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Matrix Metalloproteinase Inhibition After Myocardial Infarction: A New

Approach to Prevent Heart Failure?

Article  in  Circulation Research · September 2001

DOI: 10.1161/hh1501.094396 · Source: PubMed

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 Reviews

This Review is part of a thematic series on Matrix Metalloproteinases, which includes the following articles:

Matrix Metalloproteinase Inhibition After Myocardial Infarction: A New Approach to Prevent Heart Failure?

Matrix Metalloproteinase: Regulation and Dysregulation in the Failing Heart

Matrix Metalloproteinase and Morphogenesis
Matrix Metalloproteinase and Vascular Remodeling and Atherogenesis
Matrix Metalloproteinase: Overview of Structure, Function, and Biochemistry
Membrane-Associated Matrix Metalloproteinase in Signaling David Kass, Marlene Rabinovitch, Editors

Matrix Metalloproteinase Inhibition After

Myocardial Infarction
A New Approach to Prevent Heart Failure?
Esther E.J.M. Creemers, Jack P.M. Cleutjens, Jos F.M. Smits, Mat J.A.P. Daemen

Abstract—Increased activity of matrix metalloproteinases (MMPs) has been implicated in numerous disease processes,
including tumor growth and metastasis, arthritis, and periodontal disease. It is now becoming increasingly clear that
extracellular matrix degradation by MMPs is also involved in the pathogenesis of cardiovascular disease, including
atherosclerosis, restenosis, dilated cardiomyopathy, and myocardial infarction. Administration of synthetic MMP
inhibitors in experimental animal models of these cardiovascular diseases significantly inhibits the progression of,
respectively, atherosclerotic lesion formation, neointima formation, left ventricular remodeling, pump dysfunction, and
infarct healing. This review focuses on the role of MMPs in cardiovascular disease, in particular myocardial infarction
and the subsequent progression to heart failure. MMPs, which are present in the myocardium and capable of degrading
all the matrix components of the heart, are the driving force behind myocardial matrix remodeling. The recent finding
that acute pharmacological inhibition of MMPs or deficiency in MMP-9 attenuates left ventricular dilatation in the
infarcted mouse heart led to the proposal that MMP inhibitors could be used as a potential therapy for patients at risk
for the development of heart failure after myocardial infarction. Although these promising results encourage the design
of clinical trials with MMP inhibitors, there are still several unresolved issues. This review describes the biology of
MMPs and discusses new insights into the role of MMPs in several cardiovascular diseases. Attention will be paid to
the central role of the plasminogen system as an important activator of MMPs in the remodeling process after myocardial
infarction. Finally, we speculate on the use of MMP inhibitors as potential therapy for heart failure. (Circ Res. 2001;
89:201-210.)
Key Words: myocardial infarction 䡲 therapy 䡲 matrix metalloproteinase inhibition

M yocardial infarction (MI) leads to complex architec-

tural alterations involving both the infarcted and non-
infarcted myocardium. Dilatation of the left ventricle and
infarct thinning, also called infarct expansion, are the most
prominent structural changes in the infarct region.1 Patients
exhibiting extensive infarct expansion after MI are more
likely to experience complications, such as the development
of congestive heart failure, aneurysm formation, and myocar-
dial rupture.2 The extent of ventricular dilatation after MI is
related to several factors such as the magnitude of the initial

Original received April 12, 2001; revision received June 8, 2001; accepted June 13, 2001.
From the Departments of Pathology (E.E.J.M.C., J.P.M.C., M.J.A.P.D.) and Pharmacology (J.F.M.S.), Cardiovascular Research Institute Maastricht,
University of Maastricht, The Netherlands.
Correspondence to M.J.A.P. Daemen, MD, PhD, Department of Pathology, University of Maastricht, PO Box 616, 6200 MD Maastricht, The
Netherlands. E-mail mda@lpat.azm.nl
© 2001 American Heart Association, Inc.
Circulation Research is available at http://www.circresaha.org

201
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202 Circulation Research August 3, 2001

TABLE 1. MMPs and Their Substrates

MMP
Enzyme Classification Substrate
Collagenases
Interstitial collagenase MMP-1 Collagens I, II, III, VII, and X, gelatin, entactin, aggrecan
Neutrophil collagenase MMP-8 Collagens I, II, and III, aggrecan
Collagenase-3 MMP-13 Collagens I, II, and III, gelatin, fibronectin, laminins,
tenascin
Collagenase-479 MMP-18 Not known
Gelatinases
Gelatinase A MMP-2 Gelatin, collagens I, IV, V, VII, and X, fibronectin,
laminins, aggrecan, tenascin-C, vitronectin
Gelatinase B MMP-9 Gelatin, collagens IV, V, and XIV, aggrecan, elastin,
entactin, vitronectin
Stromelysins
Stromelysin 1 MMP-3 Gelatin, fibronectin, laminins, collagens III, IV, IX, and X,
tenascin-C, vitronectin
Stromelysin 2 MMP-10 Collagen IV, fibronectin, aggrecan
Stromelysin 3 MMP-11 Fibronectin, gelatin, laminins, collagen IV, aggrecan
Membrane-type
MMPs
MT1-MMP MMP-14 Collagens I, II, and III, fibronectin, laminins, vitronectin,
proteoglycans; activates proMMP-2 and proMMP-13
MT2-MMP MMP-15 Activates proMMP-2
MT3-MMP MMP-16 Activates proMMP-2
MT4-MMP MMP-17 Not known
MT5-MMP 80 MMP-24 Activates proMMP-2
MT6-MMP MMP-25 䡠䡠䡠
Others
Matrilysin MMP-7 Gelatin, fibronectin, laminins, collagen IV, vitronectin,
tenascin-C, elastin, aggrecan
Metalloelastase MMP-12 Elastin
Unnamed81 MMP-19 Not known
Enamelysin MMP-20 Aggrecan
MMP-23 䡠䡠䡠
Endometase MMP-26 䡠䡠䡠

damage (infarct size), to the extent of the inflammatory
response (infarct healing), and to ventricular wall stress.
Thinning of the infarct zone starts early, against a histopatho-
logical background of evolving necrosis, edema, and acute
inflammation, a period during which the affected myocardi-
um is especially prone to mechanical deformation.3 One of
the determinants of left ventricular remodeling is damage to
and loss of the myocardial extracellular matrix (ECM) during
the healing process after MI.4,5 Matrix metalloproteinases
(MMPs), which are present in the myocardium and capable of
degrading all the matrix components of the heart, are the
driving force behind myocardial matrix remodeling. The
finding that acute pharmacological inhibition of MMPs atten-
uates LV dilatation in the infarcted mouse heart led to the
proposal that MMP inhibitors could be used as a potential
therapy for patients at risk for the development of heart
failure after MI. In the present review, we describe the
biology of MMPs and discuss new insights into the role of
MMPs in the course of several cardiovascular diseases.
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Family Members of MMPs
MMPs are a family of zinc-containing endoproteinases that
share structural domains but differ in substrate specificity,
cellular sources, and inducibility. The list of MMPs has
grown rapidly in the past several years, and by now ⬎20
mammalian members have been cloned and identified (Table
1). All MMPs share the following functional features:
(1) they degrade ECM components; (2) they are secreted in a
latent proform and require activation for proteolytic activity;
(3) they contain Zn2⫹ at their active site; (4) they need
calcium for stability; (5) they function at neutral pH; and
(6) they are inhibited by specific tissue inhibitors of metal-
loproteinases (TIMPs).
Based on their substrate specificity (Table 1) and primary
structure (Figure 1), the MMP family can be subdivided into
4 groups. The first group, the collagenases, includes MMP-1
(interstitial collagenase), MMP-8 (neutrophil collagenase),
and MMP-13 (collagenase-3), which can all cleave fibrillar
collagens (types I, II, and III). Because they are tightly
 Creemers et al MMP Inhibition and Myocardial Infarction 203

TABLE 2. Effect of Cytokines and Growth Factors on MMP and

TIMP Expression
MMPs TIMPs
TNF-␣ 82 1 12*
EGF 1 1
PDGF83,84 1 1
bFGF 1 ND
IL-1 1 1
IL-6 1 1
VEGF85 1 ND
CD409 1 ND
Phorbol esters 1 1
Corticosteroids 2 ND
Retinoic acid 2 1
Heparin 2 ND
IL-486 2 2
TGF-␤83,84 12† 1
IFN-␥14,87 12‡ ND
Effects of cytokines on MMP expression involve most members of the MMP
family, and exceptions for certain members of the MMP family are not given.
Figure 1. Basic domain structure of MMPs. A, MMPs contain at Adapted from Mauviel et al13 and Gomez et al,88 unless stated otherwise. 1
least 3 homologous protein domains: the signal peptide, a indicates upregulated; 2, downregulated; VEGF, vascular endothelial growth
domain that targets the enzyme for secretion, the propeptide factor; ND, not determined; *, dose dependent; †, increases MMP-2, -9 and
domain, which is removed when the enzyme becomes acti-
decreases MMP-1, -3 expression; and ‡, cell-type specific.
vated, and the catalytic domain, which contains the zinc-binding
region and is responsible for the proteolytic activity of the
enzyme. B, Structural differences between the various classes of ever, demonstrates that gelatinases, formerly thought of as
MMPs. In gelatinases, the catalytic domain contains the gelatin- having substrate specificity for denatured collagens (gelatins)
binding domain, which has homology to the collagen-binding
domain of fibronectin. The hemopexin domain has been shown only, are able to cleave interstitial collagens as well.6,7 It has
to play a functional role in substrate binding and interactions therefore been suggested that, because of their ability to
with TIMPs. Finally, membrane-type MMPs contain a transmem- initiate and continue the degradation of fibrillar collagens,
brane domain in the C-terminal end.
gelatinases play a more important role in the remodeling of
collagenous ECM than has previously been thought.8
apposed and highly cross-linked fibrils, collagens I, II, and III
are known to be extremely resistant to cleavage by most Regulation of MMP Activity
proteinases. Collagenases cleave fibrillar collagens at unique Because MMPs, once activated, are collectively capable of
sites in the triple helix at 3⁄4 from the N-terminal end, degrading the complete ECM, it is important that the activity
generating 3⁄4 and 1⁄4 collagen fragments. Because of thermal of these enzymes is kept under tight control. The activity of
degradation and loss of stability, these fragments unfold their MMPs is controlled at the following three levels: transcrip-
triple helix and fall apart into fragmented single a-chains, the tion, activation of the latent proenzymes, and inhibition by
so-called gelatins. In the mouse, MMP-13 appears to be the their endogenous inhibitors, the TIMPs.
primary collagenase. Group 2, the gelatinases (MMP-2 and
MMP-9) is well-known for its ability to degrade gelatins. Regulation of MMP Expression
Gelatinases are also capable of degrading type IV collagen in The expression of most MMPs is generally found at low
basement membranes. Group 3 constitutes the stromelysins levels in normal adult tissue but is upregulated during certain
(MMP-3, -10, and -11), so named because they are active physiological and pathological remodeling processes. Induc-
against a broad spectrum of ECM components, including tion or stimulation at the transcriptional level is mediated by
proteoglycans, laminins, fibronectin, vitronectin, and some a variety of inflammatory cytokines, hormones, and growth
types of collagens. Group 4 contains the membrane-type factors (Table 2), such as interleukin-1 (IL-1), IL-6, tumor
MMPs (MT-MMPs), which degrade several ECM compo- necrosis factor-␣ (TNF-␣), epidermal growth factor (EGF),
nents and are also able to activate other MMPs. platelet-derived growth factor (PDGF), basic fibroblast
This substrate-based subdivision of MMPs turned out to be growth factor (bFGF), and CD40.9,10 In addition, a cell-
useful in the past. However, as more is known about the surface protein that induces MMP expression, termed extra-
enzymatic activities and substrates, its usefulness becomes cellular matrix metalloproteinase inducer (EMMPRIN) has
less clear because the substrate profile of the enzymes is often been identified in both normal and diseased human tissue.11
more gradual than absolute. For example, it was assumed for Other factors such as corticosteroids, retinoic acid, heparin,
a long time that the cleavage of intact fibrillar collagens was and IL-4 have been demonstrated to inhibit MMP gene
limited to the action of collagenases. Recent evidence, how- expression.12 Not all MMPs react similarly to the same
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204 Circulation Research August 3, 2001
stimulus. For example, transforming growth factor-␤
(TGF-␤) stimulates MMP-2 and MMP-9 but inhibits MMP-1
and MMP-3 synthesis.13 In the case of interferon-␥ (IFN-␥),
the impact on MMP expression is cell-type specific. Whereas
IFN-␥ increases MMP-1 expression in keratinocytes, it de-
creases MMP-1 expression in macrophages and fibroblasts.14
Activation Mechanisms of Latent MMPs
Although transcriptional regulation is essential for MMP
production, matrix degradation requires the latent enzymes to
be activated by proteolytic cleavage. Three different activa-
tion mechanisms have been described: (1) stepwise activa-
tion, (2) activation at the cell surface by MT-MMPs, and (3)
intracellular activation.15
The first step during stepwise activation of MMPs often
involves proteinases such as plasmin, trypsin, chymase,
elastase, or kallikrein. Of these proteinases, plasmin is
thought to be the most potent physiological activator in
vivo.16 Plasmin attacks the proteinase-susceptible region in
the propeptide domain of the MMP, which induces confor-
mational changes in the propeptide and renders the activation
site to be readily cleaved by a second proteinase, usually
another MMP.15 The generation of plasmin from plasminogen
by the action of plasminogen activators occurs largely at the
cell surface, where both plasminogen and urokinase activa-
tors are bound to plasminogen binding sites and urokinase
plasminogen activator receptors (uPARs), respectively.
Cell surface activation of MMPs is considered to be
important for pericellular degradation of the ECM during cell
migration. In addition to the plasminogen system, other
enzymes are capable of activating MMPs at the plasma
membrane. In 1994, Sato et al17,18 cloned a membrane-type
MMP (MT1-MMP) and identified it as an activator of latent
MMP-2 on the plasma membrane. Currently, five MT-MMPs
have been cloned, and it has been demonstrated that MT-
MMPs also activate other MMPs.15,19
The first evidence that members of the MMP family are
activated intracellularly came from Pei and Weiss in 1995.20
They demonstrated that stromelysin 3 (MMP-11) could be
activated by the Golgi-associated subtilisin-like proteinase
furin and could be secreted as an active enzyme. Subse-
quently, Sato et al21 reported that MT1-MMP, expressed in
Escherichia coli was also activated by furin, indicating that
MT-MMPs are also likely to be activated intracellularly. The
precise mechanism of intracellular activation and the contri-
bution to extracellular MMP activity has, however, not been
clarified.
Endogenous MMP Inhibitors
Fully activated MMPs can be inhibited by interaction with
naturally occurring, specific inhibitors, the TIMPs. TIMPs are
expressed by a variety of cell types and are present in most
tissues and body fluids. At present, the TIMP family consists
of four structurally related members, TIMP-1, -2, -3 and -4.
TIMPs bind noncovalently to active MMPs in a 1:1 molar
ratio. Inhibition is accomplished by their ability to interact
with the zinc-binding site within the catalytic domain of
active MMPs. There is a certain degree of specificity in the
activity of different TIMPs toward distinct members of the
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MMP family. Whereas TIMP-1 potently inhibits the activity
of most MMPs, with the exception of MMP-2 and MT1-
MMP, TIMP-2 is a potent inhibitor of most MMPs, except
MMP-9. In addition, TIMP-2 can form a complex with
MT1-MMP at the cell membrane, which possibly plays a
regulatory role in the proteolytic activation of MMP-2.
TIMP-3, which is insoluble and binds to the ECM, has been
shown to bind MMP-1, -2, -3, -9, and -13. TIMP-4 inhibits
MMP-1, -3, -7, and -9 and shows a high level of expression
in adult human cardiac tissue.22,23 Transcriptional regulation
of TIMPs is mediated by factors such as phorbol esters, IL-1,
and IL-613 (Table 2). Because these factors stimulate both
TIMP and MMP expression, they might have a minor effect
on the total proteolytic activity. TGF-␤ has a more complex
impact on the regulation of proteolytic activity. In this regard,
TGF-␤ upregulates the expression of MMP-2, MMP-9, and
TIMPs, while it decreases the expression of MMP-1 and
MMP-3.13
Although the role of TIMPs is clearly important in the
prevention of excessive matrix degradation by MMPs, recent
advances in TIMP research suggest that TIMP-1 and TIMP-2
are multifunctional proteins with more diverse biological
actions. It has been reported that TIMP-1 and TIMP-2 exhibit
growth factor–like activity and can inhibit angiogenesis,24 –26
whereas TIMP-3 has been implicated in apoptosis.27
In addition to the TIMP family, there are also several other
naturally occurring inhibitors of MMPs, of which
␣-macroglobulin is the most prominent. This macroglobulin
is a large (750 kDa) protein produced by the liver. It can
inhibit all 4 classes of proteinases (ie, cysteine, aspartic,
serine, and metalloproteinases), not just MMPs. However, the
large size of ␣-macroglobulin may exclude it from many sites
of connective tissue turnover. This may limit its effectiveness
as an inhibitor.
MMPs in Physiology and Disease
The turnover of ECM is an integral part of development,
morphogenesis, and tissue remodeling. In this regard, MMPs
are involved in many physiological processes, such as em-
bryonic development, ovulation, bone remodeling, and
wound healing. Their enhanced activity has also been impli-
cated in numerous disease processes, including arthritis,
tumor cell metastasis, periodontal disease, atherosclerosis,
and cardiac diseases.
Studies using synthetic MMP inhibitors have provided
more insights into the role of MMPs in the pathogenesis of
several diseases. Most MMP inhibitors used at the present
time are representatives of one chemical class, the hydrox-
amates.28 Inhibition is accomplished by binding of the hy-
droxamic group to the zinc atom present in MMPs. MMP
inhibitors have been successfully applied in several animal
models of inflammation and cellular invasion. Administration
of broad-range MMP inhibitors (BB-94, AG3340) prevented
tumor cell invasion, metastasis, and tumor angiogenesis in
rodents.29,30 Several MMP inhibitors are currently being
evaluated as treatment for patients with advanced cancer.
Preliminary clinical reports have described a decrease in
tumor marker levels in patient serum as evidence of an
antitumor effect. In arthritis, it was recently shown that the
 Creemers et al
MMP inhibitor Ro32-3555 prevented cartilage breakdown in
both rheumatoid arthritis and osteoarthritis in rats.31 During
dermal wound healing in rats, broad-range inhibition of MMP
activity by ilomastat (GM6001) resulted in an enhanced
wound strength that was associated with a decreased inflam-
matory response.32 In thioglycollate-induced peritonitis in the
mouse, ilomastat reduced the cellular infiltrate into the
peritoneum.33 MMP inhibitors have also been suggested for
therapy of vascular diseases. In the case of abdominal aortic
aneurysms, the broad-range MMP inhibitor batimastat limited
the expansion of experimental abdominal aortic aneurysms in
rats and interfered with the inflammatory response seen in
these aneurysms. Other investigators have focused on the role
of MMPs and the effect of MMP inhibition during neointima
formation. In balloon catheter–injured rat carotid arteries,
administration of ilomastat resulted in a 97% decrease in the
number of smooth muscle cells that migrated into the neoin-
tima, which retarded intima formation.34 In pigs, it was
recently demonstrated that the oral MMP inhibitor marimas-
tat inhibited constrictive arterial remodeling, which is the
major determinant of restenosis after balloon angioplasty.35
Because of the positive outcome of the first clinical trials
using synthetic MMP inhibitors in the treatment of corneal
ulcers and lung cancer,28 it is feasible that MMP inhibitors
will be used in the future for other clinical indications as well.
MMPs in Cardiac Diseases
In 1975, Montfort and Perez-Tamayo36 demonstrated that
collagenase is present in the normal myocardium. It is located
in the interstitium, in the neighborhood of its substrate,
fibrillar collagen. It is now known that myocardial MMPs are
produced by fibroblast-like cells, inflammatory cells, as well
as by cardiomyocytes,37,38 that they are predominantly pres-
ent in their latent form,39 and that they are increasingly
expressed and activated in several pathological conditions of
the heart. A number of studies have demonstrated increased
expression and activity of MMP-1, -2, -3, and -9 in human,
rat, and porcine hearts during the remodeling process after
MI.37,40 – 44 Although the data on the exact time course of
postinfarction myocardial MMP activity is diverse, it be-
comes more and more clear that MMP activation starts early
(⬍1 day after MI).41 Early upregulation of MMP activity after
infarction strongly suggests an involvement of MMPs in the
repair process of the heart. In this regard, MMPs might be
involved in several aspects of infarct healing, including early
ECM degradation, cell migration (inflammatory cells, fibro-
blasts), angiogenesis, remodeling of newly synthesized con-
nective tissue, and the regulation of growth factor activities.
The function of MMPs during the healing and remodeling
process of the left ventricle after MI is being clarified in
studies using broad-range MMP inhibitors and genetically
modified mice. Rohde et al45 first demonstrated that in vivo
MMP inhibition attenuates early left ventricular (LV) dilata-
tion 4 days after experimental MI in mice. We have also
studied the effects of a broad-range MMP inhibitor on LV
remodeling and infarct healing 1 and 2 weeks after MI in
mice.46 In that study, infarcted mice allocated ilomastat
treatment showed a significant decrease in LV dilatation after
MI as measured by echocardiography. MMP inhibitor treat-
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MMP Inhibition and Myocardial Infarction 205
ment resulted in a delay in infarct healing, clearly evidenced
by larger necrotic areas (56%), thicker infarcted walls (32%),
lower cell densities (37%), and a reduction in the deposition
of collagen (68%) in the infarct. These effects of MMP
inhibition on LV remodeling and healing were most promi-
nent 7 days after MI. Attenuated LV dilatation after MMP
inhibitor treatment might depend on preservation of the ECM
in the infarct zone, early after MI. Delayed wound healing by
MMP inhibition has also been demonstrated in vascular and
dermal wounds, where MMP activity facilitated the migration
of inflammatory cells and smooth muscle cells into the
wound.32,34,47 The negative effects of MMP inhibition on
collagen deposition may seem paradoxical, because it may be
expected that MMP inhibition prevents collagen degradation
and thus promotes collagen accumulation. An inhibitory
effect of MMP inhibition on collagen deposition is however
not new, because ilomastat treatment has comparable effects
during neointima formation.47 There are several possible
explanations for these effects of MMP inhibition. First, the
delay in healing reduced the migration of myofibroblast-like
cells into the infarct. Because myofibroblasts are the main
cell type responsible for collagen synthesis, a lower number
of myofibroblasts may result in a reduction of collagen
deposition. Second, MMPs may interfere in other pathways
than ECM degradation, which are active during the repair
process of the heart. In this view, MMPs regulate the activity
of certain growth factors, such as TNF-␣, TGF-␤, and
IL-1␤.48,49 Decreased activity of TGF-␤ might reduce the
synthesis of new collagen fibers.50
The particular importance of MMP-9 activity during in-
farct healing and LV remodeling has recently been demon-
strated in two studies. In the first study, Heymans et al51
reported that MMP-9 deficiency in mice retarded the wound
healing process after MI, which was demonstrated by a
reduced leukocyte influx into the infarct and by larger
residual necrotic areas. In addition, that study demonstrated
that lack of proteolytic activity of MMP-9 almost completely
protected against infarct rupture, an acute and usually fatal
event after MI. The significance of MMP-9 activity in early
infarct healing and rupture was emphasized by the observa-
tion that MMP-9 was predominantly found in leukocytes and
macrophages and that its activity peaked around day 2, the
period in which most of the ruptures occur. In the second
study, Ducharme et al52 demonstrated that targeted deletion of
MMP-9 also attenuated LV cavity enlargement until at least
15 days after experimental MI in mice. Limited LV dilatation
was accompanied with a reduced inflammatory response and
a decrease in collagen deposition in the infarct of MMP-9 –
deficient mice.
The most striking observation in the aforementioned ani-
mal studies is the reduction in LV dilatation after MI that can
be achieved with MMP inhibitor treatment. In humans, it is
known that extensive LV dilatation after infarction increases
the risk of complications such as the development of conges-
tive heart failure, aneurysm formation, and cardiac rupture.2
Together, these positive effects of MMP inhibition on LV
dilatation in animal models led to the proposal to use MMP
inhibitors as a potential therapy for patients at risk for the
development of heart failure after MI.
206 Circulation Research August 3, 2001
In addition to MI, dilated cardiomyopathy is associated
with an upregulation of MMP activity.53–57 Spinale et al58
reported that MMP inhibition limited LV dilatation and
resulted in a reduction in wall stress during the development
of congestive heart failure in an experimental model of rapid
cardiac pacing in pigs. Finally, the consequence of increased
MMP activity on cardiac performance has been studied in
transgenic mice expressing myocardial MMP-1, an interstitial
collagenase that is normally absent in the mouse genome. At
an age of 6 months, these mice exhibited LV hypertrophy and
hypercontractility, whereas at an age of 12 months these mice
displayed a loss of cardiac interstitial collagen, coincident
with a marked deterioration of systolic and diastolic func-
tion.5 In conclusion, the studies described above have dem-
onstrated a causal relationship between proteolytic activity,
disruption of the myocardial ECM, architectural remodeling
of the heart, and cardiac performance.
Interestingly, in the promoters of MMP-1, -3, -9, and -12,
polymorphisms have been identified, which appear to influ-
ence MMP gene expression.59 Polymorphisms in MMP-3, -9,
and -12 have already been associated with susceptibility to
cardiovascular diseases such as coronary artery disease and
abdominal aortic aneurysms.59,60 These observations also
indicate that variations in the levels of MMP transcription in
patients suffering from MI might contribute to differences in
infarct healing, LV remodeling, and the transition to end-
stage heart failure or cardiac rupture. Further research is
needed to identify a possible correlation between these events
after MI and MMP polymorphisms. The observation that
levels of MMPs and TIMPs are altered in the serum of
patients after MI has raised the possibility that MMP and
TIMP levels could predict the clinical outcome.61,62 Correla-
tions of serum TIMP-1 levels with LV end-systolic volumes
and with LV ejection fractions have already been found.61
TIMPs and Cardiac Diseases
Studies of cardiac tissue of patients with ischemic cardiomy-
opathy demonstrated in addition to an increase in MMP
activity a decrease in TIMP-1, -3, and -4 expression while
TIMP-2 expression was unchanged.55,56,63 The functional role
of TIMP-1 in the control of LV geometry and cardiac
function was recently studied in TIMP-1– deficient mice.
Echocardiography in these mice demonstrated an 18% in-
crease in LV end-diastolic volume and a 38% increase in
cardiac mass at 4 months of age. Reduced myocardial
collagen content probably accounted for the increased LV
dilatation. These results suggest that constitutive TIMP-1
expression contributes to the maintenance of normal LV
myocardial structure.64
The function of TIMP-1 has also been studied in the setting
of MI. Adenoviral human TIMP-1 overexpression in the
mouse after MI resulted in diminished leukocyte influx, less
neovascularization of the infarct, larger residual necrotic
areas, and decreased collagen content in the infarct. These
parameters indicate that infarct healing is delayed after
TIMP-1 overexpression.51 In that study, ⬇30% of the in-
farcted control mice suffered fatal cardiac rupture of the LV
wall. However, complete prevention of cardiac rupture was
achieved after TIMP-1 overexpression. Together, these re-
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Figure 2. Regulation of ECM degradation in the infarcted heart.
Circulating plasminogen is cleaved by uPA to form proteolytic
active plasmin. In addition to degrading several ECM compo-
nents directly, plasmin is involved in the activation of latent
MMPs (proMMPs) and regulates the activation and/or liberation
of growth factors (such as TGF-␤) from the ECM. The activity of
uPA and MMPs is tightly controlled by their endogenous inhibi-
tors, PAIs and TIMPs.
sults indicate that TIMP-1 is an important endogenous inhib-
itor of myocardial MMP activity.
Plasminogen System as a Regulatory System
for MMP Activity in the Heart
Plasmin, one of the serine proteases, is the active enzyme of
the plasminogen system and degrades a variety of ECM
components. A relevant feature of plasmin is the proteolytic
amplification that can be achieved by activating several
MMPs.65 The generation of plasmin is primarily controlled by
the balance between the plasminogen activators (tissue-type
plasminogen activator [tPA] and urokinase plasminogen ac-
tivator [uPA]) and their physiological inhibitors, the plasmin-
ogen activator inhibitors (PAIs). Two recent studies identified
the plasminogen system as an important regulatory system in
the onset of cardiac wound healing. In the first study, we
demonstrated that infarct healing was virtually abolished in
plasminogen-deficient mice. In the absence of plasminogen,
inflammatory cells did not migrate into the infarcted myocar-
dium. Necrotic cardiomyocytes were not removed, and the
formation of granulation tissue and scar tissue did not occur,
until at least 5 weeks after MI. In these scarless infarcted
hearts, LV dilatation was not affected compared with wild-
type mice. In addition, gelatinolytic activity of MMP-2 and
MMP-9 was depressed in the Plg⫺/⫺ hearts, suggesting that
the effect of plasmin on infarct healing may be mediated by
activation of MMPs.66 In the second study, Heymans et al51
demonstrated that uPA deficiency and adenoviral PAI-1
overexpression, but not tPA or uPAR deficiency, resulted in
impaired cardiac healing. In addition, uPA deficiency or
adenoviral PAI-1 overexpression protected against cardiac
rupture. Three distinct observations strongly suggest that the
effects of plasminogen and uPA deficiency are (partly)
mediated by reduced activation of MMPs. First, uPA was
coexpressed with MMP-9 in infiltrating leukocytes.51 Second,
MMP activity was reduced in both uPA⫺/⫺ and Plg⫺/⫺
infarcts. And third, MMP inhibition has comparable, although
 Creemers et al
less pronounced, effects on infarct healing and cardiac rup-
ture as uPA and plasminogen deficiency. Together, these two
studies have identified the plasminogen system as a new and
important regulatory system in cardiac wound healing (Figure
2). The mechanisms through which components of the
plasminogen system mediate infarct healing are based on the
proteolytic activity of plasmin. Besides degrading ECM
components and activating MMPs, which are essential con-
ditions for cell migration, the plasminogen system may act
through other mechanisms. In this regard, plasmin can acti-
vate or liberate growth factors from the ECM. For example,
TGF-␤1, a potent inhibitor of cell proliferation and a mediator
of collagen deposition, is activated by plasmin.67 Reduced
activation of latent TGF-␤1 was indeed found in 4-day-old
infarcts of uPA-deficient mice, indicating that the down-
stream pathway of the plasminogen system in infarct healing
also includes the activation of TGF-␤1.
These findings with respect to components of the plasmin-
ogen system may indicate that increased expression of plas-
minogen or uPA may predispose to cardiac rupture, whereas
increased levels of PAI-1 may be protective.51 On the other
hand, as the principal inhibitor of fibrinolysis, it has been
reported that high PAI-1 levels may accelerate the atheroscle-
rotic process by allowing fibrin deposition and thrombosis
within developing lesions. So far, epidemiological studies
have related increased levels of PAI-1, due to genetic or
metabolic determinants, to atherothrombosis.68 The influence
of increased PAI-1 levels on the risk of MI is still debated.
Finally, it has been reported that other serine proteases (ie,
serine elastase, trypsin, and cathepsin G) are able to activate
MMPs and destroy the inhibitory activity of TIMPs.69,70 The
role of serine elastase has been investigated in relation to
myocardial ischemia/reperfusion injury, and it was demon-
strated that inhibitors of these enzymes are protective against
MI. This was accomplished by inhibition of neutrophil
accumulation into the ischemic reperfused myocardium and
by inactivating cytotoxic metabolites (proteases and superox-
ide radical) released from neutrophils.71,72
MMP Inhibitors as a New Therapy for
Heart Failure
The positive effects of MMP inhibition on LV dilatation in
animal models led to the proposal to use MMP inhibitors as
a potential therapy for patients at risk for the development of
heart failure after MI. Although the promising results in
animal studies encourage the design of clinical trials with
MMP inhibitors, several issues have to be studied more
extensively. First, the precise effect of MMP inhibitor treat-
ment on cardiac function is not completely known. Second,
the timing of MMP inhibitor administration after infarction
has to be resolved, and third, the choice between narrow-
versus broad-range MMP inhibitors must be made.
With respect to evaluation of cardiac function after MMP
inhibitor treatment, Rohde et al45 used short-axis echocardi-
ography to study cardiac function in infarcted mice. That
study demonstrated that MMP inhibition resulted in signifi-
cant improvement in fractional shortening and a somewhat
smaller increase in end-systolic and end-diastolic dimensions
in the infarcted mouse heart. Because the endpoint of the
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MMP Inhibition and Myocardial Infarction 207
latter study was only 4 days after MI, further research is
needed to determine the long-term effects of MMP inhibitors
on cardiac function. Recent advances in conductance tech-
nology allow the measurement of LV pressure-volume loops
in the mouse heart. This technique, which can be used in
closed-thorax preparations, will probably be critical for the
assessment of cardiac function in MMP inhibitor–treated or
MMP knockout mice.73 Although the mouse infarct model is
an excellent model to initially study the effects of pharma-
cological agents on cardiac function and LV remodeling, it
will be necessary to evaluate the effects in other species
before extrapolation to humans.
With respect to the timing of the MMP inhibitor adminis-
tration, it should be noted that some of the animal studies
described above started drug delivery before induction of the
infarct. In patients, in whom MMP inhibitors are to be given
after infarction by definition, the positive effect on LV
dilatation might be smaller, because early infarct expansion
might not be prevented.
Selective versus broad-range MMP inhibition is another
important, yet unresolved, issue with respect to the possible
treatment of heart failure. Broad-range MMP inhibition might
be favorable to achieve maximal effects on ECM degradation.
However, possible disadvantages of broad-range MMP inhi-
bition include negative side effects such as musculoskeletal
toxicity, as seen after treatment with marimastat.74 With
respect to the important role of MMPs in physiological
processes, broad-range MMP inhibition might affect normal
tissue as well. Selective inhibition of one or a few carefully
chosen MMPs might be better in this regard. Inhibition of a
single MMP will probably be of little therapeutic value
because it is known that heart failure is associated with an
elevation of multiple MMPs. The issue of selective versus
broad-range MMP inhibition has been addressed in other
fields of research as well. In dermal wound healing, selective
inhibition of MMPs seems desirable, because nonspecific
MMP inhibition would most likely impair reepithelialization,
as a result of inhibition of MMP-1. Inhibition of MMP-13
would be more favorable in dermal wound healing, because
MMP-13 has been held responsible for the degradation of
collagens I and III and may play a role in the pathogenesis of
chronic cutaneous wounds.75 In cancer research, selective
inhibition of the gelatinases (MMP-2 and -9) has been
demonstrated to prevent tumor growth and invasion.76 Ex-
trapolated from gene-targeting studies in mice, MMP-9 might
be one of the candidates for selective inhibition after MI,
because the deficiency in MMP-9 alone reduced LV chamber
enlargement after infarction.52 Furthermore, MMP-9 gene
disruption also prevented fatal cardiac rupture to occur.58
Although the synthesis of selective MMP inhibitors for all
individual MMPs is currently a focus for many pharmaceu-
tical companies, there is still a long way to go to meet this
goal.77
Tetracyclines are frequently as effective as other MMP
inhibitors in vivo, and their beneficial influence on ECM
degradation can usually be achieved at remarkably low
(nanomolar) concentrations. Although the mechanism of
MMP inhibition seems to be different using tetracycline
compared with broad-range MMP inhibitors, the clinical
208 Circulation Research August 3, 2001
effect, ie, decreased ECM degradation might be the same. In
combination with their clinical availability, low cost, and
well-recognized safety profile, the use of tetracyclines ap-
pears to represent an ideal starting point for clinical studies on
MMP inhibition after MI.78
Conclusion
Some of the current therapies after MI retard the development
of heart failure. However, none of these therapies is able to
prevent the LV expansion process completely. For this
reason, additional therapy for these patients is desirable.
Animal studies suggest that inhibition of myocardial MMP
activity may be a promising therapeutic approach to slow
down the time course of the development of heart failure and
dysfunction. Further research is needed to evaluate long-term
effects of MMP inhibitor treatment after infarction, to resolve
the issue of selective versus broad-range MMP inhibition and
to evaluate the best time point after infarction to start MMP
inhibitor treatment.
Acknowledgments
This work was funded by grants from the Netherlands Heart
Foundation (94.012 and 99.054).
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 Matrix Metalloproteinase Inhibition After Myocardial Infarction: A New Approach to
Prevent Heart Failure?
Esther E.J.M. Creemers, Jack P.M. Cleutjens, Jos F.M. Smits and Mat J.A.P. Daemen

Circ Res. 2001;89:201-210

doi: 10.1161/hh1501.094396
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