text] [PDF]
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M. L. Lindsey, J. Yoshioka, C. MacGillivray, S. Muangman, J. Gannon, A. Verghese, M. Aikawa, P. Libby, S. M. Krane, and R. T. Lee Effect of a Cleavage-Resistant Collagen Mutation on Left Ventricular Remodeling Circ. Res., August 8, 2003; 93(3): 238 - 245. [Abstract] [Full Text] [PDF]
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S. Hayashidani, H. Tsutsui, M. Ikeuchi, T. Shiomi, H. Matsusaka, T. Kubota, K. Imanaka-Yoshida, T. Itoh, and A. Takeshita Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1229 - H1235. [Abstract] [Full Text] [PDF]
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E. M. Wilson, S. L. Moainie, J. M. Baskin, A. S. Lowry, A. M. Deschamps, R. Mukherjee, T. S. Guy, M. G. St John-Sutton, J. H. Gorman III, L. H. Edmunds Jr, et al. Region- and Type-Specific Induction of Matrix Metalloproteinases in Post-Myocardial Infarction Remodeling Circulation, June 10, 2003; 107(22): 2857 - 2863. [Abstract] [Full Text] [PDF]
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H. Chen, D. Li, T. Saldeen, and J. L. Mehta TGF-beta 1 attenuates myocardial ischemia-reperfusion injury via inhibition of upregulation of MMP-1 Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1612 - H1617. [Abstract] [Full Text] [PDF]
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V. Fontaine, M.-P. Jacob, X. Houard, P. Rossignol, D. Plissonnier, E. Angles-Cano, and J.-B. Michel Involvement of the Mural Thrombus as a Site of Protease Release and Activation in Human Aortic Aneurysms Am. J. Pathol., November 1, 2002; 161(5): 1701 - 1710. [Abstract] [Full Text] [PDF]
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M. M. Thompson and I. B. Squire Matrix metalloproteinase-9 expression after myocardial infarction: physiological or pathological? Cardiovasc Res, June 1, 2002; 54(3): 495 - 498. [Full Text] [PDF]
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A. M. Romanic, S. M. Harrison, W. Bao, C. L. Burns-Kurtis, S. Pickering, J. Gu, E. Grau, J. Mao, G. M. Sathe, E. H. Ohlstein, et al. Myocardial protection from ischemia/reperfusion injury by targeted deletion of matrix metalloproteinase-9 Cardiovasc Res, June 1, 2002; 54(3): 549 - 558. [Abstract] [Full Text] [PDF]
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M. L. Lindsey, J. Gannon, M. Aikawa, F. J. Schoen, E. Rabkin, L. Lopresti-Morrow, J. Crawford, S. Black, P. Libby, P. G. Mitchell, et al. Selective Matrix Metalloproteinase Inhibition Reduces Left Ventricular Remodeling but Does Not Inhibit Angiogenesis After Myocardial Infarction Circulation, February 12, 2002; 105(6): 753 - 758. [Abstract] [Full Text] [PDF]
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M. H. Yamani, E. M. Tuzcu, R. C. Starling, N. B. Ratliff, Y. Yu, D. G. Vince, K. Powell, D. Cook, P. McCarthy, and J. B. Young Myocardial Ischemic Injury After Heart Transplantation Is Associated With Upregulation of Vitronectin Receptor ({alpha}v{beta}3), Activation of the Matrix Metalloproteinase Induction System, and Subsequent Development of Coronary Vasculopathy Circulation, April 23, 2002; 105(16): 1955 - 1961. [Abstract] [Full Text] [PDF]
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