From the Cardiology Section, Department of Medicine, Veterans
Administration Medical Center, Houston, Tex, Baylor College of Medicine
(D.L.M.) and the Division of Cardiothoracic Surgery, Medical University of
South Carolina, Charleston (F.G.S.).
Correspondence to Francis G. Spinale, MD, PhD, Room 418 CSB, Cardiothoracic Surgery, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC.
The process of left
ventricular (LV) remodeling has been shown to be an
important predictor of morbidity and mortality in patients with heart
failure. Therefore, identifying the cascade of molecular and cellular
events that contribute to LV remodeling is likely to provide new and
novel targets for preventing disease progression in heart failure. In
this issue of Circulation, Li and
colleagues1 report that changes in the relative
abundance of tissue inhibitors of the metalloproteinases
(TIMPs) occur with the development of end-stage human heart failure,
thus raising the important possibility that alterations in the
extracellular matrix of the failing heart may contribute to disease
progression in heart failure. The purpose of this editorial was to
place the findings of the study by Li et al, as well as those of
recently published reports, in perspective with what we know about
myocardial extracellular remodeling in heart failure.
LV Remodeling in Heart Failure
The phenotype of dilated
cardiomyopathic disease in humans can be characterized
as a disproportionate increase in the ratio of LV
ventricular chamber radius to wall thickness, with no
increase in sarcomere length. The increased ratio of LV chamber radius
to wall thickness is accompanied by increased myocardial wall stress,
which can in turn promote further dilation and reduced pump function.
Taken together, these observations would suggest that significant
myocardial remodeling must occur within the LV free wall to allow for
the chamber dilation and wall thinning that occur during the
progression to severe LV dilation. Although the canonical view of LV
remodeling has held that LV dilation occurs primarily as a result of an
increase in myocyte size (hypertrophy), an increasing body
of literature now suggests that the process of LV remodeling is far
more complex than was once assumed and that important changes occur in
the extracellular matrix components of the myocardium as
the LV begins to fail.
Myocardial Extracellular Matrix Remodeling
The extracellular matrix of the heart includes a fibrillar
collagen network, a basement membrane, and proteoglycans. The
myocardial fibrillar collagens (such as collagen types I and III)
ensure structural integrity of adjoining myocytes, provide the means by
which myocyte shortening is translated into overall LV pump function,
and have been postulated to be essential for maintaining alignment of
myofibrils within the myocyte through a
collagen–integrin–cytoskeletal-myofibril relation. The collagen
matrix in the myocardium may be conceptualized as
scaffolding in which collapse of the individual components of the
scaffold may not necessarily result in an absolute loss of collagen
content but rather in a loss of structural integrity. Recent scanning
electron micrographs by Rossi and colleagues2
served as an elegant reminder that the collagen matrix in the
myocardium is a 3-dimensional structure that supports
individual myocytes. Small cuts or breaks in the overall structure of
the collagen matrix, as in a scaffold, will result in a loss of
continuity and therefore of normal function. In both human and animal
studies, changes in LV geometry and function have been associated with
changes in the fibrillar collagen network.2 3 4 5
Thus, untoward changes in myocardial collagen alignment, structure, and
support may be a fundamental structural mechanism that contributes to
the progressive LV dilation and remodeling that occurs during the
progression of CHF. Increased fibrillar collagen accumulation, or
fibrosis, has been recognized to occur in a number of cardiac disease
states. However, it is important to recognize that this so-called
"replacement fibrosis" is most likely an end-stage process that
occurs during or after destruction of the fine fibrillar collagen weave
that normally surrounds myocytes. Thus, the myocardial collagen
remodeling that occurs in progressive LV failure is due to
abnormalities not only in collagen synthesis but also in degradation.
Accordingly, the myocardial extracellular matrix can be considered to
be in a dynamic equilibrium dependent on families of molecules that
favor matrix degradation as well as families of molecules that tend to
inhibit matrix degradation. Indeed, recent clinical and basic studies
of heart failure have clearly demonstrated that a number of
extracellular degradative enzymes, collectively called the matrix
metalloproteinases (MMPs), exist within the failing
myocardium.1 4 6 7
Matrix Metalloproteinases
The MMPs have been suggested to play an important role in tissue
remodeling in both normal and pathological
conditions.8 9 10 For example, changes in MMP
activity and expression have been observed in organ morphogenesis,
menstruation and pregnancy, wound healing and inflammation, and tumor
metastasis. The MMPs are secreted by a number of cell types, including
fibroblasts, smooth muscle cells, and endothelial
cells. More recently, a preliminary study demonstrated that adult
mammalian myocytes synthesize and release MMPs.11
The general classification of these MMPs is based on substrate
specificity, but several of the MMPs can degrade a number of different
matrix components. As of this writing,
Changes in MMP mRNA levels can be influenced by a wide variety of
chemical agents, neurohormones, and cytokines, as well as by
changes in cytoskeletal architecture and basement membrane
adhesion.8 9 10 11 12 13 It is likely that protein kinase C
(PKC) is involved in the intracellular induction of MMP transcription,
because the exposure of several different cell systems to phorbol
esters, which increase PKC, causes increased MMP mRNA
expression.10 12 Thus, increased levels of
catecholamines, angiotensin II, and endothelin,
which in turn can cause a receptor-mediated increase in PKC within a
number of cell types in the myocardium, may cause increased
levels of several species of myocardial MMPs in the failing heart.
Biologically active peptides and cytokines, such as tumor
necrosis factor-
Because MMPs are secreted primarily in an inactive or pro-MMP form, MMP
activation occurs after secretion into the extracellular space. Thus,
an important control point for MMP activity is proteolytic processing
of the pro-MMPs. The propeptide of the MMP contains a cysteine switch
sequence that enfolds the zinc atom of the catalytic
site.12 MMP activation requires dissociation of
the zinc-cysteine interaction through proteolytic cleavage of the
propeptide sequence or changes in the cysteine switch conformation by
chemical perturbations. A large number of proteases and
organomercurials have been shown to activate the MMPs from the
zymogen form in vitro.8 12 It has been
demonstrated that serine proteases such as trypsin, plasmin, or
urokinase generate an identical form of active
MMP.12 Thus, a potentially important upstream
mechanism for activation of latent MMPs is the
urokinase/plasminogen cascade. One of the most frequently
studied of the MMPs with respect to zymogen activation is the
interstitial collagenase MMP-1. The first step
in MMP-1 activation is proteolytic cleavage ahead of the cysteine
residue, which results in a partially active intermediate form that is
then quickly converted to the active form by autolytic means or through
cleavage by the MMP stromelysin, or MMP-3.8 10 12
Thus, an important regulatory step in overall MMP activation involves
the expression and activational state of MMP-3. Increased myocardial
levels and activity of MMP-3 have been reported to occur in both humans
and animals with LV dilation and failure.6 7
Several studies have demonstrated that MMP zymographic activity is
increased with end-stage cardiomyopathic disease in
patients.1 4 7 In the study by Li et
al,1 MMP proteolytic activity after preactivation
with a phorbol ester and the serine protease trypsin was increased in
cardiomyopathic samples based on in vitro zymography.
This finding is consistent with past studies and suggests that
a greater proportion of recruitable MMP exists within the failing
myocardium. However, it must be recognized that the in
vitro zymographic approach usually requires preactivation of the MMP
preparations and electrophoretic separation of proteins and therefore
provides only an index of potential MMP activational states that may
exist in vivo.
A final and important control point of MMP activity is the inhibition
of activated enzyme. There is an endogenous class
of proteins called the tissue inhibitors of the matrix
metalloproteinases, or TIMPs. At present, 4 TIMPs have been
characterized with respect to being separate gene products and
influence the activity of MMPs.8 14 15 16 17 The TIMPs
are low-molecular-weight proteins (
TIMP-3 is somewhat different from other TIMPs in that it is directly
bound to components of the extracellular matrix, whereas it is believed
that TIMP-1 and TIMP-2 are freely diffusible within the
interstitial compartment.16 Thus,
TIMP-3 potentially may modulate MMP activity in a more focal manner
than other TIMPs. TIMP-3 transcription is influenced by external
stimuli in a similar manner to that of
TIMP-1.13 16 Consistent with this
observation, the study by Li et al1 reported a
reduction in TIMP-3 comparable to that of TIMP-1 levels in
cardiomyopathic myocardium. The final TIMP
currently characterized, TIMP-4, has been shown to have a unique
expression pattern. Specifically, TIMP-4 mRNA has been detected at low
levels in the kidney and colon but is absent in the lung, liver, and
brain.17 Interestingly, the only organ observed
to have high expression patterns for TIMP-4 was the
myocardium.17 However, whether TIMP-4
possesses different MMP inhibitory activity within the
myocardium remains unclear. Li et al reported that
steady-state mRNA levels for TIMP-4, unlike the other TIMPs, were
unchanged but protein levels were reduced with ischemic
cardiomyopathy. TIMP mRNA half-life is
The Two Faces of TIMPs
Although TIMPs are considered to be endogenous
inhibitors of MMPs, the in vivo function of these proteins
may not be straightforward. First, TIMPs may actually participate in
the process of MMP activation. Specifically, it has been demonstrated
that TIMP-2 forms a complex with species of membrane-type MMPs and that
the formation of this complex enhanced the activation of
pro-MMP-2.8 12 19 A second role of TIMPs that is
independent of modulating MMP activational states is through effects on
cell growth.20 For example, TIMP-1 and TIMP-2
have been shown to stimulate a growth response in fibroblast cell
cultures in a concentration-dependent manner.20
Thus, it is possible that changes in TIMP levels within the
myocardium may have multiple biological effects that would
be relevant to the cardiomyopathic disease process.
Summary
Although it is becoming increasingly clear that disease
progression in heart failure is inextricably linked to the process of
LV remodeling, the precise constellation of mechanisms that are
responsible for the LV remodeling remains unknown. In the foregoing
discussion, we have attempted to outline several lines of evidence
suggesting that discrete changes in the activity of enzymatic systems
responsible for extracellular matrix degradation within the
myocardium contribute to the process of LV remodeling in
heart failure. The results from several recent studies, including the
study by Li et al1 in this issue of
Circulation, demonstrate that myocardial MMP activity is
increased in cardiomyopathic ventricles and is
associated with changes in the endogenous
inhibitors of the MMPs, namely the TIMPs. Therefore, this
study, as well as others,4 7 adds to the
increasing body of circumstantial evidence suggesting that MMP
activation contributes to the changes in LV geometry that occur with
the progression of dilated cardiomyopathy. In this
regard, it will be important in future studies to identify upstream
mechanisms for myocardial MMP activation, as well as to develop new
strategies for inhibition of MMP expression and activity. Thus, the
concept of controlling MMP expression and/or activity as a means for
governing LV remodeling represents a new and exciting
therapeutic target for treating the failing heart.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
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Differential expression of tissue inhibitors of
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Thomas CV, Coker ML, Zellner JL, Handy JR,
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Hansen-Birkedal H, Moore WGI, Bodden MK, Windsor LJ,
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FG. Matrix metalloproteinase expression and activity in adult
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Nagase H. Activational mechanisms of matrix
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Goldberg GI, Marmer BL, Grant GA, Eisen AZ, Wilhelm S,
He C. Human 72-kilodalton type IV collagenase forms a
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designated TIMP. Proc Natl Acad Sci U S A. 1989;86:8207–8211.
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Silbiger SM, Jacobsen VL, Cupples RL, Koski RA. Cloning
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Leco KJ, Khokha R, Pavloff N, Hawkes SP, Edwards DR.
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© 1998 American Heart Association, Inc.
Editorial
Activation of Matrix Metalloproteinases in the Failing Human Heart
Breaking the Tie That Binds
Key Words: Editorials • metalloproteinases • heart failure • remodeling
20 MMPs have been identified
and characterized.10 12 The classes of MMPs that
may have particular relevance to myocardial remodeling are the
collagenases, which include MMP-1; the stromelysins, which
include MMP-3; the gelatinases, which include MMP-9 and MMP-2; and the
membrane-type MMPs. After synthesis, the MMPs are secreted into the
extracellular space as a proenzyme, or zymogen. The general structure
of the MMPs is centered around a zinc-containing catalytic domain
contained within an upstream propeptide region and a C-terminal
glycoprotein/collagen-binding domain. The propeptide region
undergoes proteolytic cleavage to yield the active MMP. The C-terminal
region is structurally distinct for each MMP species; it provides the
capacity to bind to extracellular substrates and therefore imparts
specificity. The activity of MMPs is strictly regulated at 3 levels:
transcription, activation, and inhibition/deactivation. 
(TNF-) and interleukin-1, have been demonstrated
to increase MMP transcription in several cell
systems.13 Given that increased levels of such
cytokines as TNF- have been identified in patients with LV
failure, it is possible that proinflammatory cytokines
contribute to LV remodeling through upregulation of specific myocardial
MMPs. The promoter regions of the MMP-1 and the MMP-3 genes have some
common regulatory DNA sequences, but there are several additional
upstream response elements in the MMP-3 gene.8 13
Thus, increased extracellular stimuli, such as neurohormones and
cytokines, may induce differential levels of MMP-1 and MMP-3
expression. The gelatinases MMP-9 and MMP-2 also contain dissimilar
promoter sequences and regulatory elements.8 13
This laboratory reported previously that MMP-3 and MMP-9 levels were
increased in dilated cardiomyopathy, whereas MMP-1
levels were decreased and MMP-2 levels unchanged, suggesting that there
is differential regulation of myocardial MMP expression in the failing
human heart.7 20 to 30 kDa) and can complex
with high efficiency to activated MMPs. TIMPs bind to the
active site of the MMPs by blocking access to the collagen substrate.
The MMP/TIMP complex is a tight, noncovalent bond with an extremely
high affinity for the MMPs (Kd
10-9).14 The TIMPs
appear to bind MMPs in a stoichiometric 1:1 molar ratio and occupy the
catalytic domain of the activated enzyme. Therefore, TIMPs form
an important endogenous system for regulating actual MMP
activity in vivo. In light of the potential importance of these
inhibitory proteins to modulate MMP activity, the TIMP
family of secreted proteins is a field of active interest in many areas
of cardiovascular biology.9 The
findings by Li et al1 provide evidence to suggest
that changes in the stoichiometric ratio of MMPs to TIMPs have occurred
with end-stage cardiomyopathic disease. Specifically,
TIMP-1 and TIMP-3 levels were reduced in
cardiomyopathic samples, whereas TIMP-2 levels were
unchanged compared with control myocardium. It has been
demonstrated previously that TIMP-1 and TIMP-2 expression is
differentially regulated by a number of external
stimuli.13 For example, such cytokines as
TNF- can modify the expression of TIMP-1 through the induction of
nuclear transcription factors, whereas TIMP-2 expression appears to be
unaffected by cytokine stimulation.13 18
In a previous study,7 we reported increased MMP-9
with no change in MMP-2 levels, whereas Li et al reported a reduction
in TIMP-1 abundance with no change in TIMP-2 levels in
cardiomyopathic myocardium. Whether these
reported changes in MMPs and TIMPs with end-stage
cardiomyopathy reflect alterations in specific
pro-MMP/TIMP complexes, MMP stability, and/or activational states
remains to be established. 60 hours,
and whether changes in the stability of TIMP mRNA occur with changes in
external stimuli remains to be established.8
Nevertheless, the observation of discordant mRNA and protein levels for
TIMP-4 suggests that posttranscriptional/translational alterations may
have occurred with ischemic cardiomyopathy.
Because TIMP-4 appears to be expressed selectively in high abundance in
the myocardium, future investigations into the function and
regulation of this specific TIMP in cardiac disease states would be
warranted.
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Y. Y. Li, Y. Feng, C. F. McTiernan, W. Pei, C. S. Moravec, P. Wang, W. Rosenblum, R. L. Kormos, and A. M. Feldman Downregulation of Matrix Metalloproteinases and Reduction in Collagen Damage in the Failing Human Heart After Support With Left Ventricular Assist Devices Circulation, September 4, 2001; 104(10): 1147 - 1152. [Abstract] [Full Text] [PDF]
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M.H. Yacoub A novel strategy to maximize the efficacy of left ventricular assist devices as a bridge to recovery Eur. Heart J., April 1, 2001; 22(7): 534 - 540. [PDF]
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J. Fielitz, S. Hein, V. Mitrovic, R. Pregla, H. R. Zurbrugg, C. Warnecke, J. Schaper, E. Fleck, and V. Regitz-Zagrosek Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1443 - 1449. [Abstract] [Full Text] [PDF]
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B. K. Podesser, D. A. Siwik, F. R. Eberli, F. Sam, S. Ngoy, J. Lambert, K. Ngo, C. S. Apstein, and W. S. Colucci ETA-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H984 - H991. [Abstract] [Full Text] [PDF]
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A. J. Woodiwiss, O. J. Tsotetsi, S. Sprott, E. J. Lancaster, T. Mela, E. S. Chung, T. E. Meyer, and G. R. Norton Reduction in Myocardial Collagen Cross-Linking Parallels Left Ventricular Dilatation in Rat Models of Systolic Chamber Dysfunction Circulation, January 2, 2001; 103(1): 155 - 160. [Abstract] [Full Text] [PDF]
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 D. A. Siwik, P. J. Pagano, and W. S. Colucci Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts Am J Physiol Cell Physiol, January 1, 2001; 280(1): C53 - C60. [Abstract] [Full Text] [PDF]
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E. J. Birks, V. J. Owen, P. B. J. Burton, A. E. Bishop, N. R. Banner, A. Khaghani, J. M. Polak, and M. H. Yacoub Tumor Necrosis Factor-{alpha} Is Expressed in Donor Heart and Predicts Right Ventricular Failure After Human Heart Transplantation Circulation, July 18, 2000; 102(3): 326 - 331. [Abstract] [Full Text] [PDF]
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M. G. St. J. Sutton and N. Sharpe Left Ventricular Remodeling After Myocardial Infarction : Pathophysiology and Therapy Circulation, June 27, 2000; 101(25): 2981 - 2988. [Full Text] [PDF]
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D. A. Siwik, D. L.-F. Chang, and W. S. Colucci Interleukin-1{beta} and Tumor Necrosis Factor-{alpha} Decrease Collagen Synthesis and Increase Matrix Metalloproteinase Activity in Cardiac Fibroblasts In Vitro Circ. Res., June 23, 2000; 86(12): 1259 - 1265. [Abstract] [Full Text] [PDF]
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P. Rouet-Benzineb, J.-M. Buhler, P. Dreyfus, A. Delcourt, R. Dorent, J. Perennec, B. Crozatier, A. Harf, and C. Lafuma Altered balance between matrix gelatinases (MMP-2 and MMP-9) and their tissue inhibitors in human dilated cardiomyopathy: potential role of MMP-9 in myosin-heavy chain degradation Eur J Heart Fail, December 17, 1999; 1(4): 337 - 352. [Abstract] [Full Text] [PDF]
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D. L. Mann Mechanisms and Models in Heart Failure : A Combinatorial Approach Circulation, August 31, 1999; 100(9): 999 - 1008. [Full Text] [PDF]
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A. L. Chancey, G. L. Brower, J. T. Peterson, and J. S. Janicki Effects of Matrix Metalloproteinase Inhibition on Ventricular Remodeling Due to Volume Overload Circulation, April 23, 2002; 105(16): 1983 - 1988. [Abstract] [Full Text] [PDF]
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