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transgenic mouse phenotype
early in the development of heart failure
Cardiovascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Myocardial extracellular matrix
remodeling regulated by matrix metalloproteinases (MMPs) is implicated
in the progression of heart failure. We hypothesized that MMP
inhibition may modulate extracellular matrix remodeling and prevent the
progression of heart failure. The effects of the MMP inhibitor BB-94
(also known as batimastat) on MMP expression, collagen
expression, collagen deposition, collagen denaturation, and left
ventricular structure and function in transgenic mice with
cardiac-restricted overexpression of tumor necrosis factor-
(TNF-) (TNF1.6) were assessed. The results showed that BB-94 reduced
the expression of collagens, increased insoluble collagen and the ratio
of undenatured to total soluble collagen, and prevented myocardial
hypertrophy and diastolic dysfunction in young TNF1.6 mice.
Furthermore, the treatment significantly improved cumulative survival
of TNF1.6 mice. However, MMP inhibition did not have salutary effects
on ventricular size and function in old mice with established heart
failure. The results suggest that MMP activation may play a critical
role in changes of myocardial function through the remodeling of
extracellular matrix, and MMP inhibition may serve as a potential
therapeutic strategy for heart failure, albeit within a narrow window
during the development of heart failure.
metalloendopeptidases; ventricular remodeling; extracellular matrix; collagen
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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MATRIX METALLOPROTEINASES (MMPs, EC 3.4.24) are a family of functionally related zinc-containing proteinases that are capable of degrading all the components of the extracellular matrix (ECM). The collagenous matrix provides the support essential for maintaining alignment of myofibrils within the myocyte as well as for maintaining myocyte alignment within the myocardium (2, 7). Denatured collagens do not function as a structural support for myofibrils and myocytes. Activation of MMPs may result in fibrillar collagen denaturation, collagen degradation, and the synthesis of new fibrous tissue. As the initial step of collagen degradation and structural reformation, collagen denaturation may be a result of excessive exposure to active MMPs (18). Therefore, activated MMPs may play an important role in cardiac ECM remodeling that accompanies the development of heart failure (6, 19, 35). Indeed, elevation of MMP activity has been previously identified in the failing hearts of both animal models and humans (5, 16, 32, 35, 36). ECM remodeling, which contributes to left ventricular remodeling and dilation (9, 10), is a cumulative result of matrix protein synthesis, denaturation, degradation, and structural reformation. The process of ECM remodeling is not only a change in the amount but also a change in the quality of matrix proteins (17, 22, 40).
Previous studies from our laboratory demonstrated a robust increase in
MMP-2 and MMP-9 gelatinolytic activity, extensive collagen deposition,
and denaturation and ECM remodeling in mice with heart failure
secondary to cardiac restricted overexpression of tumor necrosis
factor- (TNF-) (TNF1.6 mice) (18). These changes in
the ECM were associated with diastolic dysfunction and cardiac dilation. Anti-TNF- therapy abolished MMP-9 and reduced MMP-2, reduced collagen expression and denaturation, and improved cardiac diastolic function of young animals (18). Furthermore, the
expression of both MMPs and tissue inhibitors of metalloproteinases can
be regulated by proinflammatory cytokines (20). Therefore,
we hypothesized that the beneficial effects of anti-TNF- therapy in
TNF1.6 mice might be due to the indirect inhibition of MMPs in the
myocardium. To test this hypothesis, we attenuated MMP activity in
TNF1.6 transgenic mice by using the synthetic MMP inhibitor BB-94
(batimastat, British Biotech Pharmaceuticals). BB-94 inhibits MMPs with
IC50 values in the low nanomolar range and has broad
specificity for members of the MMP family but little activity against
angiotensin-converting enzyme or enkephalinase (3). The
effects of MMP inhibition by BB-94 on the expression, deposition, and
denaturation of collagen and on heart failure phenotype and survival of
TNF1.6 mice were examined.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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TNF1.6 mice and cardiac sample collection. TNF1.6 mice were created as previously reported (13). The offspring of TNF1.6 mice develop cardiac hypertrophy, dilation, and failure. TNF1.6 mice and wild-type littermates bred in house were used in the present study.
Mice were anesthetized with intraperitoneal injection of 2.5% Avertin (18 µl/g body wt, 2,2,2 tribromoethanol). After echocardiography, the mice were euthanized while under deep anesthesia, and the body weight was recorded. The heart was excised and rinsed in ice-cold phosphate-buffered saline (PBS). Ventricular tissues were weighed and snap-frozen in liquid nitrogen for protein and enzymatic analyses. This study was performed according to the guidelines as outlined in the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health. All procedures were performed according to the protocols approved by the Institutional Animal Care and Use Committee, University of Pittsburgh.BB-94 treatment. BB-94 was suspended in PBS containing 0.01% Tween 20 by sonication. Both young (4-wk-old) and old (40-wk-old) TNF1.6 mice were treated with BB-94 at a dosage of 40 µg/g or its vehicle by intraperitoneal injection three times a week for 8 wk or until the animal died. The final ages of the surviving animals were 12 and 48 wk old, respectively. The dosage and method of administration of BB-94 were suggested by the manufacturer (British Biotech Pharmaceuticals) and were comparable to those utilized in Phase I/II studies in humans. In the present study, the average plasma level of BB-94 after 56 h of administration was 39.9 ± 20 nM (means ± SD) as measured by liquid chromatography mass spectrometry. This plasma level is greater than the published IC50 of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9 (30, 39).
Measurement of MMP gelatinolytic activity. MMP gelatinolytic activity in 100 µg of myocardial extracts was measured by gelatin zymography as described previously (16, 37). The images were digitized, and gelatinolytic zones were quantified using ImageQuant software (Molecular Dynamics) (18).
Western blot of MMPs. Western blot analyses of MMP-9 and MMP-13 were performed as described previously (16). MMP-13 was detected with antibody against pro-MMP-13 (AB8120 at 0.3 µg/ml, Chemicon), which also recognizes smaller fragments of MMP-13 (positive control CC1047, Chemicon). The reactions were developed with Supersignal West Dura Extended Duration Substrate (Pierce), and the images were visualized by exposure to X-ray films. The membranes were then stripped with IgG elution solution (Pierce) and probed with pro-MMP-9 antibody (AB19047 at 0.3 µg/ml, Chemicon; positive control CC069, Chemicon). After the final detection, the filters were stained with BLOT-FastStain (Chemicon). The films and filters were digitized and quantified with the ImageQuaNT software. Only the band that migrated with the positive control was quantified.
Collagen subtype expression and content determination.
For the quantification of collagen subtype expression,
glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-normalized transcript levels of both pro-1(I) and pro-1(III) for type I and type III collagens were determined by Northern blot analysis using mouse pro-1(I) and pro-1(III) cDNA probes and protocols previously reported by us (16, 25).
Echocardiography. Cardiac ultrasound studies were performed with an Acuson Ultrasonograph as described in our previous studies (11, 18). A dynamically focused 13-mHz annular array transducer was placed on a layer of acoustic coupling gel applied to the left hemithorax. Diastolic transmitral left ventricular inflow velocities were interrogated from angulated parasternal long-axis views by using a 7.0-mHz Doppler transducer with a sample volume length of 3.5-7.5 mm. Two-dimensionally targeted M-mode and color flow mapping-guided Doppler studies were performed at baseline and after the intraperitoneal administration of isoproterenol (300 ng/g body wt). Heart rate responses to isoproterenol were maximal within 1 to 2 min after injection. The entire imaging process was completed within 10 to 15 min.
Frozen frames of echocardiograms were printed with a video printer. The limb-lead electrocardiogram was patched into the ultrasonograph for timing purposes. M-mode measurements of left ventricular end-diastolic diameter and end-systolic diameter were made from original tracings by using the leading-edge of the American Society of Echocardiography and by using the steepest continuous endocardial echoes. End diastole was taken at the onset of the QRS complex, and end systole was taken at the peak of posterior wall motion. Three beats were averaged for each measurement. Spectral Doppler waveforms were analyzed for peak early- and late-diastolic transmitral velocities. The early peak transmitral flow-to-late transmitral flow velocity ratio (E/A ratio) was calculated as described elsewhere (12).Statistical analysis. The quantitative data are presented as means ± SD unless stated otherwise. Independent t-test or one-way ANOVA was applied to compare changes in different experimental groups. When a significant F value was obtained, comparison among the means was performed post hoc with the Student-Newman-Keuls analysis test using the SPSS statistical analysis software. Censored data animal survival curves were compared using Kaplan-Meier analysis (8). Statistical significance was considered to occur at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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MMP gelatinolytic activity and MMP expression after BB-94
treatment.
After treatment of TNF1.6 mice with BB-94 or its vehicle for 8 wk, the
gelatinolytic activity of MMP-2 and MMP-9 was examined by gelatin
zymography, and the expression of MMP-9 and MMP-13 was examined using
Western blot analysis. Although the gelatinolytic activity of MMP-9 was
reduced with the treatment, MMP-2 did not change (Fig.
1). Western blot did not show significant
change in the expression of MMP-9 or MMP-13 with BB-94 treatment (Fig. 2).
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MMP inhibition reduced myocardial procollagen synthesis, collagen
deposition, and denaturation.
Because collagens and their partially degraded fragments are
substrates of MMPs and collagen deposition is a function of both synthesis and degradation, enhanced activities of MMPs might alter collagen deposition, thereby effecting changes in myocardial ECM structure and function. On the contrary, inhibition of MMPs may prevent
the synthesis and deposition of collagens in the heart. As shown in
Fig. 3, the transcripts of pro-1(I)
and pro-1(III) collagens were significantly reduced by BB-94
treatment in the TNF1.6 mouse heart [pro-1(I), P < 0.01; pro-1(III), P < 0.05]. At the protein level,
total soluble collagen as well as insoluble collagen were increased in
the TNF1.6 mouse heart. The ratio of undenatured collagen to total
soluble collagen was reduced in the TNF1.6 mouse heart, but
significantly increased with BB-94 treatment in young TNF1.6 mice
(P < 0.05, Fig.
4B). In contrast, there was a
further increase in insoluble collagen and the ratio of insoluble to
total soluble collagen with BB-94 treatment in young TNF1.6 mice
(P < 0.05, Fig. 4, C and D). Those
changes in collagens after BB-94 treatment were not seen in 48-wk-old
TNF1.6 mice.
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MMP inhibition prevented ventricular hypertrophy.
We have demonstrated previously that TNF1.6 mice develop marked
cardiac hypertrophy at 12 wk of age and marked ventricular dilation at
older ages (18). To assess whether BB-94 treatment had any
effect on ventricular hypertrophy, we measured changes in ventricular
weight and wall thickness in TNF1.6 mice by two independent methods:
gravimetric and echocardiographic. Both methods have been shown to
reliably measure mouse ventricular weight (13). As shown
in Table 1, the significantly increased
ventricular weight as measured by gravimetric method was attenuated by
BB-94 treatment (P < 0.05). Echocardiography also
demonstrated similar changes in ventricular mass and posterior wall
thickness of TNF1.6 mice treated with BB-94. In addition, BB-94
inhibited the development of ventricular dilation in 12-wk-old mice. In
contrast, in 48-wk-old mice, treatment with BB-94 failed to influence
ventricular hypertrophy or dilation (Table 1).
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MMP inhibition improved myocardial function and survival of TNF1.6 mice. As reported previously, TNF1.6 mice develop abnormalities in myocardial diastolic and systolic functions (18). The majority of mice that died of heart failure had hydrothorax, markedly dilated left atrium, along with dilated ventricles. Doppler echocardiographic measurements of transmitral left ventricular inflow revealed that the E/A ratio was significantly reduced in female TNF1.6 mice relative to wild-type mice at 12 wk of age, suggesting diastolic dysfunction (21). Treatment of these female mice with BB-94 significantly increased the transmitral inflow E/A ratio, suggesting improved myocardial diastolic function. Indeed, the E/A ratio was returned to that of the wild-type mice after BB-94 treatment (P < 0.05, Table 1). However, treatment with BB-94 had no effect on baseline or isoproterenol-stimulated systolic performance in 12-wk-old TNF1.6 mice as measured by fractional shortening (Table 1). In 48-wk-old TNF1.6 animals, treatment with BB-94 had no effect on fractional shortening, whereas the treatment significantly improved isoproterenol responsiveness (P < 0.01, Table 1), although the change was small and of uncertain physiological significance.
Of the 27 TNF1.6 mice treated with BB-94, 4 died during the treatment. In contrast, 8 of 22 vehicle-treated TNF1.6 mice died (Table 2). Thus treatment of TNF1.6 mice with BB-94 significantly improved cumulative animal survival (P < 0.02). Most of the mortality was in the male group. As we reported previously that there are sex-related differences in the survival of TNF1.6 mice (11), we further analyzed the survival of young male TNF1.6 mice with or without BB-94 treatment. The result showed that the treatment effected a beneficial effect on the survival of young male TNF1.6 mice as that seen in combined male and female TNF1.6 mice (Fig. 5).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Myocardial ECM remodeling and fibrosis seen in animal models of
heart failure and in patients with this disease are implicated in
cardiac dysfunction and may have prognostic significance. Because ECM
remodeling is mediated by a family of MMPs that regulate collagen synthesis and degradation, investigators have sought to understand the
potential therapeutic benefits of MMP inhibition (24, 31). The present study demonstrated that direct inhibition of MMPs by BB-94
recapitulated the effects of anti-TNF- therapy. The changes in the
ECM resemble those seen after anti-TNF- therapy: reduced collagen
synthesis and collagen denaturation (18). In addition, the
treatment also improved survival of the TNF1.6 mice.
BB-94 was the first MMP inhibitor proven effective in limiting tumor metastases and growth and in improving survival in experimental animals with cancer (4, 38). These effects were putatively due to attenuating the invasive activity of cancer cells by inhibiting MMPs or the activation of latent MMPs in vivo (41). The present study took advantage of the MMP inhibitory function of BB-94 to assess the effects of MMP inhibition in ECM and myocardial remodeling in a well-defined heart failure model (TNF1.6 heart failure mice) that demonstrate substantial myocardial activation of MMPs and ECM remodeling.
Eight weeks of therapy with BB-94 in young TNF1.6 mice effectively reduced collagen synthesis and collagen denaturation, supporting the hypothesis that MMPs not only denature and degrade collagens, but also regulate collagen synthesis in vivo. These changes in the properties of collagens after BB-94 treatment were associated with diminished ventricular hypertrophy and dilation and enhanced diastolic compliance, but did not influence ventricular contractility. The mechanisms of diminished ventricular hypertrophy with MMP inhibition are not clear. It may be due to the blocking of the release of matrix-associated growth factors (14, 34) or the disturbance of matrix protein-mediated signal transduction among as well as into cardiac cells.
The regulation of the ECM is a complex biological process. For example, it is paradoxical that enhanced fibrosis is accompanied by increased MMPs in the failing heart and other conditions (1, 18, 19). Because fibrosis is the end result of both matrix synthesis and degradation, multiple mechanisms may be involved in this phenomenon. Degraded products of matrix proteins (matrikines) may serve as stimulators for collagen synthesis (19, 23), which may in turn result in increased deposition of poorly structured fibrotic tissue in the myocardium. Inhibition of MMPs may prove to be effective in preventing fibrosis and improving myocardial function. Indeed, in addition to the present study, treatment of the spontaneously hypertensive heart failure rat with PD-166793 reduces collagen volume fraction but not collagen mRNA expression (15). However, the mechanisms and the myocardial functional changes in those animals have not been defined. Changes in insoluble collagen as well as the ratio of undenatured to total soluble collagen observed in the present study may represent less damage to the matrix after inhibition of MMPs. The present study suggests that direct inhibition of MMPs may reduce matrix degradation and the production of matrikines, which may inhibit further synthesis and deposition of poorly structured matrix in the myocardium and improve heart failure phenotype.
Our results are also consistent with previous studies of MMP inhibition in other models of heart failure (24, 31). MMP inhibition with PD-166793 during the development of pacing-induced congestive heart failure in pigs limits left ventricular dilation, reduces wall stress, and prevents worsening of left ventricular fractional shortening (24, 31). Furthermore, administration of another broad-spectrum MMP inhibitor (CP-471474) also attenuated early left ventricular dilation after experimental myocardial infarction in mice (29). However, in contrast with previous studies, the TNF1.6 mouse heart failure model provides an opportunity to assess the effectiveness of therapy in later stages of heart failure. In contrast to the salutary effects of BB-94 in young TNF1.6 mice, treatment in older mice failed to substantially alter ventricular size or hemodynamics, despite a small but significant improvement in isoproterenol responsiveness. These results suggest that cardiac cell slippage and ECM remodeling have substantially affected the structural integrity of the collagen scaffolding of the heart; mere inhibition of further MMP activities has little effect on cardiac morphology or function in established heart failure.
In addition to the changes in the ECM with BB-94 treatment, one important finding is the improvement of survival of TNF1.6 mice with heart failure, especially in young male TNF1.6 mice. Although the mechanisms for this effect are not clear, we would speculate that inhibition of MMP activity might be pivotal to preventing alterations in cardiac structure and geometry in heart failure, which ultimately determines cardiac function and survival. One could also speculate that MMPs may function to release bioactive substances from the matrix and that inhibition of MMPs may limit the production of substances that participate in altering cardiac structure, function, and survival of animals with heart failure.
Despite the salutary changes in heart failure observed with BB-94
treatment, one should note the limitations of the study. Because BB-94
is a broad-spectrum MMP inhibitor, it is not clear which one of the
members of the MMP gene family may play more important roles. Moreover,
BB-94 may also affect a disintegrin and metalloprotease (ADAM) family
members (including TNF--converting enzyme), effects on TNF-
shedding are difficult to rule out, although the present study did not
find any change in the cardiac levels of TNF- in young TNF1.6 mice
(untreated = 185.5 ± 31.6 pg/mg myocardium, treated = 179.3 ± 22.6 pg/mg myocardium) and marginal reduction in old
TNF1.6 mice (untreated = 143.4 ± 11.7 pg/mg myocardium,
treated = 93.9 ± 13.5 pg/mg myocardium) with BB-94
treatment. More selective MMP inhibitors usually do not have such
effects. Thus the development of more selective MMP inhibitors will be
of most significance in the chronic treatment of heart failure.
In conclusion, treatment of TNF1.6 mice with the MMP inhibitor BB-94 reduced collagen synthesis, decreased collagen denaturation, prevented myocardial hypertrophy and diastolic dysfunction, and improved survival of TNF1.6 heart failure mice. However, BB-94 had few, if any, effects in older TNF1.6 mice. These results suggest MMP inhibition may be an effective way of limiting extensive ECM remodeling and progression of heart failure when administered during the early phase of the disease.
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ACKNOWLEDGEMENTS |
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We appreciate the help of P. Conjoice and Dr. Steve Wood from British Biotech Pharmaceuticals for measurement of plasma levels of BB-94. BB-94 was kindly provided by the British Biotech Pharmaceuticals.
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FOOTNOTES |
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This study was supported in part by National Heart, Lung, and Blood Institute Grants 1U01 HL-66949-01 to Y. Y. Li, C. F. McTiernan, and A. M. Feldman and HL-60032-01 to C. F. McTiernan and A. M. Feldman. T. Kadokami was a Bill Hillgrove Fellowship recipient.
Address for reprint requests and other correspondence: Yun You Li, Cardiovascular Institute, Univ. of Pittsburgh School of Medicine, BST 1750, 200 Lothrop St., Pittsburgh, PA 15213 (E-mail: liyuny{at}pitt.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00233.2001
Received 24 March 2001; accepted in final form 19 November 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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P < 0.05 compared with TNF1.6.
