© 1995 American Heart Association, Inc.
Articles |
Matrix Metalloproteinases and Cardiovascular Disease
From the Divisions of Cardiology (C.M.D., J.R.M.) and Cardiovascular Genetics (A.M.H.), Department of Medicine, University College London (UK) Medical School.
Correspondence to Dr Adriano M. Henney, Department of Medicine, University College London Medical School, Rayne Institute, University St, London WC1E 6JJ, UK. E-mail ahenney@med.ucl.ac.uk.
Key Words: matrix metalloproteinase • cardiovascular disease • tissue inhibitor of metalloproteinase
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Introduction |
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 Top Introduction The Matrix Metalloproteinase...MMPs and Matrix RemodelingClinical ImplicationsReferences |
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The vessel wall is an integrated functional component of the circulatory system that is continually remodeling in response to hemodynamic conditions and disease states. The endothelium releases locally active mediators, such as nitric oxide and endothelin, which have immediate vasoactive properties and longer-term trophic effects on the medial SMCs. Vascular tone and compliance are determined by these SMCs, which not only actively control wall tension but also synthesize the major structural components of the vessel wall: collagens types I, III, IV, and V, elastin, proteoglycans, and glycoproteins. These components interact to form a complex network that gives blood vessels their elastic physical characteristics. Continual mechanical stresses will cause weakening of the vessel wall if the structural integrity and physical properties of the matrix are not maintained. The matrix composition determines not only the physical elastic properties of the vessel wall but also its cellular components via stored growth factors in the matrix and growth factor activation by MMPs. The matrix, therefore, rather than being merely a system of scaffolding for the surrounding cells, is a dynamic structure that is central to the control of vascular remodeling. Connective tissue repair and remodeling to maintain matrix integrity involves the synthesis and removal of these proteins, a process that depends on the action of a range of proteases and their inhibitors. Evidence suggests that there are two systems that predominate and interact to achieve homeostasis within the vessel wall: the plasminogen activator-plasmin system and the MMPs. This review focuses on discussing the increasing evidence that supports a role for enzymes of the MMP family in the pathogenesis of atherosclerosis and postangioplasty restenosis.
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The Matrix Metalloproteinase Family |
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TopIntroductionThe Matrix Metalloproteinase...MMPs and Matrix RemodelingClinical ImplicationsReferences |
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MMPs are a family of Zn2+- and Ca2+-dependent enzymes, which are important in the resorption of extracellular matrices in both normal physiological processes and pathological states. Nine MMPs* have been identified, cloned, and sequenced, and these are divided into three groups based broadly on substrate preferences (Table
). A number of diverse nomenclatures for the MMPs
are currently in use. These have traditionally related to the order of
identification, the molecular weight, or the substrate specificity; we
have chosen to use the latter system, but all are included in the
Table. The MMP subgroups include the collagenases that
degrade structural type I to III collagens only, the type IV
collagenases/gelatinases, which act in particular on the
basement membrane components and partially degraded collagen, and the
stromelysins, which have a broad substrate specificity (proteoglycans,
laminin, fibronectin, gelatin, and basement membrane collagens). There
is also a new member of the MMP family characterized by being an
integral part of the plasma membrane rather than a secreted protein,
MT-MMP. Taken together, the MMPs, once activated, can
completely degrade all extracellular matrix components. It is
important, therefore, that the activity of these enzymes is kept under
tight control, and this operates at three levels: transcription,
activation of latent proenzymes, and inhibition of proteolytic
activity1 2 (Figure).
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Transcriptional Regulation
A number of cytokines and growth factors have been shown
to induce or stimulate the synthesis of MMPs, including IL-1, PDGF, and
TNF-
, whereas others, such as TGF-ß, heparin, and
corticosteroids, have an inhibitory effect.
Studies of the collagenase and stromelysin gene promoters
have identified a number of consensus sequences for nuclear binding
proteins, including
12-O-tetradecanoyl-phorbol-13-acetate–responsive
elements and activator protein-1 sites.1 Many
of these cytokines and growth factors have been identified as
important mediators in atherosclerosis and
restenosis.
Proenzyme Activation
The second level of control of the MMPs is in the activation of
the latent proenzymes. Although some plasmin-independent pathways
exist, plasmin is a potent activator of most MMPs,
promoting cleavage of the latent propeptides to the active
molecule.3 4 The roles of uPA and its specific receptor
(uPA-r) and inhibitors (PAI-1 and PAI-2) have been studied
in relation to tissue invasion and cell surface
proteolysis.5 It is thought that the binding and
activation of uPA on its receptor provides a mechanism for localizing
proteolytic activity at the leading edge of the cell.6 uPA
and uPA-r are expressed by a variety of cells, including monocytes and
macrophages, and it has been shown that antibodies and
inhibitors of uPA prevent matrix degradation.7
There are similarities between this proteolytic system and the clotting
cascade; eg, while plasmin cleaves and therefore activates
stromelysin, the resultant active enzyme can activate other
proenzymes, forming a positive-feedback loop. When the
collagenases are cleaved at the carboxy terminal by
stromelysin, there is a fivefold to eightfold increase in their
proteolytic activity.
The recently described MT-MMP is an integral membrane protein and an activator of progelatinase A,8 localizing this proteolytic activation process to the cell surface, thus mirroring the plasminogen/plasmin activator system. This raises the exciting possibility of parallel transmembrane control systems for all the metalloproteinases. Experiments using mice in which genes of the plasminogen/plasmin activator system have been inactivated have shown that vascular injury–induced neointimal formation and deendothelialization are greatly reduced in uPA-deficient mice, unaltered in tissue-type plasminogen activator–deficient animals, and greatly accelerated in PAI-1 knockouts.9 This suggests that there is likely to be a high degree of redundancy in the systems controlling cell surface proteolysis, so that pathological (and possibly pharmacological) events that block one aspect of matrix breakdown may cause the recruitment of an alternative rescue mechanism.
Inhibitors of MMPs
The MMPs are inhibited by a family of naturally occurring specific
inhibitors, TIMPs, and less specifically by
2-macroglobulin and exogenous substances such as
heparin. The contribution of 2-macroglobulin is,
however, limited by the large size of the molecule. TIMPs are secreted
multifunctional proteins that are essential in the regulation of
connective tissue metabolism. Three members of this family
have been identified to date: TIMP-1, TIMP-2, and TIMP-3. TIMP-1 and
TIMP-2 share only 42% amino acid identity, but they are essentially
interchangeable in their ability to inhibit MMPs; however, they are
distinguished by their interaction with the
progelatinases.10 TIMP-3 shares only 37% amino acid
identity with TIMP-1 and 42% with TIMP-2 and appears to be localized
specifically to the extracellular matrix, unlike the other
TIMPs.11 All three inhibitors retain the six
disulfide bridges necessary for maintaining their three-dimensional
structure. TIMP-1 is synthesized by most types of connective tissue
cells, as well as macrophages, and acts against all members of
the collagenase, stromelysin, and gelatinase classes of
enzyme. It forms high-affinity, irreversible (in vivo), noncovalent
complexes with the active forms of the enzymes. It is highly expressed
in actively resorbing tissues, and its role is to regulate enzyme
activity tightly, at the level of activation of MMPs from both their
latent form and their catalytic activity.11 The net level
of proteinase activity is therefore dependent on the relative
concentrations of active enzymes and inhibitors. TIMP-2 has
a dual inhibitory action, binding to progelatinase A and
stabilizing this inactive form of the enzyme, whereas the same
"stabilization site" in the active gelatinase A molecule makes
this form more susceptible to inhibition.12 Independent of
their antiproteolytic properties, the TIMPs also act as growth factors
for erythroid precursors, but this function as yet has no known
application to atherosclerotic processes. Expression studies suggest
that different MMPs may have specific physiological
roles: TIMP-1 is highly inducible by cytokines and hormones,
whereas TIMP-2 expression is largely constitutive, following the
pattern of expression of gelatinase A, with which it interacts
specifically.13 Under conditions in which TIMP-2 has been
observed to respond to certain stimuli, the response is in direct
contrast to that of TIMP-1. These data suggest that there are
differences in the regulatory elements present in the promoters of
these two genes that are responsible for this differential pattern of
expression. Five hundred nineteen base pairs of the 5' flanking
sequence have been cloned and characterized for the human TIMP-2
gene,14 but information about the TIMP-1 promoter is only
available for the mouse gene.15 Comparison of these two
promoters has revealed a number of differences that are
consistent with the differential regulation of the two genes.
Therefore, there is a molecular mechanism for coregulation of the MMPs
and their inhibitors, forming a linked cascade with a
parallel and tightly regulated system controlling the overall
composition of the extracellular matrix.
Cytokine Activation
New evidence, however, points to another tier in the control of
the metalloproteinases and suggests that they may have a much wider
regulatory role than previously thought. Two groups have demonstrated
that TNF-, itself a growth factor regulating the metalloproteinases
at the transcriptional level, is regulated by the MMPs. TNF-, a
potent proinflammatory and immunoregulatory cytokine, is
synthesized as a precursor that is cleaved to the active form. It has
been demonstrated that metalloproteinase inhibitors can
prevent this posttranslational activation and that the addition of
collagenase, stromelysin, matrilysin, and the gelatinases
will restore its activity.16 17 Therefore, MMPs are
capable of regulating cytokine activity and may initiate
cellular processes as well as participate in them.
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MMPs and Matrix Remodeling |
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TopIntroductionThe Matrix Metalloproteinase...MMPs and Matrix RemodelingClinical ImplicationsReferences |
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The importance of extracellular matrix stability in the maintenance of vessel wall integrity is illustrated by the consequences in the vasculature of weakened connective tissue seen in rare single-gene disorders of connective tissue, such as Ehlers-Danlos syndrome type IV and Marfan’s syndrome. The disruption of connective tissue turnover and the consequent effect on matrix stability has been implicated in a number of diseases, but the role of MMPs has never been proved. The recent descriptions of mutations in the TIMP-3 gene in patients with Sorsby’s fundus dystrophy are the first to be identified in the MMP/TIMP family.18 Although Sorsby’s fundus dystrophy is a rare disease, this discovery establishes the principle that disruption of MMP-mediated matrix remodeling does affect the composition and function of tissues. It also suggests that more common genetic variation in these genes may contribute to the pathogenesis of common multifactorial disorders in both the eye and other organs, through a less severe interference in the control of matrix turnover. In this context, recent work from this laboratory has described a common stromelysin promoter variant that is associated with the progression of atherosclerosis.19
It is clear that MMPs will be important in any process in which matrix turnover and repair take place; hence, they have a potential role in many aspects of vascular biology, from atherosclerosis to posttransplantation coronary disease. We will discuss two of these processes in which the role of MMPs is being studied in detail: (1) the development of the atherosclerotic plaque and, in particular, the weakening of plaque caps before fissuring and (2) the liberation of the SMC from its pericellular matrix cage as a prerequisite to proliferation and migration after angioplasty.
Atherosclerosis
One of the earliest events in the formation of the atherosclerotic
plaque is the adherence of circulating monocytes to the vascular
endothelium, through which they gain entry to the
subintimal tissue. Once there, a series of complex cell-cell
interactions takes place over a long period, involving the secretion of
a wide variety of growth factors and cytokines.20
These include TNF-, IL-1, and PDGF, which are known to stimulate MMP
synthesis in varying proportions in human aortic SMCs and in some types
of human vascular endothelial cells.21 22 23
As mentioned above, significant differences exist between the
regulation of gelatinase A/TIMP-2 and the remainder of the MMP family
and TIMP-1. The latter are inducible by cytokines and growth
factors such as TNF- and IL-1, but TIMP-2 and gelatinase A have a
more constant pattern of expression.21 With time, the
matrix of the vessel wall becomes modified through the migration and
proliferation of cells and the deposition of extracellular matrix,
eventually resulting in the formation of a plaque. The process of
cellular migration has been studied in vitro by using the rat vascular
SMC, and gelatinase A has been determined to be essential for cells to
cross a basement membrane barrier (composed of type IV collagen). In
addition, it has been found that cells must be in an active
proliferating state in order to migrate through the basement
membrane.24 Unless other cellular events can breach the
basement membrane of the vessel wall, this appears to be a limiting
step in plaque formation that is governed by the MMPs.
The typical advanced atherosclerotic plaque is characterized by a thickened intimal layer and an asymmetrical lesion that encroaches into the lumen. The lesion itself may be fibrous or may contain a large core of lipid covered by a fibrous cap, which can vary greatly in thickness. The cells found in these advanced lesions are predominantly macrophages and SMCs, but "foam cells" are also common. These are cells (usually macrophages) that have engorged extracellular lipid and have accumulated it in their cytoplasm, giving them a characteristic foamy appearance. The lipid pools within advanced plaques are unable to bear the circumferential stress exerted on the vessel during systole, causing the stress to be redistributed across the cap. Depending on the structure and composition of the cap matrix, regions of high circumferential stress may become concentrated on particular regions of the cap.25 Davies et al26 have shown that a number of factors combine to increase the stress on plaque caps, including the loss, both in content and organization, of components of the connective tissue matrix and the size of the lipid core. Thus, intimal tearing, the most common event initiating coronary thrombosis, occurs in regions of cap connective tissue weakness. This is correlated with the accumulation of macrophages and is most commonly found in the shoulders of the plaque. There is no direct evidence of an association between an individual’s MMP activity and increased chance of vessel occlusion, but this theory is now further supported by the finding of an increase in intracellular gelatinase B production in atherectomy specimens from patients with unstable angina compared with specimens from patients with stable angina.27
Metalloproteinases are known to be expressed in human atherosclerotic
plaques by both SMCs and foam cells; this has been demonstrated by both
in situ zymography and in situ hybridization.28 29
Stromelysin mRNA transcripts were localized to both SMCs and
macrophages in frozen sections of both fibrous and
lipid-rich atherosclerotic plaques. The accumulation of large
numbers of macrophages and foam cells is not a feature of the
normal vessel wall, and it is likely that the extensive synthesis of
stromelysin observed in these specimens is a pathological event. TIMP-1
has been identified in association with the matrix in normal aortas by
radioimmunoassay, raising the possibility that in the pathological
specimens the delicate balance between the MMPs and their coregulated
inhibitors has been lost.30 Further evidence
comes from work involving degenerative aortic disease in which
gelatinase B has been identified from homogenates of the
luminal aspect of atherosclerotic aortas but not normal
aortas.31 It is possible that cytokines, such as
TNF-, induce the production of stromelysin and other MMPs in
a localized area of mechanical stress, which then activates the
proteolytic cascade described above and results in plaque rupture and
vascular occlusion. In addition, studies using immunoprecipitation to
examine human abdominal aortic aneurysm specimens have shown
high levels of TIMP and gelatinase B localized to the vasa vasorum,
which may be involved in the maintenance and possibly the
genesis of this lesion.32 Further investigation is
required to elucidate both the expression and the function of the MMPs
in the vessel wall in physiological and
pathological situations.
Angioplasty Restenosis
The role of the MMPs in iatrogenic postprocedural vasculopathy has
also attracted much interest. Coronary artery disease is the
major cause of death in the United Kingdom, and angina pectoris due to
atheromatous coronary lesions is a cause of
significant morbidity. Percutaneous transluminal
coronary angioplasty has become a widely used treatment for
angina, in which the atheromatous narrowing is
compressed into the vessel wall by using a balloon catheter. Initially,
this procedure has a >80% technical success rate, but the usefulness
of angioplasty is limited by the fact that 25% to 50% of patients
have a recurrence of their symptoms within 6 months because of
restenosis at the original site.33 34 This is
due to a combination of events: the migration and rapid growth of
medial vascular SMCs, producing a characteristic lesion of
fibrocellular intimal hyperplasia.35 However, there is
also clinical evidence, detected by intravascular ultrasound, of a
change in total vessel dimensions after angioplasty.36
Maturation of the lesion is associated with a greater preponderance of
extracellular matrix. Studies of animal models, principally the rat,
suggest that growth factors regulate this process, with basic
fibroblast growth factor controlling SMC replication and PDGF
regulating cell migration. Restenosis probably
represents an exaggeration of the normal healing and repair
processes within the blood vessel wall, because intimal hyperplasia is
present to some degree in all patients after angioplasty. This has
been the focus of research, because the appeal of angioplasty to both
the patient and the physician is clear. However, restenosis
has been resistant to therapeutic intervention. Preventing the
accumulation of an occlusive neointima may be possible
through the manipulation of the normal healing processes in the vessel
wall. There is considerable evidence suggesting that a wide range of
cellular components of both normal and diseased vessel walls, such as
SMCs, macrophages, and fibroblasts, can degrade the
extracellular matrix. Of particular interest, it has been shown that
vascular SMCs are capable of producing enzymes that will degrade both
basement membranes and the extracellular matrix.21
In vitro models have been used to demonstrate the induction of collagenase and stromelysin gene expression in response to mechanical injury in vascular SMCs37 ; this phenomenon supplies a possible molecular "on-off switch" for postinjury restenosis. Animal models are now providing further information. In the rat carotid artery, there is constitutive expression of gelatinase A with some induction at 4 to 5 days after angioplasty, whereas gelatinase B was induced the first day after injury.38 The authors suggest that active gelatinase B may therefore be controlling the migration of SMCs from the media to the intima. Studies of the plasminogen activator system after balloon injury in both the rat and rabbit models have shown acute upregulation of uPA activity,39 40 which could activate the MMP cascade. The pig shows the same pattern of enzyme activity on zymography, with gelatinase B induced at 3 days and gelatinase A induced at 7 days. Both enzymes persist at elevated levels for up to 21 days.41 The relevance of these findings to vascular SMC migration and proliferation is confirmed by the 97% reduction in the early migration of SMCs into the intima when a metalloproteinase inhibitor was administered systemically.38 It is clear that the SMC can alter its surrounding matrix if stimulated by the appropriate cytokines, and it is logical to assume that its ability to burrow its way into the intima and then proliferate would depend on removal of the intervening structures, principally the extracellular matrix. However, arresting migration may not prevent restenosis, because a compensatory increase in proliferation could result in the same degree of luminal obstruction and indeed, 80% of the bulk of the end-stage restenotic lesion is connective tissue rather than SMCs.
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Clinical Implications |
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TopIntroductionThe Matrix Metalloproteinase...MMPs and Matrix RemodelingClinical ImplicationsReferences |
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To date, most clinical and preclinical studies of the therapeutic manipulation of the extracellular matrix have been in the fields of arthritis, malignancy, and periodontal disease.42 The hypothesis is that the migration of a cell would be hindered by inhibition of MMP activity, confining it within its matrix cage. If this hypothesis is applied to cardiovascular disease, the migration and proliferation of a vascular SMC into the atherosclerotic plaque or angioplasty site would be prevented by an MMP inhibitor.
Collagenase and TIMP-1 are known to exist at higher levels
in the serum of patients with prostate cancer, the level of
collagenase is higher in patients with
metastases,43 and invasive lung tumor cells express
MT-MMP.8 In vitro studies have shown that the natural
inhibitors of the MMPs, the TIMPs, can reduce matrix
degradation and invasion by a number of cells.44 TIMP-2
has also been transfected into cells, which then show a marked
reduction in invasion when introduced into the nude mouse model,
concomitant with inhibition of local MMP activity.45
Therefore, in vivo animal studies are under way but face a number of
problems. In particular, there is no clear localizing mechanism for an
MMP antagonist, because none of the MMPs have been shown to
be specific for malignant cells (or abnormal vessel walls). Local
delivery systems are a possibility, but it is likely that other
processes such as wound healing, angiogenesis, and
fibrinolysis would be affected, with additional
consequences resulting from the removal of an activating mechanism for
cytokines, such as TNF-. The difficulty of delivery of large
molecules to the target tissue has also been experienced in both
oncology and rheumatology.
Possible mechanisms of MMP inhibition include (1) increasing the levels of natural inhibitors (TIMPs) either by exogenous administration of recombinant TIMPs or by increasing their local production, (2) administration of synthetic inhibitors, and (3) decreasing the production of MMPs.
Exogenously administered TIMPs are liable to be metabolized and denatured and will tend to aggregate and adhere to surfaces, therefore limiting tissue penetration. They have been used in mouse models of arthritis but could not be shown conclusively to be effective. The upregulation of TIMP production might be achieved with the administration of cytokines, such as TGF-ß or retinoids, but it is likely that these compounds will have numerous side effects limiting their use, since they are active in many cellular processes. Continued improvement in transfection techniques makes a molecular approach to overexpress the TIMP-1 or TIMP-2 genes themselves more attractive than targeting common cellular processes. The in vivo work in nude mice showing reduction in local invasion supports this approach.45
A number of synthetic inhibitors have been investigated, namely, tetracycline-derived antibiotics, anthracyclines, and synthetic peptides. The action of tetracyclines on MMPs is unrelated to the antimicrobial activity and may be due to its action as a zinc chelator. Although the tetracyclines are potent inhibitors of collagenase in vitro, their action in animal models is less impressive.46 Clinical trials have shown minocycline therapy (versus placebo) to be beneficial in patients with rheumatoid arthritis who exhibit clinical markers such as joint tenderness, but these effects have been modest compared with the improvement expected from other therapies for this disease.47 48
This chain of events from initial promise in vitro to a lack of clinical effect will be familiar to cardiologists with an interest in angioplasty restenosis. Several synthetic peptides are being investigated with some success (eg, in the rat carotid model of restenosis), but these investigations may be hampered in a clinical setting by poor bioavailability, rapid hepatic and renal metabolism, and possible toxic systemic effects. Side effects that may be unacceptable to a patient undergoing therapy for cardiovascular disease may be acceptable to an oncology patient whose alternative is chemotherapy. Inhibition of enzyme synthesis may be approached from both conventional and molecular standpoints. TGF-ß, retinoids, and corticosteroids all downregulate MMP transcription. However, corticosteroids have already proved ineffective in the treatment of restenosis. Heparin has been shown to inhibit the production of stromelysin, 92-kD gelatinase B, and collagenase and already has an established place in angioplasty protocols.49 However, it does not eliminate the activity of these MMPs or influence the others, and it does not prevent atherosclerosis or restenosis. At a molecular level, local application of antisense oligonucleotides to the MMP genes is possible, but the effects are unknown.
The vascular system is a tempting target for MMP inhibitors (both molecular and pharmacological) because it offers opportunities for direct local transluminal delivery, which would eliminate many of the problems encountered with systemic delivery. Even if successful delivery of an inhibitor or downregulation of the MMPs could be achieved, we have little information about the possible results. The lack of matrix proteinases may result in an accumulation of an abnormal matrix, which might be occlusive or increase the fragility of an atherosclerotic plaque. Although experiments are being devised to answer these questions, the greatest challenge is to elucidate the molecular mechanisms controlling both the inhibition and activation of the MMPs and TIMPs to allow a more specific approach to any therapeutic manipulation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Dollery was supported by a Medical Research Council Clinical Training Fellowship and The Jean Shanks Foundation. Work in the laboratories of Dr McEwan and Dr Henney was funded by The Wellcome Trust, The British Heart Foundation, and The Special Trustees of University College London Medical School and The Middlesex Hospital.
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Footnotes |
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1 Note added in proof. Twelve MMPs have now been identified, including collagenase-3 (MMP13), MT-MMP 1 (MMP14) and MT-MMP 2 (MMP15).
Received May 15, 1995; accepted June 29, 1995.
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I. Loftus and M. Thompson The role of matrix metalloproteinases in vascular disease Vascular Medicine, May 1, 2002; 7(2): 117 - 133. [Abstract] [PDF]
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H.R. Lijnen, E. Maquoi, L.B. Hansen, B. Van Hoef, L. Frederix, and D. Collen Matrix Metalloproteinase Inhibition Impairs Adipose Tissue Development in Mice Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 374 - 379. [Abstract] [Full Text] [PDF]
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Y. Y. Li, T. Kadokami, P. Wang, C. F. McTiernan, and A. M. Feldman MMP inhibition modulates TNF-alpha transgenic mouse phenotype early in the development of heart failure Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H983 - H989. [Abstract] [Full Text] [PDF]
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A. C. Newby Vitronectin is implicated as the matrix takes control of neointima formation Cardiovasc Res, March 1, 2002; 53(4): 779 - 781. [Full Text] [PDF]
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W. S. Bradham, B. Bozkurt, H. Gunasinghe, D. Mann, and F. G. Spinale Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective Cardiovasc Res, March 1, 2002; 53(4): 822 - 830. [Abstract] [Full Text] [PDF]
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G. S. Cherr, S. J. Motew, J. A. Travis, J. Fingerle, L. Fisher, M. Brandl, J. K. Williams, and R. L. Geary Metalloproteinase Inhibition and the Response to Angioplasty and Stenting in Atherosclerotic Primates Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 161 - 166. [Abstract] [Full Text] [PDF]
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M. V. Gurjar, J. Deleon, R. V. Sharma, and R. C. Bhalla Role of reactive oxygen species in IL-1beta -stimulated sustained ERK activation and MMP-9 induction Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2568 - H2574. [Abstract] [Full Text] [PDF]
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S. Jormsjo, C. Whatling, D. H. Walter, A. M. Zeiher, A. Hamsten, and P. Eriksson Allele-Specific Regulation of Matrix Metalloproteinase-7 Promoter Activity Is Associated With Coronary Artery Luminal Dimensions Among Hypercholesterolemic Patients Arterioscler Thromb Vasc Biol, November 1, 2001; 21(11): 1834 - 1839. [Abstract] [Full Text] [PDF]
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 M. V. Gurjar, J. DeLeon, R. V. Sharma, and R. C. Bhalla Mechanism of inhibition of matrix metalloproteinase-9 induction by NO in vascular smooth muscle cells J Appl Physiol, September 1, 2001; 91(3): 1380 - 1386. [Abstract] [Full Text] [PDF]
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J. Silence, F. Lupu, D. Collen, and H. R. Lijnen Persistence of Atherosclerotic Plaque but Reduced Aneurysm Formation in Mice With Stromelysin-1 (MMP-3) Gene Inactivation Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1440 - 1445. [Abstract] [Full Text] [PDF]
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P. J. Pollanen, P. J. Karhunen, J. Mikkelsson, P. Laippala, M. Perola, A. Penttila, K. M. Mattila, T. Koivula, and T. Lehtimaki Coronary Artery Complicated Lesion Area Is Related to Functional Polymorphism of Matrix Metalloproteinase 9 Gene: An Autopsy Study Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1446 - 1450. [Abstract] [Full Text] [PDF]
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D Tousoulis, G J Davies, C Tentolouris, G Goumas, C Stefanadis, and P Toutouzas Vasomotor effects of L- and D-arginine in stenotic atheromatous coronary plaque Heart, September 1, 2001; 86(3): 296 - 301. [Abstract] [Full Text] [PDF]
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D. A. Smith, S. D. Irving, J. Sheldon, D. Cole, and J. C. Kaski Serum Levels of the Antiinflammatory Cytokine Interleukin-10 Are Decreased in Patients With Unstable Angina Circulation, August 14, 2001; 104(7): 746 - 749. [Abstract] [Full Text] [PDF]
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P. Schoenhagen, K. M. Ziada, D. G. Vince, S. E. Nissen, and E. M. Tuzcu Arterial remodeling and coronary artery disease: the concept of "dilated" versus "obstructive" coronary atherosclerosis J. Am. Coll. Cardiol., August 1, 2001; 38(2): 297 - 306. [Abstract] [Full Text] [PDF]
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Y. Hu, A. H. Baker, Y. Zou, A. C. Newby, and Q. Xu Local Gene Transfer of Tissue Inhibitor of Metalloproteinase-2 Influences Vein Graft Remodeling in a Mouse Model Arterioscler Thromb Vasc Biol, August 1, 2001; 21(8): 1275 - 1280. [Abstract] [Full Text] [PDF]
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A. Watanabe, M. Kurabayashi, M. Arai, K. Sekiguchi, and R. Nagai Combined effect of retinoic acid and basic FGF on PAI-1 gene expression in vascular smooth muscle cells Cardiovasc Res, July 1, 2001; 51(1): 151 - 159. [Abstract] [Full Text] [PDF]
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L. J. Feldman, M. Mazighi, A. Scheuble, J.-F. Deux, E. De Benedetti, C. Badier-Commander, E. Brambilla, D. Henin, P. G. Steg, and M.-P. Jacob Differential Expression of Matrix Metalloproteinases After Stent Implantation and Balloon Angioplasty in the Hypercholesterolemic Rabbit Circulation, June 26, 2001; 103(25): 3117 - 3122. [Abstract] [Full Text] [PDF]
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C. Joffs, H. R. Gunasinghe, M. M. Multani, B. H. Dorman, J. M. Kratz, A. J. Crumbley III, F. A. Crawford Jr, and F. G. Spinale Cardiopulmonary bypass induces the synthesis and release of matrix metalloproteinases Ann. Thorac. Surg., May 1, 2001; 71(5): 1518 - 1523. [Abstract] [Full Text] [PDF]
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 M. Aikawa and P. Libby Vascular inflammation and activation: new targets for lipid lowering Eur. Heart J. Suppl., May 1, 2001; 3(suppl_B): B3 - B11. [Abstract] [PDF]
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 S. Bellosta, M. Canavesi, E. Favari, L. Cominacini, G. Gaviraghi, R. Fumagalli, R. Paoletti, and F. Bernini Lalsoacidipine Modulates the Secretion of Matrix Metalloproteinase-9 by Human Macrophages J. Pharmacol. Exp. Ther., March 1, 2001; 296(3): 736 - 743. [Abstract] [Full Text]
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E. Mostafa Mtairag, S. Chollet-Martin, M. Oudghiri, N. Laquay, M.-P. Jacob, J.-B. Michel, and L. J. Feldman Effects of interleukin-10 on monocyte/endothelial cell adhesion and MMP-9/TIMP-1 secretion Cardiovasc Res, March 1, 2001; 49(4): 882 - 890. [Abstract] [Full Text] [PDF]
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J. A. Cooper, G. J. Miller, K. A. Bauer, J. H. Morrissey, T. W. Meade, D. J. Howarth, S. Barzegar, J. P. Mitchell, and R. D. Rosenberg Comparison of Novel Hemostatic Factors and Conventional Risk Factors for Prediction of Coronary Heart Disease Circulation, December 5, 2000; 102(23): 2816 - 2822. [Abstract] [Full Text] [PDF]
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C. D. Douillet, V. Velarde, J. T. Christopher, R. K. Mayfield, M. E. Trojanowska, and A. A. Jaffa Mechanisms by which bradykinin promotes fibrosis in vascular smooth muscle cells: role of TGF-beta and MAPK Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2829 - H2837. [Abstract] [Full Text] [PDF]
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 Y. Y. Li, Y. Q. Feng, T. Kadokami, C. F. McTiernan, R. Draviam, S. C. Watkins, and A. M. Feldman Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy PNAS, November 7, 2000; 97(23): 12746 - 12751. [Abstract] [Full Text] [PDF]
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D Tousoulis, C Tentolouris, T Crake, G Goumas, C Stefanadis, P Toutouzas, and G Davies Complex stenosis morphology and vasomotor responses to inhibition of nitric oxide synthesis Heart, November 1, 2000; 84(5): 529 - 534. [Abstract] [Full Text]
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I. Morishima, T. Sone, K. Okumura, H. Tsuboi, J. Kondo, H. Mukawa, H. Matsui, Y. Toki, T. Ito, and T. Hayakawa Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1202 - 1209. [Abstract] [Full Text] [PDF]
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 J. Salzmann, G A. Limb, P. T Khaw, Z. J Gregor, L. Webster, A. H Chignell, and D. G Charteris Matrix metalloproteinases and their natural inhibitors in fibrovascular membranes of proliferative diabetic retinopathy Br J Ophthalmol, October 1, 2000; 84(10): 1091 - 1096. [Abstract] [Full Text]
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A. Vieillard-Baron, E. Frisdal, S. Eddahibi, I. Deprez, A. H. Baker, A. C. Newby, P. Berger, M. Levame, B. Raffestin, S. Adnot, et al. Inhibition of Matrix Metalloproteinases by Lung TIMP-1 Gene Transfer or Doxycycline Aggravates Pulmonary Hypertension in Rats Circ. Res., September 1, 2000; 87(5): 418 - 425. [Abstract] [Full Text] [PDF]
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U. Ikeda, M. Shimpo, R. Ohki, H. Inaba, M. Takahashi, K. Yamamoto, and K. Shimada Fluvastatin Inhibits Matrix Metalloproteinase-1 Expression in Human Vascular Endothelial Cells Hypertension, September 1, 2000; 36(3): 325 - 329. [Abstract] [Full Text] [PDF]
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B. J. G. L. de Smet, D. de Kleijn, R. Hanemaaijer, J. H. Verheijen, L. Robertus, Y. J. M. van der Helm, C. Borst, and M. J. Post Metalloproteinase Inhibition Reduces Constrictive Arterial Remodeling After Balloon Angioplasty : A Study in the Atherosclerotic Yucatan Micropig Circulation, June 27, 2000; 101(25): 2962 - 2967. [Abstract] [Full Text] [PDF]
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M. P. Bendeck, C. Irvin, M. Reidy, L. Smith, D. Mulholland, M. Horton, and C. M. Giachelli Smooth Muscle Cell Matrix Metalloproteinase Production Is Stimulated via {alpha}v{beta}3 Integrin Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1467 - 1472. [Abstract] [Full Text] [PDF]
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H. R. Lijnen, B. Van Hoef, M. Dewerchin, and D. Collen {alpha}2-Antiplasmin Gene Deficiency in Mice Does Not Affect Neointima Formation After Vascular Injury Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1488 - 1492. [Abstract] [Full Text] [PDF]
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E. Creemers, J. Cleutjens, J. Smits, S. Heymans, L. Moons, D. Collen, M. Daemen, and P. Carmeliet Disruption of the Plasminogen Gene in Mice Abolishes Wound Healing after Myocardial Infarction Am. J. Pathol., June 1, 2000; 156(6): 1865 - 1873. [Abstract] [Full Text] [PDF]
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N. Varo, M. J. Iraburu, M. Varela, B. Lopez, J. C. Etayo, and J. Diez Chronic AT1 Blockade Stimulates Extracellular Collagen Type I Degradation and Reverses Myocardial Fibrosis in Spontaneously Hypertensive Rats Hypertension, June 1, 2000; 35(6): 1197 - 1202. [Abstract] [Full Text] [PDF]
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S. Jormsjo, S. Ye, J. Moritz, D. H. Walter, S. Dimmeler, A. M. Zeiher, A. Henney, A. Hamsten, and P. Eriksson Allele-Specific Regulation of Matrix Metalloproteinase-12 Gene Activity Is Associated With Coronary Artery Luminal Dimensions in Diabetic Patients With Manifest Coronary Artery Disease Circ. Res., May 12, 2000; 86(9): 998 - 1003. [Abstract] [Full Text] [PDF]
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