(Circulation. 2000;101:1833.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Matrix Metalloproteinase-2 Contributes to Ischemia-Reperfusion Injury in the Heart
From the Departments of Pediatrics (P.-Y.C., R.S.), Pharmacology (P.-Y.C., G.S., W.W., M.W.R., R.S.), and Obstetrics/Gynecology (M.W.R.), University of Alberta, Edmonton, Alberta, Canada, and the Department of Clinical Chemistry, Medical University, Wroclaw, Poland (M.W.).
Correspondence to Dr Richard Schulz, Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada. E-mail richard.schulz{at}ualberta.ca
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Abstract |
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Background—Matrix metalloproteinases (MMPs) contribute to collagen degradation and remodeling of the extracellular matrix after myocardial infarction; however, their role in myocardial dysfunction immediately after ischemia and reperfusion is unknown.
Methods and Results—We measured the release of MMPs into the coronary effluent of isolated, perfused rat hearts during aerobic perfusion and reperfusion after ischemia. Aerobically perfused control hearts expressed pro-MMP-2 and MMP-2, as well as an unidentified 75-kDa gelatinase. These enzymes were also detected in the coronary effluent. After 20 minutes of global no-flow ischemia, there was a marked increase in pro-MMP-2 in the coronary effluent that peaked within the first minute of reperfusion. The release of pro-MMP-2 into the coronary effluent during reperfusion was enhanced with increasing duration of ischemia and correlated negatively with the recovery of mechanical function during reperfusion (r2=0.99). MMP-2 antibody (1.5 to 15 µg/mL) and the inhibitors of MMPs doxycycline (10 to 100 µmol/L) and o-phenanthroline (3 to 100 µmol/L) improved whereas MMP-2 worsened the recovery of mechanical function during reperfusion.
Conclusions—These results show that acute release of MMP-2 during reperfusion after ischemia contributes to cardiac mechanical dysfunction. The inhibition of MMPs may be a novel pharmacological strategy for the treatment of ischemia-reperfusion injury.
Key Words: ischemia • reperfusion • metalloproteinases • myocardium
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Matrix metalloproteinases (MMPs) belong to the zinc-containing endopeptidases.1 The MMPs are synthesized in a latent form (zymogen or pro-MMP) and are activated by proteolytic cleavage of an amino-terminal domain2 or conformational changes such as those induced by oxidative stress.3 They are involved in the remodeling of the extracellular matrix in tissue during various physiological and pathological conditions, such as embryonic development, inflammation, and cancer.4 Extracellular matrix is important in the structure as well as the function of the heart and vascular tissues.5 After myocardial infarction, increased activity of MMPs may be responsible for the degradation of extracellular matrix.6 7 Upregulation of myocardial MMPs has also been associated with fetal development, ventricular remodeling in heart failure, and in neointima formation after arterial injury.8 9 10
Among the metalloproteinases, MMP-2 (pro-MMP-2, 72 kDa; active enzyme: MMP-2, 62 kDa) and MMP-9 (pro-MMP-9, 92 kDa; active enzyme: MMP-9, 84 kDa) have been found in endocardial and subendocardial layers and interstitial tissue.11 Both are involved in the degradation of collagen type IV, a major component of the basement membrane.
Changes in MMP activity or expression that affect matrix remodeling occur on the time scale of hours to days. However, these enzymes may also stimulate cellular transduction processes in a rapid way before changes in the collagen matrix occur.12 Indeed, we have previously identified MMP-2 in human platelets13 and found that MMP-mediated platelet aggregation results in a rapid translocation (within seconds) and release of this enzyme from platelets.13 14 Thus, MMP-2 release in platelets mediates an acute signaling response in platelets that results in their aggregation. Therefore, we wished to investigate whether there could be a role for MMPs in the heart in the setting of acute myocardial ischemia-reperfusion injury.
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Methods |
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This investigation conforms to the Guide to the Care and Use of Experimental Animals published by the Canadian Council on Animal Care (revised 1993).
Materials
Male Sprague-Dawley rats (250 to 300 g) were used for the
experiments. Polyclonal MMP-2 antibody and purified rabbit IgG
(negative control for the MMP-2 antibody) were prepared as
described.14 The supernatant from phorbol
ester–activated human fibroblast HT1080 cells (American Type
Culture Collection), which contains large amounts of pro-MMP-2, MMP-2,
pro-MMP-9, and MMP-9, was used as a standard. All other reagents were
purchased from Sigma.
A semipurified preparation of MMP-2 from HT1080 cell–conditioned medium was prepared in bulk by affinity chromatography with gelatin-sepharose.15 The protein content was estimated by ultraviolet spectrometry at 280 nm.
Heart Perfusions
Hearts were rapidly excised from
pentobarbital-anesthetized rats and briefly rinsed by immersion
into ice-cold Krebs-Henseleit buffer. Spontaneously beating hearts were
perfused via the aorta at a constant pressure of 60 mm Hg with
Krebs-Henseleit buffer at 37°C as previously
described.16
A water-filled latex balloon connected to a pressure transducer was inserted into the left ventricle through an incision in the left atrium and through the mitral valve, and the volume was adjusted to achieve an end-diastolic pressure of 8 to 12 mm Hg. Heart rate and left ventricular pressure were monitored on a polygraph. The RPP was calculated as the product of heart rate and left ventricular developed (systolic minus end-diastolic) pressure. Coronary flow was measured with an in-line ultrasonic flow probe (Transonic Systems Inc) positioned proximal to the perfusion cannula. Hearts maintained a steady state of coronary flow, heart rate, and left ventricular developed pressure for at least 80 minutes after stabilization as previously reported.16
Ischemia and Reperfusion Protocol
After 25 minutes of aerobic perfusion, hearts were subjected to
15, 20, or 25 minutes of global no-flow ischemia induced by
clamping of the aortic inflow line. This was followed by 30 minutes of
aerobic reperfusion when the clamp was reopened. Coronary
effluent (6 mL) was collected for determining MMP activities at times
ending at 25 minutes of aerobic perfusion and at 1, 2, 5, 10, 20, and
30 minutes of reperfusion. Because equal volume samples were collected,
the period of time required to collect samples varied during early
reperfusion. The average time required to collect the coronary
effluent samples was 26 seconds for the aerobic perfusion sample and
between 26 and 60 seconds for the reperfusion samples. The samples were
stored at 4°C and processed on the same day.
Preparation of Heart Extracts
Hearts were freeze-clamped and crushed at liquid
N2 temperature and then homogenized
by sonication in 50 mmol/L Tris-HCl (pH 7.4) containing 3.1
mmol/L sucrose, 1 mmol/L DTT, 10 µg/mL leupeptin, 10 µg/mL
soybean trypsin inhibitor, 2 µg/mL aprotinin, and 0.1%
Triton X-100. The homogenate was centrifuged at
10 000g at 4°C for 10 minutes, and the supernatant was
collected and stored at -80°C until use.
Modulation of Ischemia-Reperfusion by MMP-2 or Its
Inhibitors
In some experiments after 15 minutes of aerobic perfusion,
either semipurified MMP-2 (100 ng/mL) or MMP-2 antibody (1.5 to 15
µg/mL), doxycycline (10 to 100 µmol/L)17 or
o-phenanthroline (3 to 100
µmol/L)13 (two inhibitors of
MMPs),18 19 or phosphoramidon (20
µmol/L, an inhibitor of metalloproteinases without
inhibitory effects on MMPs)18 19 was infused
for the last 10 minutes of aerobic perfusion and for the first 10
minutes of reperfusion. The solutions were infused at a constant rate
of 0.1 mL/min, and the concentrations of the stock solutions were
prepared on the basis of an average coronary flow of 14 mL/min.
The vehicles for the test agents were as follows: semipurified MMP-2,
17 mmol/L NaCl; MMP-2 antibody, Krebs-Henseleit buffer solution of
rabbit IgG (15 µg/mL); doxycycline and
phosphoramidon, water; and o-phenanthroline,
aqueous DMSO such that the concentration of DMSO reaching the heart was
<0.2% (vol/vol).
Measurement of MMPs by Zymography
Samples of coronary effluent (6 mL) were concentrated
30-fold in volume in Centricon 10 concentrating vessels
(5000g, 4°C, Amicon Inc) and analyzed for
gelatinolytic activity by
zymography.13 14 To investigate the
inhibitory profile of some reagents on the
gelatinolytic activities of MMPs,
o-phenanthroline (100 µmol/L), doxycycline (10 to
100 µmol/L), or phosphoramidon (20
µmol/L) was added to the incubation buffer during the
overnight incubation in some experiments. To quantify the
activities of the detected enzymes, zymograms were digitally scanned,
and the band intensities were analyzed14 and
expressed as a specific activity per milligram protein in the
coronary effluent.
Western Blot Analysis
Protein (40 µg) from heart extracts prepared as above was
applied to 7% polyacrylamide gels. Electrophoresis was carried
out under reducing conditions.20 After electrophoresis,
samples were electroblotted onto polyvinylidene difluoride
membranes (Schleicher and Schuell) and probed with MMP-2 antibody (1
µg/mL).14
Determination of Neutralizing Activity of MMP-2 Antibody
Human recombinant MMP-2 (10 ng; Oncogene) was preincubated for
15 minutes at 37°C with 2 µg of MMP-2 antibody in 60 µL of
50 mmol/L Tris-HCl buffer (pH 7.6) containing 5 mmol/L
CaCl2 and 150 mmol/L NaCl. Gelatin (150 ng;
prepared from fetal bovine skin collagen type I, a gift from Dr Paul
Scott, University of Alberta) was added, and the mixture was incubated
for 60 minutes at 37°C. Gelatin degradation products were
analyzed by SDS-PAGE under nonreducing conditions as mentioned
above. The protein bands were visualized by silver
staining.21
Protein Assay
Protein concentrations were measured either by the Bradford
protein assay (BioRad) or by the bicinchoninic acid assay (Sigma) with
BSA as a standard.
Statistical Analysis
Data are expressed as mean±SEM. One-way or 2-way ANOVA (simple
or repeated measures) or Student’s t test was used as
appropriate. Pearson’s correlation test was used to analyze
the relationship between 2 continuous variables. A value of
P<0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Expression and Release of MMPs into Coronary Effluent During Aerobic Perfusion
Gelatinolytic activities were detected by zymography at 75, 72, and 62 kDa in the myocardium from aerobically perfused hearts (Figure 1A
).
The 72- and 62-kDa forms were identified as pro-MMP-2 and MMP-2,
respectively, by comparison to the HT1080 cell–derived standard. In
addition, MMP-2 was detected in this tissue by Western blot
analysis (Figure 1A). As in the profile observed in
heart tissue, at 25 minutes of aerobic perfusion, 3 bands of
gelatinolytic activity (75, 72, and 62 kDa) were
also observed in the coronary effluent (Figure 1A).
Quantitative analysis of the zymograms from the
coronary effluents showed the following rank order of
activities: 72>>62>unidentified 75 kDa (Figure 1B).
Gelatinolytic activities in heart tissue were
inhibited during zymography in the presence of
o-phenanthroline or doxycycline but not by
phosphoramidon, suggesting that the bands
represent MMP activity (Figure 1C). Pro-MMP-9 and MMP-9
activities were not detected by zymography of heart tissue or
coronary effluents obtained during aerobic perfusion.
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Release of MMP-2 Into Coronary Effluent During Reperfusion
After Ischemia
The specific activities of 72- and 62-kDa MMPs in coronary
effluents collected during aerobic reperfusion and during reperfusion
after 20 minutes of global no-flow ischemia showed that within
the first minute of reperfusion, there was an acute enhancement in the
release of pro-MMP-2 into the coronary effluent from the heart,
as shown by the marked increase in the 72-kDa activity, compared with
the baseline coronary effluent sampled during aerobic perfusion
(Figure 2A). The 72-kDa activity peaked
in the first minute of reperfusion (3.5 times baseline values) and
gradually decreased to baseline aerobic values after 10 minutes of
reperfusion (Figure 2B). An increase in the 62-kDa activity was
also found in the coronary effluent after reperfusion, which
peaked at 5 minutes of reperfusion (20 times baseline values) (Figure 2B). After 20 minutes of reperfusion, both specific activities
in the coronary effluents returned to baseline aerobic values.
An increase in 75-kDa activity was also observed during reperfusion
(Figure 2A). Concomitantly with the enhanced release of
pro-MMP-2 and MMP-2 into the coronary effluent during
reperfusion, a significant decrease in their heart tissue content (by
69% and 71%, respectively) was observed at the end of 30
minutes of reperfusion (Figure 2C).
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Ischemia Duration, MMP-2 Release, and Recovery of
Myocardial Function During Reperfusion
The release of pro-MMP-2 into the coronary effluent during
reperfusion in hearts subjected to 15, 20, or 25 minutes of
ischemia was compared (Figure 3).
During the first minute of reperfusion, the 72-kDa specific activity
progressively enhanced with increasing duration of ischemia
(Figure 3A and 3B). This increased pro-MMP-2 release was
accompanied by a concomitant decrease in the recovery of rate-pressure
product (RPP) at 30 minutes of reperfusion (Figure 3C). There was an inverse correlation between the pro-MMP-2
activity in the coronary effluent and the recovery of RPP
(r2=0.99, P<0.05).
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Effect of MMP-2 on Functional Recovery of Ischemic-Reperfused
Hearts
Control hearts subjected to a shorter (15 minutes) duration of
ischemia showed a complete recovery of mechanical function
after 30 minutes of aerobic reperfusion. In contrast, infusion of 100
ng/mL of semipurified MMP-2 significantly impaired the recovery of RPP
(Figure 4).
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Effects of MMP Inhibitors on Functional Recovery of
Ischemic-Reperfused Hearts
In control hearts, the recovery of RPP during reperfusion after 20
minutes of global no-flow ischemia was significantly depressed
compared with preischemia values (Figure 5A). There was a concentration-dependent
increase in the recovery of RPP in hearts treated with MMP-2 antibody
but not in those treated with rabbit IgG (Figure 5A). A gelatin
degradation assay showed that this antibody inhibited the activity of
MMP-2 (data not shown).
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Doxycycline (10 to 100 µmol/L) and o-phenanthroline
(3 to 100 µmol/L), but not phosphoramidon
(20 µmol/L), concentration-dependently improved the recovery of
RPP during reperfusion (Figure 5B
). MMP-2 antibody, doxycycline,
and phosphoramidon did not affect coronary flow
or RPP during aerobic perfusion (data not shown). However,
o-phenanthroline at 10 µmol/L (data not shown) and
100 µmol/L significantly depressed RPP (Figure 5B) and at
100 µmol/L also significantly increased coronary flow
during aerobic perfusion (from 12.8±0.3 to 14.3±0.6 mL/min, n=6,
P<0.05).
We also examined the relationship between the ability of doxycycline to
inhibit MMP activity and its ability to improve the recovery of RPP in
hearts subjected to ischemia-reperfusion injury. Doxycycline
(10 to 100 µmol/L), when added during zymography, caused a
concentration-dependent inhibition of pro-MMP-2 activity in control
hearts (Figure 6A and 6B). Doxycycline,
when infused into hearts at the same concentrations,
concentration-dependently improved the recovery of RPP as measured at
30 minutes of reperfusion (Figure 6C). There was a significant
correlation between the inhibition of pro-MMP-2 activity and the
recovery of RPP caused by doxycycline
(r2=0.98, P<0.01).
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Discussion |
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We studied the expression and liberation of MMPs in isolated rat hearts during aerobic perfusion and reperfusion after global no-flow ischemia.
Expression and Release of MMPs in Aerobically Perfused
Hearts
Gelatinolytic activities corresponding to
molecular weights of 75, 72, and 62 kDa were expressed in heart
tissue. The 72- and 62-kDa forms corresponded to pro-MMP-2 and MMP-2,
respectively, and have already been described in human, rat, and
porcine hearts.8 9 10 This is the first report to show that
pro-MMP-2, MMP-2, and 75-kDa gelatinases are released into the
coronary effluent of aerobically perfused rat hearts and that
pro-MMP-2 constitutes the major gelatinase activity. In the heart,
MMP-2 is ubiquitously distributed and has been localized to
endothelial, endocardial, and subendocardial layers as
well as to the mesenchymal cells.8 9 10 11 We did not identify
any pro-MMP-9 or MMP-9 activity in the heart tissue or coronary
effluent. The 75-kDa gelatinase may be a modified form of MMP-2 or an
activation product of MMP-9 by the action of neutrophil
elastase.22
Expression and Release of MMPs in Hearts Subjected to
Ischemia-Reperfusion Injury
The release of MMPs from the heart into the coronary
effluent was immediately increased as a consequence of ischemia
and reperfusion. The release of pro-MMP-2 and MMP-2 peaked during the
first and fifth minutes of reperfusion, respectively, and their release
was enhanced with increasing duration of ischemia. Moreover,
the release of MMPs was associated with impaired mechanical function of
the heart, because both chemically unrelated inhibitors
of MMP activity (doxycycline and o-phenanthroline) and MMP-2
antibody were able to improve the functional recovery of
ischemic-reperfused hearts. Ischemia-reperfusion
resulted in a clear-cut depletion of pro-MMP-2 and MMP-2 activity in
the myocardium, showing that the activation and release of
MMP-2 into the perfusate is a consequence of this injury.
Ischemia-reperfusion injury of the porcine heart in vivo increased MMP-1 and MMP-9 activities in the myocardium, an effect ascribed to infiltrating leukocytes.23 If blood leukocytes were the main source of MMP-9 during reperfusion, this would explain the lack of detectable MMP-9 activity in our experiments using crystalloid buffer–perfused, isolated hearts.
Role of MMP-2 in the Development of Myocardial
Ischemia-Reperfusion Injury
These findings suggest a novel role for MMP-2 in the development
of myocardial stunning in the reperfusion period after
ischemia. The evidence for the involvement of this enzyme in
the injury is compelling: (1) there was a marked release of pro-MMP-2
during reperfusion, (2) there was a negative correlation between
pro-MMP-2 release during reperfusion and functional recovery of hearts
subjected to increasing duration of ischemia, (3) infusion of
semipurified MMP-2 worsened the recovery of function after
ischemia and reperfusion, (4) there was a positive correlation
between the ability of the MMP inhibitor doxycycline to
improve the recovery of mechanical function and its ability to inhibit
myocardial MMP-2 activity, and (5) there was a protective effect of a
neutralizing antibody to MMP-2 in ischemic-reperfused
hearts.
Mechanisms of Activation and Action of MMP-2 in
Ischemia-Reperfusion Injury
Pro-MMPs may be activated through the breakage of the
zinc-cysteine bond, which exposes its catalytic site, followed by
proteolytic activation,2 or through oxidant-induced
conformational changes without a change in molecular
weight.3 11 Indeed, the powerful oxidant peroxynitrite
activated pro-MMP-2 in human smooth muscle cells24
and purified procollagenase in activated
neutrophils.3 The biosynthesis of peroxynitrite in the
heart is greatly enhanced during the first minute of reperfusion after
ischemia.25 Because the time courses of
peroxynitrite and pro-MMP-2 release are similar, we suggest that this
oxidant may be involved in pro-MMP-2 activation during reperfusion.
Endogenous tissue inhibitors of
metalloproteinases (TIMPs) also control the activity of MMPs.
Interestingly, peroxynitrite inactivated TIMP-1 in
vitro,26 and ischemic-reperfused hearts showed
decreased TIMP-1 gene expression.27 Thus, decreased
expression and/or activity of TIMPs may contribute to enhanced MMP
activity seen during ischemia-reperfusion injury.
Apart from the extracellular matrix, little is known about other possible targets of MMP action in the cell. For example, the translocation of MMP-2 to the platelet surface membrane is likely to activate specific adhesion receptors.14 Interestingly, in hearts of patients with dilated cardiomyopathy, both MMP-2 and MMP-9 were found to be closely associated with sarcomeres.28 Moreover, these MMPs were shown to be able to digest myosin heavy chain, and its degradation products were found in cardiomyopathic heart tissue. This indicates that contractile proteins may represent a molecular target for the detrimental actions of MMP-2 in the myocardium.28
Pharmacological Prevention of Myocardial Dysfunction Caused by
MMPs
Many synthetic MMP inhibitors are now in clinical
trials for the treatment of such disorders as cancer and rheumatoid
arthritis. Our results suggest that MMP-2 may be a viable target for
the therapeutic intervention of ischemia-reperfusion injury.
Phenanthroline was the most efficacious inhibitor of MMPs,
followed by doxycycline and then by phosphoramidon,
which failed to inhibit MMPs. Rohde et al29 recently
showed that an MMP inhibitor attenuates left
ventricular dilation in a mouse infarct model.
Tetracycline antibiotics, including doxycycline, have been shown to possess additional activities as inhibitors of MMPs, independent of their antibacterial activity.30 Recent epidemiological studies have indicated a reduced risk of first-time acute myocardial infarction in patients receiving only tetracycline- or quinolone-type antibiotics.31 Some forms of heart diseases may be associated with bacterial infections, such as chlamydia,32 and this may at least partially explain the beneficial effect of these antibiotics in preventing heart attacks.31 Our data, however, suggest that protective actions of tetracyclines on the myocardium may indeed be due to inhibition of MMP-2 activity. Phenanthroline and tetracyclines might also have additional effects on free radical generation, cell growth, and vascular reactivity.30
MMPs and Ischemia-Reperfusion Injury In Vivo
Our findings in the isolated perfused heart indicate that
myocardium subjected to ischemia-reperfusion injury
releases MMP-2 and that its liberation is of pathological significance
for the development of mechanical dysfunction. In the setting of
ischemia-reperfusion in vivo, activation of blood cells, such
as platelets and leukocytes,33 is likely to result in
the release of MMP-2, MMP-9, and possibly other proteases that may also
contribute to the development of myocardial stunning. Clearly, more
work is necessary to explore the biological and pharmacological
significance of the liberation of MMPs during
ischemia-reperfusion injury.
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Acknowledgments |
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This project was funded by grants from the Medical Research Council of Canada (MRC) to Dr Schulz (MT-14741) and Dr Radomski (MT-14074). Dr Cheung was an MRC Fellow and a graduate trainee of the Alberta Heritage Foundation for Medical Research (AHFMR). Dr Radomski is an AHFMR Scholar. Dr Schulz is a Senior AHFMR Scholar and was an MRC Scholar. We thank Dr Paul Scott (University of Alberta) for helpful advice.
Received September 9, 1999; revision received November 5, 1999; accepted November 15, 1999.
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  A. D. Kandasamy and R. Schulz Glycogen synthase kinase-3{beta} is activated by matrix metalloproteinase-2 mediated proteolysis in cardiomyoblasts Cardiovasc Res, September 1, 2009; 83(4): 698 - 706. [Abstract] [Full Text] [PDF]
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A. D. Kandasamy, A. K. Chow, M. A.M. Ali, and R. Schulz Matrix metalloproteinase-2 and myocardial oxidative stress injury: beyond the matrix Cardiovasc Res, August 20, 2009; (2009) cvp268v2. [Abstract] [Full Text] [PDF]
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 A. Sokal, M. Zembala, A. Radomski, A. Kocher, J. Pacholewicz, J. Los, E. Jedrzejczyk, M. Zembala, and M. Radomski A differential release of matrix metalloproteinases 9 and 2 during coronary artery bypass grafting and off-pump coronary artery bypass surgery. J. Thorac. Cardiovasc. Surg., May 1, 2009; 137(5): 1218 - 1224. [Abstract] [Full Text] [PDF]
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A. Haghikia and D. Hilfiker-Kleiner MiRNA-21: a key to controlling the cardiac fibroblast compartment? Cardiovasc Res, April 1, 2009; 82(1): 1 - 3. [Full Text] [PDF]
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S. Roy, S. Khanna, S.-R. A. Hussain, S. Biswas, A. Azad, C. Rink, S. Gnyawali, S. Shilo, G. J. Nuovo, and C. K. Sen MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue Cardiovasc Res, April 1, 2009; 82(1): 21 - 29. [Abstract] [Full Text] [PDF]
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K. Hishikari, J.-i. Suzuki, M. Ogawa, K. Isobe, T. Takahashi, M. Onishi, K. Takayama, and M. Isobe Pharmacological activation of the prostaglandin E2 receptor EP4 improves cardiac function after myocardial ischaemia/reperfusion injury Cardiovasc Res, January 1, 2009; 81(1): 123 - 132. [Abstract] [Full Text] [PDF]
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 F. G. Spinale, C. N. Koval, A. M. Deschamps, R. E. Stroud, and J. S. Ikonomidis Dynamic Changes in Matrix Metalloprotienase Activity Within the Human Myocardial Interstitium During Myocardial Arrest and Reperfusion Circulation, September 30, 2008; 118(14_suppl_1): S16 - S23. [Abstract] [Full Text] [PDF]
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 C. LaCroix, J. Freeling, A. Giles, J. Wess, and Y.-F. Li Deficiency of M2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H810 - H820. [Abstract] [Full Text] [PDF]
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 F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]
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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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 H. Stapel, S.-C. Kim, S. Osterkamp, P. Knuefermann, A. Hoeft, R. Meyer, C. Grohe, and G. Baumgarten Toll-like receptor 4 modulates myocardial ischaemia-reperfusion injury: Role of matrix metalloproteinases Eur J Heart Fail, November 1, 2006; 8(7): 665 - 672. [Abstract] [Full Text] [PDF]
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M. A. Alfonso-Jaume, M. R. Bergman, R. Mahimkar, S. Cheng, Z. Q. Jin, J. S. Karliner, and D. H. Lovett Cardiac ischemia-reperfusion injury induces matrix metalloproteinase-2 expression through the AP-1 components FosB and JunB Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1838 - H1846. [Abstract] [Full Text] [PDF]
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 H. Matsusaka, T. Ide, S. Matsushima, M. Ikeuchi, T. Kubota, K. Sunagawa, S. Kinugawa, and H. Tsutsui Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload Hypertension, April 1, 2006; 47(4): 711 - 717. [Abstract] [Full Text] [PDF]
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L. Turnbull, H.-Z. Zhou, P. M. Swigart, S. Turcato, J. S. Karliner, B. R. Conklin, P. C. Simpson, and A. J. Baker Sustained preconditioning induced by cardiac transgenesis with the tetracycline transactivator Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1103 - H1109. [Abstract] [Full Text] [PDF]
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G.-Y. Wang, M. R. Bergman, A. P. Nguyen, S. Turcato, P. M. Swigart, M. C. Rodrigo, P. C. Simpson, J. S. Karliner, D. H. Lovett, and A. J. Baker Cardiac transgenic matrix metalloproteinase-2 expression directly induces impaired contractility Cardiovasc Res, February 15, 2006; 69(3): 688 - 696. [Abstract] [Full Text] [PDF]
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 Z. Giricz, M. M. Lalu, C. Csonka, P. Bencsik, R. Schulz, and P. Ferdinandy Hyperlipidemia Attenuates the Infarct Size-Limiting Effect of Ischemic Preconditioning: Role of Matrix Metalloproteinase-2 Inhibition J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 154 - 161. [Abstract] [Full Text] [PDF]
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H. Matsusaka, M. Ikeuchi, S. Matsushima, T. Ide, T. Kubota, A. M. Feldman, A. Takeshita, K. Sunagawa, and H. Tsutsui Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1858 - H1864. [Abstract] [Full Text] [PDF]
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G. Sawicki, H. Leon, J. Sawicka, M. Sariahmetoglu, C. J. Schulze, P. G. Scott, D. Szczesna-Cordary, and R. Schulz Degradation of Myosin Light Chain in Isolated Rat Hearts Subjected to Ischemia-Reperfusion Injury: A New Intracellular Target for Matrix Metalloproteinase-2 Circulation, July 26, 2005; 112(4): 544 - 552. [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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 C. Banfi, V. Cavalca, F. Veglia, M. Brioschi, S. Barcella, L. Mussoni, L. Boccotti, E. Tremoli, P. Biglioli, and P. Agostoni Neurohormonal activation is associated with increased levels of plasma matrix metalloproteinase-2 in human heart failure Eur. Heart J., March 1, 2005; 26(5): 481 - 488. [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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 T. A. Sutton, K. J. Kelly, H. E. Mang, Z. Plotkin, R. M. Sandoval, and P. C. Dagher Minocycline reduces renal microvascular leakage in a rat model of ischemic renal injury Am J Physiol Renal Physiol, January 1, 2005; 288(1): F91 - F97. [Abstract] [Full Text] [PDF]
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K. J. Kelly, T. A. Sutton, N. Weathered, N. Ray, E. J. Caldwell, Z. Plotkin, and P. C. Dagher Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury Am J Physiol Renal Physiol, October 1, 2004; 287(4): F760 - F766. [Abstract] [Full Text] [PDF]
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 K. Egi, N. E. Conrad, J. Kwan, C. Schulze, R. Schulz, and S. M. Wildhirt Inhibition of inducible nitric oxide synthase and superoxide production reduces matrix metalloproteinase-9 activity and restores coronary vasomotor function in rat cardiac allografts Eur. J. Cardiothorac. Surg., August 1, 2004; 26(2): 262 - 269. [Abstract] [Full Text] [PDF]
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 K. Kaikita, T. Hayasaki, T. Okuma, W. A. Kuziel, H. Ogawa, and M. Takeya Targeted Deletion of CC Chemokine Receptor 2 Attenuates Left Ventricular Remodeling after Experimental Myocardial Infarction Am. J. Pathol., August 1, 2004; 165(2): 439 - 447. [Abstract] [Full Text] [PDF]
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 C. E. Berry and J. M. Hare Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications J. Physiol., March 15, 2004; 555(3): 589 - 606. [Abstract] [Full Text] [PDF]
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T.-l. Yue, W. Bao, B. M. Jucker, J.-l. Gu, A. M. Romanic, P. J. Brown, J. Cui, D. T. Thudium, R. Boyce, C. L. Burns-Kurtis, et al. Activation of Peroxisome Proliferator-Activated Receptor-{alpha} Protects the Heart From Ischemia/Reperfusion Injury Circulation, November 11, 2003; 108(19): 2393 - 2399. [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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C. J. Schulze, W. Wang, W. L. Suarez-Pinzon, J. Sawicka, G. Sawicki, and R. Schulz Imbalance Between Tissue Inhibitor of Metalloproteinase-4 and Matrix Metalloproteinases During Acute Myoctardial Ischemia-Reperfusion Injury Circulation, May 20, 2003; 107(19): 2487 - 2492. [Abstract] [Full Text] [PDF]
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P. Pacher, L. Liaudet, P. Bai, J. G. Mabley, P. M. Kaminski, L. Virag, A. Deb, E. Szabo, Z. Ungvari, M. S. Wolin, et al. Potent Metalloporphyrin Peroxynitrite Decomposition Catalyst Protects Against the Development of Doxorubicin-Induced Cardiac Dysfunction Circulation, February 18, 2003; 107(6): 896 - 904. [Abstract] [Full Text] [PDF]
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C. Qun Gao, G. Sawicki, W. L Suarez-Pinzon, T. Csont, M. Wozniak, P. Ferdinandy, and R. Schulz Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction Cardiovasc Res, February 1, 2003; 57(2): 426 - 433. [Abstract] [Full Text] [PDF]
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D. Li, V. Williams, L. Liu, H. Chen, T. Sawamura, T. Antakli, and J. L. Mehta LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1795 - H1801. [Abstract] [Full Text] [PDF]
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W. Wang, C. J. Schulze, W. L. Suarez-Pinzon, J. R.B. Dyck, G. Sawicki, and R. Schulz Intracellular Action of Matrix Metalloproteinase-2 Accounts for Acute Myocardial Ischemia and Reperfusion Injury Circulation, September 17, 2002; 106(12): 1543 - 1549. [Abstract] [Full Text] [PDF]
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V. Falk, P.M. Soccal, J. Grunenfelder, G. Hoyt, T. Walther, and R.C. Robbins Regulation of matrix metalloproteinases and effect of MMP-inhibition in heart transplant related reperfusion injury Eur. J. Cardiothorac. Surg., July 1, 2002; 22(1): 53 - 58. [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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 P. Jurasz, A. W.Y. Chung, A. Radomski, and M. W. Radomski Nonremodeling Properties of Matrix Metalloproteinases: The Platelet Connection Circ. Res., May 31, 2002; 90(10): 1041 - 1043. [Full Text] [PDF]
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Y. Ben-Yosef, N. Lahat, S. Shapiro, H. Bitterman, and A. Miller Regulation of Endothelial Matrix Metalloproteinase-2 by Hypoxia/Reoxygenation Circ. Res., April 19, 2002; 90(7): 784 - 791. [Abstract] [Full Text] [PDF]
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P. Pacher, L. Liaudet, P. Bai, L. Virag, J. G. Mabley, G. Hasko, and C. Szabo Activation of Poly(ADP-Ribose) Polymerase Contributes to Development of Doxorubicin-Induced Heart Failure J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 862 - 867. [Abstract] [Full Text] [PDF]
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M. P. Bendeck, M. Conte, M. Zhang, N. Nili, B. H. Strauss, and S. M. Farwell Doxycycline Modulates Smooth Muscle Cell Growth, Migration, and Matrix Remodeling after Arterial Injury Am. J. Pathol., March 1, 2002; 160(3): 1089 - 1095. [Abstract] [Full Text] [PDF]
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W. Wang, G. Sawicki, and R. Schulz Peroxynitrite-induced myocardial injury is mediated through matrix metalloproteinase-2 Cardiovasc Res, January 1, 2002; 53(1): 165 - 174. [Abstract] [Full Text] [PDF]
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 D. GOUKASSIAN, A. DIEZ-JUAN, T. ASAHARA, P. SCHRATZBERGER, M. SILVER, T. MURAYAMA, J. M. ISNER, and V. ANDRES Overexpression of p27Kip1 by doxycycline-regulated adenoviral vectors inhibits endothelial cell proliferation and migration and impairs angiogenesis FASEB J, September 1, 2001; 15(11): 1877 - 1885. [Abstract] [Full Text] [PDF]
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T. Etoh, C. Joffs, A. M. Deschamps, J. Davis, K. Dowdy, J. Hendrick, S. Baicu, R. Mukherjee, M. Manhaini, and F. G. Spinale Myocardial and interstitial matrix metalloproteinase activity after acute myocardial infarction in pigs Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H987 - H994. [Abstract] [Full Text] [PDF]
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 G. Miserocchi, A. Passi, D. Negrini, M. Del Fabbro, and G. De Luca Pulmonary interstitial pressure and tissue matrix structure in acute hypoxia Am J Physiol Lung Cell Mol Physiol, May 1, 2001; 280(5): L881 - L887. [Abstract] [Full Text] [PDF]
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 P. Jurasz, G. Sawicki, M. Duszyk, J. Sawicka, C. Miranda, I. Mayers, and M. W. Radomski Matrix Metalloproteinase 2 in Tumor Cell-induced Platelet Aggregation: Regulation by Nitric Oxide Cancer Res., January 1, 2001; 61(1): 376 - 382. [Abstract] [Full Text]
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 W. J. Lane, S. Dias, K. Hattori, B. Heissig, M. Choy, S. Y. Rabbany, J. Wood, M. A. S. Moore, and S. Rafii Stromal-derived factor 1-induced megakaryocyte migration and platelet production is dependent on matrix metalloproteinases Blood, December 15, 2000; 96(13): 4152 - 4159. [Abstract] [Full Text] [PDF]
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C. Fernandez-Patron, K. G. Stewart, Y. Zhang, E. Koivunen, M. W. Radomski, and S. T. Davidge Vascular Matrix Metalloproteinase-2-Dependent Cleavage of Calcitonin Gene-Related Peptide Promotes Vasoconstriction Circ. Res., October 13, 2000; 87(8): 670 - 676. [Abstract] [Full Text] [PDF]
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Y. Ben-Yosef, N. Lahat, S. Shapiro, H. Bitterman, and A. Miller Regulation of Endothelial Matrix Metalloproteinase-2 by Hypoxia/Reoxygenation Circ. Res., April 19, 2002; 90(7): 784 - 791. [Abstract] [Full Text] [PDF]
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