© 1999 American Heart Association, Inc.
Integrative Physiology |
Matrix Metalloproteinase Inhibition During the Development of Congestive Heart Failure
Effects on Left Ventricular Dimensions and Function
From the Division of Cardiothoracic Surgery (F.G.S., M.L.C., S.R.K., R.P., W.V.H., M.J.C., S.B.K., M.R.Z.), Medical University of South Carolina, Charleston, and Cardiovascular Pharmacology (H.H., L.L.J., J.T.P.), Parke-Davis, Ann Arbor, Mich.
Correspondence to Francis G. Spinale, MD, PhD, Cardiothoracic Surgery, Room 625, Strom Thurmond Research Building, 770 MUSC Complex, Medical University of South Carolina, 114 Doughty St, Charleston, SC 29425.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—The development of congestive heart failure (CHF) is associated with left ventricle (LV) dilation and myocardial remodeling. The matrix metalloproteinases (MMPs) play a significant role in extracellular remodeling, and recent studies have demonstrated increased MMP expression and activity with CHF. Whether increased MMP activity directly contributes to the LV remodeling with CHF remains unknown. Accordingly, this study examined the effects of chronic MMP inhibition (MMPi) on LV size and function during the progression of CHF. Pigs were assigned to the following groups: (1) CHF, rapid pacing for 3 weeks at 240 bpm (n=12); (2) CHF/MMPi, rapid pacing and concomitant MMPi (PD166793, 20 mg/kg per day [n=10]), and (3) control (n=11). With pacing CHF, LV fractional shortening was reduced (19±1 versus 45±1%), and end-diastolic dimension increased (5.67±0.11 versus 3.55±0.05 cm), compared with baseline values (P<0.05). In the CHF/MMPi group, LV endocardial shortening increased (25±2%) and the end-diastolic dimension was reduced (4.92±0.17 cm) compared with CHF-only values (P<0.05). LV midwall shortening was reduced to a comparable degree in the CHF-only and CHF/MMPi groups. LV peak wall stress increased 3-fold with pacing CHF compared with controls and was significantly reduced in the CHF/MMPi group. LV myocardial stiffness was unchanged with CHF but was increased in the CHF/MMPi group. LV myocyte length was increased with pacing CHF compared with controls (180±3 versus 125±4 µm, P<0.05) and was reduced in the CHF/MMPi group (169±4 µm, P<0.05). Basal-state myocyte shortening velocity was reduced with pacing CHF compared with controls (33±2 versus 66±1 µm/s, P<0.05) and was unchanged in the CHF/MMPi group (31±2 µm/s). Using an ex vivo assay system, myocardial MMP activity was increased with pacing CHF and was reduced with chronic MMPi. In summary, concomitant MMPi with developing CHF limited LV dilation and reduced wall stress. These results suggest that increased myocardial MMP activity contributes to LV myocardial remodeling in developing CHF.
Key Words: congestive heart failure • metalloproteinases • myocyte function
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The development of congestive heart failure (CHF) is accompanied by left ventricle (LV) dilation and pump dysfunction.1 2 3 In patients with CHF, the progressive LV dilation is associated with an increased incidence in morbidity and mortality.1 2 3 4 These clinical observations, as well as experimental studies, suggest that LV remodeling is an important contributory event in the progression to severe CHF.1 2 3 4 5 6 7 8 9 However, the mechanisms that contribute to the changes in LV geometry and function that occur during the CHF process remain unclear. An important constituent of the LV myocardium is the fibrillar collagen matrix, which contributes to the maintenance of LV geometry and the structural alignment of adjoining myocytes.10 11 12 13 Alterations in collagen structure and composition have been reported to occur within the LV myocardium in several cardiac disease states, which in turn may influence LV geometry.5 6 7 10 11 14 15 16 17 An endogenous enzyme system responsible for extracellular collagen degradation and remodeling is the matrix metalloproteinases (MMPs).18 19 20 21 22 23 24 25 26 27 Increased myocardial MMP activity has been reported to occur with the development of severe CHF, such as in cardiomyopathic disease.5 6 25 26 27 However, whether heightened MMP activity contributes to the LV remodeling that occurs during the evolution of the CHF process remains unknown. Accordingly, the overall goal of the present study was to determine whether chronic MMP inhibition would influence LV geometry and function in the setting of CHF.
Chronic pacing–induced tachycardia in animals causes well-defined, predictable, and progressive LV dilation, contractile dysfunction, and neurohormonal system activation.5 6 14 15 16 28 29 These functional and neurohormonal changes are similar to the clinical spectrum of CHF.1 2 Therefore, this chronic pacing model may provide an opportunity to identify contributory events responsible for the progression of LV dilation and dysfunction that occurs with CHF. It has been previously demonstrated that the fibrillar collagen weave supporting adjacent myocytes is reduced with the development of pacing-induced CHF.5 14 15 16 Using in vitro proteolytic assay systems, increased LV myocardial MMP activity has been observed with the development of pacing-induced CHF.5 6 These past studies provide indirect evidence to suggest that fibrillar collagen degradation and remodeling contribute to the progressive LV dilation in this model of CHF. Accordingly, the present study was designed to test the central hypothesis that chronic interruption of myocardial MMP activity will reduce the LV dilation that invariably occurs in this model of CHF.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Dose Selection Studies
Three Yorkshire pigs (22 to 25 kg, male, Hambone Farms, Orangeburg, SC) were chronically instrumented with an aortic vascular access port to measure arterial blood pressure in the conscious state, as described previously.5 29 After a recovery period of 7 to 10 days, the animal was returned to the laboratory for baseline studies. For these studies, the animals were sedated with diazepam (Valium, 20 mg PO, Hoffmann-La Roche) and placed in a custom-designed sling. The vascular access port was entered using a 12-gauge Huber needle (Access Technologies), and basal and resting arterial pressures and heart rate were recorded. Pressures from the fluid-filled aortic catheter were obtained using an externally calibrated transducer (Statham P23ID, Gould). After baseline studies, the pigs were then used for initial MMP inhibition dosage studies. All animals were treated and cared for in accordance with the NIH Guide for the Care and Use of Laboratory Animals (National Research Council, Washington, 1996).
The MMP inhibitor chosen for these studies was PD166793,
which has a chemical formulation of
(S)-2-(4'-bromo-biphenyl-4-sulfonylamino-3-methyl butyric
acid) and has global MMP inhibitory activity in the
8 to 10 µmol/L range, based on in vitro assay systems (Table 1
).30 31 32 This MMP
inhibitor was also examined with respect to activity
against angiotensin-converting enzyme (prepared from rabbit
lung),33 neutral endopeptidase (24.11,
membrane fraction from Burkitt lymphoma cell line),34
endothelin-converting enzyme (membrane fraction from CHO cells
transfected with human endothelin-converting enzyme 1),35
and tumor necrosis factor-
convertase (tumor necrosis factor-
release from stimulated leukocytes; PanLabs Inc).36
Concentrations of up to 100 µmol/L of PD166793 did not exhibit
inhibitory activity against these proteolytic systems
(Table 1). These results demonstrated that this compound
possessed no activity against other enzymatic systems that have been
identified to be relevant in the CHF process.37 38
|
A single oral dose of 10 mg/kg PD166793 was administered in one pig, and a second pig was simultaneously administered a single 10 mg/kg dose of the MMP inhibitor intravenously. A pharmacokinetic profile was constructed using these initial data, and it was predicted that an oral delivery of 20 mg/kg per day of PD166793 would provide significant MMP plasma inhibitory activity at trough levels. Accordingly, the 3 pigs underwent 20 mg/kg QD (morning) treatment using the MMP inhibitor PD166793 for 5 days. This dosage regimen resulted in a drug plasma level that inhibited MMP activity by 100%, based on the ex vivo thiopeptilide assay.30 31 32
Experimental Protocol and Animal Model Preparation
After the MMP inhibition dose selection studies, the effects of
concomitant treatment with MMP inhibition with chronic rapid pacing
were examined. Weight-matched pigs (22 to 23 kg) were randomly assigned
to 3 groups, as follows: (1) rapid atrial pacing (240 bpm) for 3 weeks
(n=12), (2) concomitant MMP inhibition (PD166793 20 mg/kg per day) and
rapid pacing (n=10), and (3) sham controls (no pacing; n=11). The
drug treatment was begun 3 days before the initiation of pacing and
continued for the entire 21-day pacing protocol. The procedures used
for the placement of the pacing electrode and pacemaker have been well
described previously.5 14 28 39 40 41 Ten to fourteen days
after recovery from the surgical procedure, baseline studies were
performed, and the protocols described above were begun.
LV Function and Hemodynamic Measurements
Weekly measurements of LV size and function were obtained in the
rapid pacing group (n=8) and in the rapid pacing and MMP inhibition
group (n=7). At the conclusion of the 3-week protocol, LV function was
examined in all of the pigs entered in the protocol. For these studies,
the animals were brought to the laboratory, and the pacemaker was
deactivated. All measurements were performed at an ambient
resting heart rate within 30 to 40 minutes after pacemaker
deactivation. Two-dimensional and M-mode
echocardiographic studies (2.25-MHz transducer, ATL
Ultramark VI) were used to image the LV from a right parasternal
approach.29 40 LV endocardial fractional shortening was
calculated as (end diastolic dimension–end
systolic dimension)/end diastolic dimension and was
expressed as a percentage. LV midwall fractional shortening was
calculated at the level of the LV minor axis using methods described
previously by Gaasch et al42 and Shimizu et
al.43 The mean velocity of circumferential fiber
shortening corrected for heart rate
(Vcfc) was calculated using the LV
echocardiographic dimension measurements and the aortic
pressure trace, as described previously.44 Peak
circumferential global average wall stress was computed using a
spherical model of reference:
(g/cm2)=[PD/4h(1+h/D)]x1.36,
where P=peak aortic pressure measured from the access port,
D=minor axis dimension at end diastole,
h=wall thickness, and 1.36 is a coefficient constant for
conversion to g/cm2. This stress computation was
chosen because it reflects the LV wall stress pattern that will be most
affected by the changes in LV geometry due to the myocardial remodeling
process.
It has been demonstrated previously that significant changes in LV geometry and loading conditions occur with pacing-induced CHF.14 15 28 29 39 40 41 To more carefully examine LV ejection performance in relation to changes in LV afterload, LV endocardial and midwall fractional shortening were measured after incremental increases in LV myocardial wall stress in 5 control pigs, as described previously.5 40 This approach for measuring the LV shortening-stress relation has been reviewed in detail previously.44 45 46 To determine LV performance in the context of LV afterload during the entire ejection phase, mean circumferential wall stress was computed.42 43 The LV shortening-mean stress points for the control pigs were subjected to linear regression, and the 95% confidence interval was computed. The LV ejection-mean stress points for each of the rapid pacing groups were then plotted with respect to these normal control relationships.
After completion of the 21-day protocol, a final set of LV function and hemodynamic measurements were performed, and plasma was collected for neurohormonal profiles and MMP inhibitor compound levels. The pigs were anesthetized as described in the previous section, and the LV and pericardium harvested. The LV was divided and processed for myocyte isolation, perfusion-fixed for histology, and flash-frozen for MMP assays. A subset of animals (control [n=4], rapid pacing [n=4], and pacing with MMP inhibition [n=3]) were instrumented for LV diastolic function studies as described in the following paragraph.
LV Stiffness Properties
The fibrillar collagen matrix has been implicated as an
influence on LV myocardial stiffness
properties.11 14 17 47 48 LV diastolic
function has been well characterized previously in this pacing model of
CHF.14 40 49 50 51 Because the goal of the present study
was to manipulate myocardial fibrillar collagen degradative processes,
indices of LV chamber and myocardial stiffness were determined. All of
these studies were performed within 3 hours after the morning drug
treatment. A bolus of 1 µg/kg of sufentanyl was administered, an
endotracheal tube placed, and mechanical ventilation initiated. A
sternotomy was performed, the pericardium was completely excised, and a
vascular ligature was placed around the inferior vena cava
to perform transient caval occlusion. A previously calibrated
microtipped transducer (7.5F, Millar Instruments, Inc) was placed in
the LV through a small apical stab wound. Four piezoelectric crystals
(2 mm, Sonometrics) were positioned on the LV anterior free wall
to obtain orthogonal myocardial wall-thickness dimensions. One crystal
was placed on the LV endocardial surface through a small myocardial
incision and sutured in place. The 3 remaining crystals were placed at
equal distances on the LV epicardial surface to form a triangular array
around the endocardial crystal. From this crystal array, 6 unique
distances between crystal pairs were recorded at a sampling
frequency of 100 Hz and digitized (Pentium-Sonolab, Sonometrics). After
placement of the instruments, baseline LV pressures and dimensions were
recorded and digitized.
Indices of LV diastolic function were determined by computations of the regional LV chamber stiffness constant (Kc) and myocardial stiffness constant (Km).40 48 Calculations for Kc were based on analyses of the LV end-diastolic pressure versus LV end-diastolic chamber dimension using an exponential function given by P=AeKcD, where P is LV end-diastolic pressure, D is chamber dimension, and A and Kc are fitting constants. The natural logarithm of this function was used to compute Kc by linear regression. Calculations of Km were based on the analyses of the stress-strain relationship.40
Neurohormonal and MMP Inhibitor Measurements
The plasma samples were assayed for renin activity,
catecholamine levels, and plasma MMP inhibition levels.
Plasma renin activity was determined by computing
angiotensin I production using a radioimmunoassay
(NEA-026, New England Nuclear). Plasma norepinephrine was
measured using HPLC and normalized to pg/mL of plasma. Plasma and
myocardial measurements of the MMP inhibitor PD166793 were
first extracted through a chromatography column, and
compound levels determined by reverse-phase HPLC.
LV Myocyte Contractile Function
Myocytes were isolated from the LV free wall using methods
described previously by this laboratory.5 28 29 39 41
Briefly, the left circumflex coronary artery was perfused with
a collagenase solution (0.5 mg/mL, Worthington, type II;
146 U/mg), and the liberated myocytes (5x104
cells/mL) were resuspended in cell culture medium (M199, Gibco
Laboratories). LV myocyte contractility was examined
using computer-assisted videomicroscopy.28 41
Specifically, the LV myocytes were stimulated at 1 Hz and the profiles
of the contracting myocyte digitized.28 29 41 All
measurements were performed using identical electrical field
stimulation parameters. After baseline measurements,
contractile function was also examined after a specific inotropic
stimulus in each myocyte either after ß-adrenergic receptor
stimulation with 25 nmol/L isoproterenol (Sigma) or in the presence of
8 mmol/L extracellular Ca2+.
LV Myocardial Fibrillar Collagen Structure
Full-thickness sections of the perfused LV
myocardium were immersed in fresh fixative overnight.
Slices 4 µm in thickness were cut from the blocks and mounted on
glass slides. The sections were then rehydrated and stained using the
picrosirius histochemical technique.52 The sections were
then digitized at a final magnification of 320x and analyzed
with an image-analysis system (Sigma Scan/Image, Jandel). The
percentage area of extracellular staining was computed from 15 random
fields within the midmyocardium to exclude large epicardial
arteries and veins and any cutting or compression
artifact.14 29 48 The collected pericardial samples were
fixed overnight and prepared in a similar fashion.
LV Zymographic MMP Activity
MMP Zymography
The LV myocardial samples were prepared for zymographic studies
as described previously.5 6 20 26 LV MMP gelatinase
activity and abundance were examined by substrate-specific
zymography.5 6 26 To provide an internal control with
respect to the zymographic activity, cell culture medium samples from a
cultured human fibrosarcoma HT 1080 cell line were
included.53 The zymograms were digitized, and the
size-fractionated banding pattern, which indicated MMP proteolytic
activity, was determined by quantified image analysis (Gel Pro
Analyzer, Media Cybernetics). The lysis areas were measured by
2-dimensional integrated optical density computations and are expressed
in pixels.
MMP Substrate Assay
Quantitative MMP activity was determined in crude LV myocardial
extracts (which were not detergent treated or separated by
electrophoresis) using gelatin as the MMP substrate. A gelatin
matrix was used that was conjugated to quenched FITC (Molecular
Probes). Gelatin-FITC (1 mg/mL diluted in 1% agarose, 50 mmol/L
Tris-Cl, 5 mmol/L CaCl2, and 0.02%
NaN3 [pH 7.5]) was loaded onto a 96-well plate
(50 µg/well; Nalge Nunc International) and allowed to polymerize
(25°C, 30 minutes). LV myocardial extracts were loaded onto the wells
(95 µg total protein) and incubated (37°C, 2 hours). The
proteolytic release of the FITC chromogen was recorded using
dual-wavelength spectrophotometry (490/570 nm, S2000 Microplate Reader,
Fisher Scientific).
To confirm the concentration dependency as well as specificity of this
system, serial dilutions of a purified recombinant construct of the
catalytic domain for the human gelatinase, MMP-2, was used. The MMP-2
catalytic domain construct was obtained through expression in
Escherichia coli using an optimized DNA codon that encodes
the human MMP-2 amino acid sequence with the fibronectin binding domain
deleted.32 A concentration-dependent proteolysis of
the FITC-labeled gelatin substrate was observed (Figure 1, inset). Next, LV myocardial extracts
(25 µg total protein) were incubated with the gelatin substrate in
the presence of the following: the serine protease
inhibitor aprotinin (100 µmol/L, Miles, Inc); the
metal-chelating agent EDTA (20 mmol/L, Sigma); and a
previously characterized global MMP inhibitor, galardin
(5 mmol/L).54 55 These studies are summarized in
Figure 1. Serine protease inhibition had no effect on gelatinase
activity, whereas chelation by EDTA predictably reduced proteolytic
activity. The MMP inhibitor galardin reduced gelatinase
activity. These inhibitory studies indicated that this
gelatinase assay system was primarily due to myocardial MMP activity.
Using gelatin-FITC standards (10 to 50 µg), logarithmic
transformation, and linear regression, the sample readings obtained due
to myocardial proteolytic activity were converted to a known gelatinase
activity (µg/hour). Gelatinase activity was then normalized to the
yield of LV myocardial extract obtained from the original weight of the
LV myocardial samples. The final results were plotted as gelatinase
activity (µg/hour) on the ordinate and LV myocardial content (µg/g)
on the abscissa.
|
MMP-2 Activity by Antibody Capture Assay
An additional series of studies was performed in which specific
MMP-2 activity was measured by an antibody capture method. For this
assay, purified MMP-2 or control LV myocardial extracts (50 µg total
protein) were incubated on a 96-well microtiter plate in which a
monoclonal MMP-2 antibody was immobilized (RPN2631,
Amersham Pharmacia Biotech). The specificity and concentration
dependency of this MMP-2 activity assay system was first examined using
full-length MMP-2 standards (1 to 12 ng/mL) purified from a transfected
HT1080 cell line, as described previously.26 53 After
this, the standards used in this assay were serial dilutions of the
purified MMP-2 catalytic domain. The standards or LV myocardial
extracts were incubated overnight at 4°C and then washed. An enzyme
substrate solution was then added that contained
chromogenic peptide substrate S-2444 (Amersham Pharmacia
Biotech). The reaction was allowed to proceed at 37°C for 2 hours,
and the absorbance at 405 nm was recorded. The absorbance
from the cleaved chromogenic substrate was linear, with
increasing concentrations of the MMP-2 catalytic domain construct, and
proteolytic activity was reduced by 95% in the presence of the MMP
inhibitor PD166793 (10 µg/mL). LV myocardial MMP-2
activity was expressed as ng/hour per gram of LV
myocardium. These measurements were performed in the
presence and absence of increasing concentrations of the MMP
inhibitor (2 to 10 µg/mL). On the basis of these studies,
it was demonstrated that significant inhibition of LV myocardial MMP-2
activity was achieved in the presence of the MMP inhibitor
and was concentration dependent (Figure 2). The effective concentration of
PD166793, which resulted in 50% inhibition of LV myocardial MMP-2
activity (EC50), was computed to be 5
µmol/L (Figure 2).
|
Data Analysis
Indices of LV and myocyte function were compared among the 3
treatment groups using multiway ANOVA. For comparisons of LV function
with each week of pacing, an ANOVA for repeated measures was used. If
the ANOVA revealed significant differences, pairwise tests of
individual group means were compared using Bonferroni probabilities.
For comparisons of neurohormonal profiles and MMP activity, the
Student-Neuman-Keuls test was used. The chamber and myocardial
stiffness constants were compared among the 3 groups using the
Mann-Whitney test. All statistical procedures were performed using the
BMDP statistical software package. Results are presented as
mean±SEM. Values of P<0.05 were considered to be
statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
All of the pigs entered into the rapid pacing protocol were successfully studied. Steady-state plasma levels at the conclusion of the study for the MMP inhibitor were 93±10 µmol/L, and myocardial concentrations were 15.7±2.5 µg/g. A significant linear relationship was observed between plasma and myocardial levels of the MMP inhibitor (r=0.94, P<0.05). The myocardial concentration of the MMP inhibitor was consistent for the concentration necessary to significantly inhibit myocardial MMP-2 proteolytic activity (Figure 2
). The plasma levels of PD166793 obtained in
the present study are consistent with levels necessary for
inhibition against several MMP species (Table 1).
LV Function and Neurohormones With Rapid Pacing: Effects of Chronic
MMP Inhibition
Representative LV
echocardiographic recordings taken at each week
of rapid pacing, with and without concomitant MMP inhibition, are shown
in Figure 3. Weekly indices of LV
function obtained with chronic rapid pacing and with MMP inhibition are
summarized in Figure 4. In the untreated
rapid pacing group, LV end-diastolic dimension and peak
wall stress increased from baseline values in a time-dependent manner.
These changes in LV geometry were associated with a decline in LV
fractional shortening. In the rapid pacing and concomitant MMP
inhibition group, the degree of LV dilation was significantly
attenuated when compared with untreated rapid pacing values. This
reduction in LV end-diastolic dimension was translated into
a significant reduction in LV peak wall stress when compared with rapid
pacing–only values. LV fraction shortening fell significantly in the
rapid pacing and MMP inhibition group but remained higher than
untreated rapid pacing values.
|
|
LV function and hemodynamics are summarized in Table 2 for baseline conditions (before
pacemaker activation) and after 21 days of rapid pacing. After 21 days
of chronic rapid pacing without treatment, ambient resting heart rate
was increased and resting blood pressure decreased from baseline
values. In the rapid pacing–only group, Vcfc
decreased by >30% from baseline values. In the rapid pacing and MMP
inhibition group, resting heart rate was increased and mean
arterial pressure was reduced from baseline conditions.
However, resting heart rate was lower in the rapid pacing and MMP
inhibition group when compared with rapid pacing–only values. In the
rapid pacing and MMP inhibition group, the LV end-diastolic
dimension was reduced and wall thickness was increased from untreated
rapid pacing values. As a result, LV peak wall stress was significantly
lower in the rapid pacing and MMP inhibition group when compared with
rapid pacing–only values. LV fractional shortening increased by 44%
in the rapid pacing and MMP inhibition group when compared with the
untreated rapid pacing group. In the rapid pacing and MMP inhibition
group, LV Vcfc was greater than the rapid
pacing–only values, but this difference did not reach statistical
significance. LV midwall fractional shortening was significantly
reduced in the rapid pacing group and remained significantly reduced in
the MMP inhibition group.
|
To more carefully examine the relationship between indices of LV
ejection and LV afterload (wall stress), both the LV endocardial and
midwall fractional shortening–mean stress relationships were
determined (Figure 5). After chronic
pacing, a downward and rightward shift was observed, indicating a
significant decline in LV ejection
performance.44 45 46 In the rapid pacing and MMP
inhibition group, a reduction in LV wall stress occurred that resulted
in a leftward shift in the LV ejection-stress relationships when
compared with values from the untreated rapid pacing group. However, in
the MMP inhibition group, the steady-state values for these indices of
LV ejection performance remained below the 95% confidence
interval obtained from normal control animals. Thus, consistent
with past reports, these relatively load-insensitive indices of LV
systolic performance were markedly impaired, with
chronic rapid pacing.5 40 46 Moreover, whereas MMP
inhibition during chronic rapid pacing reduced LV wall stress, the
results from this analysis demonstrated persistent defects in
LV myocardial contractile performance.
|
) or with rapid pacing and MMP
inhibition (MMPi) treatment (
) are shown. After
chronic pacing, a significant downward and rightward shift was
observed, which indicates a significant decline in LV ejection
performance.The chamber and myocardial stiffness constants were computed in a subset of pigs from the control, rapid pacing, and rapid pacing with MMP inhibition groups. As reported previously, these indices of LV stiffness properties were examined using the portion of the stress-strain relations in which LV pressures were comparable.40 49 50 51 In the rapid pacing group, the LV chamber stiffness constant, Kc, was unchanged from control values (1.7±0.3 versus 1.7±0.2). The LV myocardial stiffness constant, Km, was higher with rapid pacing, but this did not reach statistical significance (11.4±1.7 versus 8.9±1.2, respectively, P=0.25). In the rapid pacing and MMP inhibition group, both LV chamber and myocardial stiffness constants were increased from control values (3.1±0.5 and 18.3±2.1, respectively, P<0.05).
Plasma renin activity and norepinephrine values increased
by >3-fold in the rapid pacing–only group (Table 2). These
indices of neurohormonal activation were similarly increased with rapid
pacing and concomitant MMP inhibition. There was no difference in LV
mass/body weight in the rapid pacing group compared with sham controls
(3.6±0.2 versus 3.1±0.2 g/kg), and this remained unchanged in the MMP
inhibition group (3.7±0.2 g/kg, P=0.25).
At necropsy, there was some observable pericardial thickening in both rapid pacing groups, but the pericardium was nonadherent to the epicardial surface. Pericardial thickness, computed from fixed and embedded sections, was increased from controls in the rapid pacing group (116±6 versus 220±53 µm, P<0.05) and was also increased in the MMP inhibition group (224±26 µm, P<0.05). No other changes in gross organ appearance or musculoskeletal morphology could be appreciated. The joints and cartilage of all extremities appeared grossly normal.
LV Myocyte Contractility With Rapid Pacing:
Effects of Chronic MMP Inhibition
Myocyte contractile function was examined in >300 LV myocytes
from the sham control group, after 3 weeks of chronic rapid pacing, and
with rapid pacing and concomitant MMP inhibition, and the results are
summarized in Table 3. LV myocyte resting
length was increased in the untreated rapid pacing group when compared
with controls. In the rapid pacing and MMP inhibition group, resting
myocyte length was reduced from untreated rapid pacing values but
remained significantly increased from normal control values.
Steady-state myocyte contractile function was significantly reduced in
the untreated rapid pacing group when compared with normal control
values. In the rapid pacing and MMP inhibition group, indices of
steady-state myocyte contractile function were unchanged from untreated
CHF values. However, the time to peak contraction and total contraction
duration were reduced from rapid pacing–only values. ß-Receptor
stimulation with isoproterenol increased myocyte function from basal
values in all 3 groups. However, in the presence of isoproterenol,
myocyte contractile function was significantly blunted in the untreated
rapid pacing group and the MMP inhibition group when compared with
normal control values. With inotropic stimulation, indices of active
relaxation, such as the time to 50% relaxation and total contraction
duration, were improved in the rapid pacing and MMP inhibition group
when compared with rapid pacing–only values.
|
LV Myocardial Collagen With Rapid Pacing: Effects of MMP
Inhibition
LV myocardial fibrillar collagen structure and relative content
were examined using picrosirius staining and histomorphometry (Figure 6). In the rapid pacing group, the
fibrillar collagen weave surrounding individual myocytes appeared
reduced and disrupted when compared with normal control sections. The
relative collagen volume fraction was reduced in the rapid pacing group
compared with control (4.8±0.8 versus 2.3±0.4%, respectively,
P<0.05). In the rapid pacing and MMP inhibition group, the
fibrillar collagen weave appeared increased between adjoining myocytes.
In addition, specific regions of the myocardium contained a
thickened fibrillar collagen weave. The overall LV myocardial volume
fraction was 10.6±0.9%, which was higher than rapid pacing–only and
control values (P<0.05).
|
LV Myocardial Zymographic Activity With Rapid Pacing: Effects of
MMP Inhibition
LV myocardial MMP zymographic activity was examined in LV
myocardial extracts from the control, rapid pacing, and rapid pacing
with MMP inhibition groups. Zymographic activity was increased in the
rapid pacing group compared with controls (7719±665 versus 4910±854
pixels, P<0.05). In the rapid pacing and MMP inhibition
group, MMP zymographic activity was increased from controls and was
similar to untreated rapid pacing–only values (8583±840 pixels).
During separation and electrophoresis, this in vitro assay system
separates and removes any of the MMP inhibitor from the LV
myocardial samples. Thus, this zymographic assay reflects total LV
myocardial MMP abundance and does not reflect actual MMP activity in
vivo. To more carefully determine the effects of MMP inhibition on
myocardial MMP activity, gelatinase activity was quantified in crude LV
myocardial homogenates in which purification and
electrophoretic separation were not performed (Figure 7). LV myocardial gelatinase activity was
increased in the rapid pacing group at all myocardial extract
concentrations, which indicated increased myocardial MMP activity. In
the MMP inhibition group, myocardial gelatinase activity was
normalized, which provides evidence that the MMP inhibitor
PD166793 decreased MMP activity from rapid pacing values in vivo. In an
additional series of studies, gelatinolytic
activity was examined in LV myocardial extracts after activation with
the organomercurial p-aminophenylmercuric acetate
(APMA).21 23 LV myocardial gelatinase activity after
APMA activation was computed as a percentage change from unstimulated,
basal values (Figure 7). In the pacing CHF group, LV myocardial
gelatinase activity significantly increased from baseline. In the rapid
pacing and MMP inhibition group, LV myocardial gelatinase activity
after APMA stimulation was significantly blunted.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The progression of LV dilation in patients with CHF has been demonstrated to be associated with an increased incidence of morbidity and mortality.1 2 3 4 Furthermore, experimental studies have demonstrated that an attenuation of LV dilation in the setting of CHF was associated with improved survival.8 9 The LV myocardial extracellular matrix has been implicated as playing an important role in maintaining chamber shape and myocyte alignment.10 11 12 13 56 57 Increased activity of the MMPs, an enzyme system responsible for extracellular remodeling, has been reported in both clinical and experimental forms of CHF.5 6 25 26 27 However, whether and to what degree MMP inhibition may influence the LV remodeling process with developing CHF remained unexplored. Chronic rapid pacing in animals has been demonstrated previously to cause LV dilation and pump dysfunction in a progressive and time-dependent manner, which invariably produces severe CHF.5 6 14 15 16 28 29 39 40 41 Accordingly, in the present study, chronic MMP inhibition was instituted in this rapid pacing model to examine the effects on LV function and dimensions in an evolving CHF process. The significant findings of the present study were 2-fold. First, concomitant MMP inhibition with rapid pacing reduced the degree of LV dilation and wall stress, which was accompanied by improved LV endocardial fractional shortening. Second, MMP inhibition during the progression of pacing CHF had minimal effects on indices of LV myocardial and myocyte contractility, which suggests that the basis for the improvement in LV fractional shortening was primarily a reduction in LV load. These findings suggest that a contributory mechanism for the LV remodeling that occurs during the progression of the CHF process is heightened MMP activity within the LV myocardium.
It has been reported previously that the institution of angiotensin-converting enzyme inhibition reduced the degree of LV dilation in a number of cardiac disease states.1 8 9 29 Furthermore, past studies have demonstrated that the effects of angiotensin-converting enzyme inhibition on LV geometry and function were likely due to local myocardial effects rather than to changes in systemic hemodynamics.58 Taken together, these past studies suggest that modulation of local neurohormonal and enzymatic pathways within the LV myocardium may influence the LV remodeling process with CHF. In the present study, MMP inhibition with rapid pacing did not significantly influence systemic blood pressure or neurohormonal profiles when compared with untreated pacing CHF values. Furthermore, with ex vivo myocardial MMP assay systems, the dosing strategy of MMP inhibition used in the present study reduced myocardial MMP proteolytic activity when compared with untreated CHF values. Thus, the reduction in the degree of LV dilation that was achieved with concomitant MMP inhibition and rapid pacing was likely due to inhibition of MMP activity at the level of the LV myocardium rather than secondary to systemic hemodynamic or neurohormonal effects. However, it must be recognized that the present study only focused on the effects of MMP inhibition on the LV myocardium. It has been demonstrated previously that vascular smooth muscle cells elaborate a full complement of MMP species.22 23 24 In light of the fact that MMP inhibition may potentially influence vascular wall architecture, future studies that are focused on measurements of vascular compliance with chronic MMP inhibition are warranted.
In the present study, concomitant MMP inhibition with rapid pacing was associated with an increase in LV endocardial fractional shortening when compared with untreated pacing CHF values. However, it must be recognized that the increase in this index of LV pump function was modest. The LV midwall shortening fraction has been used previously in the setting of LV hypertrophy to quantify myocardial fiber shortening in the circumferential orientation.42 43 In the present study, computed LV midwall shortening was significantly reduced in the pacing CHF group and was unchanged from these values with MMP inhibition. In both pacing CHF groups, the LV ejection-stress relation fell outside of normal limits, which indicated impaired LV myocardial contractile performance. Indeed, the present study demonstrated that the development of pacing-induced CHF was accompanied by diminished myocyte steady-state contractility, which was not significantly affected by MMP inhibition. Thus, with pacing CHF, both in vivo and in vitro indices of contractile performance were depressed and remained reduced with MMP inhibitor treatment. These results suggest that the basis for the increased LV endocardial fractional shortening with rapid pacing and MMP inhibition was primarily a favorable effect on LV remodeling rather than an intrinsic effect on LV myocardial contractile performance.
An important determinant of collagen degradation is activation of the MMPs, which have high selectivity and affinity for components of the extracellular matrix.18 19 20 21 22 23 24 MMPs are secreted in a proenzyme form and are activated through a number of enzymatic pathways.18 19 21 Several past studies using in vitro methodologies have demonstrated that LV myocardial MMP activity was increased in association with changes in LV geometry.5 6 25 26 27 59 Increased LV myocardial MMP activity has been demonstrated in human end-stage cardiomyopathic disease.26 27 Consistent with these past reports, the present study demonstrated significantly increased MMP zymographic activity in LV myocardial extracts after the development of pacing-induced CHF. However, this in vitro observation does not address whether in vivo MMP activity directly contributed to the LV remodeling process with developing CHF. The present study demonstrated that in vivo MMP inhibition significantly influenced the LV remodeling process with chronic rapid pacing. Results from the present study demonstrated that LV MMP zymographic activity, an index of LV myocardial MMP abundance, was unchanged from pacing CHF values with concomitant MMP inhibition. These observations suggest that the attenuation of LV dilation that was achieved with MMP inhibition did not cause a reduction in overall LV myocardial MMP content. Past studies from this laboratory have demonstrated that pacing CHF is associated with increased expression of a number of species of MMPs within the myocardium.5 6 On the basis of the results from the present study, future studies that use more quantitative measures of myocardial MMP species expression with chronic MMP inhibition are warranted. Nevertheless, the unique results from the present study provide direct evidence to suggest that a contributory mechanism for the LV myocardial remodeling that occurs during the progression of a CHF process is increased LV myocardial MMP activity.
Consistent with past reports,5 6 28 29 39 40 41 the LV dilation that occurred with chronic rapid pacing was not associated with a concomitant increase in LV mass. Thus, significant LV myocardial remodeling must occur in this model of pacing-induced CHF. The development of pacing-induced CHF was associated with increased myocyte length. The increased myocyte length parallels the significant LV dilation and myocardial remodeling that occurs in this CHF process.5 28 29 In the present study, MMP inhibition during chronic rapid pacing reduced resting myocyte length. These findings suggest that a contributory cellular mechanism for the reduction in LV dilation with MMP inhibition during chronic rapid pacing is a reduction in myocyte length. As demonstrated in the present study, the increased LV dimension and reduced wall thickness with pacing-induced CHF resulted in significantly elevated LV peak wall stress. The relative degree of LV dilation and wall thinning with concomitant MMP inhibition and rapid pacing was attenuated. Past results provide evidence to suggest that mechanisms for the failure of a significant hypertrophic response with pacing-induced CHF include reduced myocyte cross-sectional area, changes in cytoskeletal protein expression, increased contractile protein degradation rates, and induction of myocyte cell death through apoptosis.14 15 28 29 39 40 41 57 60 61 Whether and to what degree MMP inhibition influenced these cellular and molecular processes with pacing CHF remains to be established.
In light of the fact that the development of CHF is associated with significant alterations in LV loading conditions and neurohormonal systems, the determination of intrinsic properties of contractile performance in vivo can be difficult. Accordingly, isolated LV myocyte contractile function was measured in the normal control state, after chronic rapid pacing, and after MMP inhibition with chronic pacing. Consistent with past reports,5 28 29 41 the development of pacing CHF resulted in diminished indices of steady-state contractile function. Furthermore, pacing-induced CHF caused diminished myocyte inotropic responsiveness after ß-adrenergic receptor stimulation or in the presence of increased extracellular Ca2+. MMP inhibition during chronic rapid pacing did not significantly improve steady-state contractile function and had minimal effects on myocyte inotropic response. It has been demonstrated previously that the rate of LV isovolumic pressure decline, which is an index of active myocardial relaxation, is altered with pacing CHF.40 49 50 51 Indices of active myocyte relaxation, such as the velocity of myocyte lengthening and time to 50% relaxation, were prolonged with pacing CHF. These defects in active myocyte relaxation likely contribute to the prolonged time of isovolumic relaxation that has been reported previously.40 49 50 51 Certain indices of myocyte active relaxation, such as time to 50% relaxation, were reduced in the MMP inhibition group when compared with untreated CHF values. Whether this decrease in the time to 50% of myocyte relaxation can be translated into a measurable change in LV isovolumic relaxation under ambient in vivo conditions remains to be established. It has been postulated that an important system for the translation of myocyte shortening into an overall LV ejection is the collagen-integrin-myocyte cytoskeletal complex.11 12 13 Abnormalities in LV myocyte interactions with the extracellular domain have been reported to occur with pacing CHF.39 Thus, MMP inhibition may have resulted in improved transduction of myocyte shortening into an LV ejection.
The reduced LV dilation that was observed with concomitant MMP inhibition during rapid pacing may have been due, at least in part, to increased myocardial collagen content and improved extracellular support. MMP inhibition was associated with a relative increase in collagen content from both untreated CHF and control values. Changes in the relative composition of the myocardial fibrillar collagen matrix have been implicated in the influence of LV myocardial stiffness characteristics.11 14 17 48 Consistent with past reports from a number of laboratories,40 49 50 51 the present study demonstrated that the LV dilation and myocardial remodeling that occurs with pacing CHF is not associated with significant alterations in LV chamber or myocardial stiffness properties. In an isolated LV heart preparation, Wolff et al50 reported a significant overlap between the diastolic stress-strain relation in normal and pacing CHF preparations. In the present study, indices of LV chamber and myocardial stiffness increased with MMP inhibition. A number of factors influence LV chamber stiffness, such as loading conditions and myocardial active relaxation processes, as well as myocardial stiffness. The findings from the present study demonstrated that the increased LV chamber stiffness with MMP inhibition was likely due to an absolute increase in LV myocardial stiffness. Given that LV myocardial stiffness reflects intrinsic material properties of the myocardium itself, this increase in myocardial stiffness with MMP inhibition was likely due to changes in myocardial collagen content and structure. Thus, whereas MMP inhibition reduced LV chamber dimensions during the development of pacing CHF, this was accompanied by negative effects on LV chamber compliance characteristics and myocardial stiffness properties.
It must be recognized that the present study used only one dosing regimen of MMP inhibition. This dose, which was selected on pharmacokinetic studies, was demonstrated to induce physiological and biological responses in this pacing model of CHF with respect to LV dimensions and wall stress patterns, LV compliance properties, myocardial MMP activity, and relative collagen content. Using an ex vivo gelatinolytic assay system that provided an index of MMP activity in crude LV myocardial extracts, an attenuation of MMP activity from pacing CHF values could be demonstrated in myocardial samples with chronic MMP inhibitor treatment. To more carefully explore whether the myocardial concentration of MMP inhibitor that was achieved with chronic dosing influenced MMP activity, MMP proteolytic activity was examined in myocardial extracts after activation with the organomercurial APMA. It has been demonstrated previously that APMA causes conformational changes in the MMP propeptide and thereby exposes the catalytic domain to the proteolytic substrate.62 In LV myocardial extracts from the chronic MMP inhibition group, total MMP proteolytic activity after APMA stimulation was significantly reduced from untreated pacing CHF values. Furthermore, the myocardial concentration of the MMP inhibitor that was achieved in the present study was demonstrated to produce significant inhibitory effects of MMP-2 activity with an antibody-capture assay. These results demonstrated that significant MMP-inhibitory activity was achieved with the dosing regimen used in the present study. However, it must be recognized that these studies were performed under in vitro conditions and therefore cannot completely represent the degree of in vivo MMP inhibitory activity. For example, using in vitro assay systems, the inhibitor may dissociate from MMP binding sites during preparation of the myocardial samples. Furthermore, the in vitro assay systems used in the present study were performed under optimal conditions. Thus, whether dose-dependent effects of MMP inhibition exist at the level of the myocardium or to what degree alternative dosing strategies would influence the degree of LV dilation, collagen accumulation and myocardial stiffness properties warrant further study.
In the present study, concomitant MMP inhibition ameliorated the LV dilation and increased wall stress that invariably occurs with the progression of pacing CHF. However, it must be recognized that chronic MMP inhibition did not completely prevent the changes in LV size with chronic rapid pacing. In the current experimental preparation, LV stroke volume and cardiac output were not directly measured. It has been demonstrated previously that this model of pacing CHF is associated with an exhaustion of the Frank-Starling mechanism.15 Thus, whether and to what degree the changes in LV geometry that occurred with MMP inhibition influenced the LV preload-ejection relation could not be addressed in the present study. The persistent defects in LV and myocyte function with MMP inhibition and rapid pacing were accompanied by significantly increased neurohormonal system activity. Thus, although the present study suggests that increased LV myocardial MMP activity contributes to the changes in LV geometry in this model of CHF, a number of other cellular and molecular mechanisms contribute to the development and progression of this cardiac disease process. For example, alterations in Ca2+ homeostatic processes, accelerated myofibril degradation, and defects in myocyte intracellular signaling pathways have all been identified to occur with pacing CHF.29 41 60 63
There are a number of species of MMPs that have different specificities to the fibrillar collagens.17 18 19 20 21 22 23 24 Moreover, an important control point of MMP activity is the tissue inhibitors of MMPs (TIMPs).19 20 23 24 These TIMPs form tight complexes with MMPs and therefore play an important role in overall MMP enzymatic activity. The MMP assays performed in the present study could not address whether potential changes in TIMP abundance and/or the stoichiometric relation to specific MMPs may have occurred with pacing CHF or with concomitant MMP inhibition. Thus, an important future direction will be to examine how the activity of specific species of MMPs and the relative association with TIMPs influence the LV remodeling process in the setting of developing CHF. It has been demonstrated previously that a number of proteolytic enzyme systems exist that can contribute to the tissue remodeling process.23 24 For example, the serine proteinases such as plasmin, kallikrein, and elastase make up the largest class of mammalian proteinases and contribute to extracellular remodeling.23 In the present study, MMP inhibition did not completely prevent the degree of LV dilation with rapid pacing. Thus, it is likely that other proteolytic systems contribute to the LV remodeling process in this model of CHF. Nevertheless, the unique findings of the present study suggest that heightened LV myocardial MMP activity contributes to LV remodeling during the progression of the CHF process.
|
Acknowledgments |
|---|
This work was supported in part by NIH Grants HL-59165 and HL-57952 (to F.G.S.), an unrestricted Basic Research Grant from Parke-Davis (to F.G.S.), an American Heart Association Grant-in-Aid (to F.G.S.), and an AHA Medical Student Research Fellowship (to S.B.K.). F.G.S. is an Established Investigator of the AHA. We express our sincere appreciation to Patrick O'Brien (Parke-Davis) for the MMP inhibitor synthesis and characterization studies and to Richard Dyer for providing the MMP-2 catalytic domain and suggestions regarding the in vitro assays.
Received August 10, 1998; accepted June 9, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Konstam MA, Kronenberg MW, Rousseau MF, Udelson JE, Melin J, Stewart D, Dolan N, Edens TR, Ahan S, Kinan D, Howe DM, Kilcoyne L, Metherall J, Benedict C, Yusuf S, Pouleur H, for the SOLVD investigators. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilation in patients with asymptomatic systolic dysfunction. Circulation. 1993;88:2277–2283.
2. Cohn JN, Johnson GR, Shabetai R, Loeb H, Tristani F, Rector T, Smith R, Fletcher R, for the V-HeFT VA Cooperative Studies Group. Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. Circulation. 1993;87(suppl VI):VI5–VI16.
3. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure: Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314;1547–1552.
4. Baughman K. New medical therapies for advanced left ventricular dysfunction. Cardiol Clin. 1995;13:27–34.[Medline] [Order article via Infotrieve]
5.
Spinale FG, Coker ML, Thomas CV, Walker JD,
Mukherjee R, Hebbar L. Time-dependent changes in matrix
metalloproteinase activity and expression during the progression of
congestive heart failure: relation to ventricular and
myocyte function. Circ Res. 1998;82:482–495.
6. Coker ML, Thomas CV, Clair MJ, Hendrick JW, Krombach RS, Galis ZS, Spinale FG. Myocardial matrix metalloproteinase activity and abundance with congestive heart failure. Am J Physiol. 1998;274:H1506–H1523.
7.
Bozkurt B, Kribbs SB, Clubb FJ, Michael LH, Didenko
VV, Hornsby PJ, Seta Y, Oral H, Spinale FG, Mann D.
Pathophysiologically relevant concentrations of
tumor necrosis factor- promote progressive left
ventricular dysfunction and remodeling in rats.
Circulation. 1998;97:1382–1391.
8.
Weinberg EO, Schoen FJ, George D, Kagaya Y, Douglas
PS, Litwin SE, Schunkert H, Benedict CR, Lorell BH.
Angiotensin converting enzyme inhibition prolongs survival
and modifies the transition to heart failure in rats with pressure
overload hypertrophy due to ascending aortic
stenosis. Circulation. 1994;90:1410–1422.
9. Litwin SE, Katz SE, Weinburg EO, Lorell BH, Aurigemma GP, Douglas PS. Serial echocardiographic-Doppler assessment of left ventricular geometry and function in rats with pressure-overload hypertrophy: chronic angiotensin-converting enzyme inhibition attenuates the transition to heart failure. Circulation. 1995;91;2642–2654.
10. Factor SM. Role of extracellular matrix in dilated cardiomyopathy. Heart Failure. 1994;9:260–268.
11. Weber KT, Anversa P, Armstrong PW, Brilla CG, Burnett JC, Cruickshank JM, Devereux RB, Giles TD, Corsgaard N, Leier CV, Mendelsohn FAO, Motz WH, Mulvany MJ, Strauer BE. Remodeling and reparation of the cardiovascular system. J Am Coll Cardiol. 1992;20:3–16.[Abstract]
12. Borg TK, Burgess ML. Holding it all together: organization and function(s) of the extracellular matrix of the heart. Heart Failure. 1993;8:230–238.
13. Borg TK, Terracio L. Interaction of the extracellular matrix with cardiac myocytes during development and disease. In: Robinson TF, Kinne RKH, eds. Cardiac Myocyte-Connective Tissue Interactions in Health and Disease. Basel, Switzerland: Karger; 1990:113–130.
14.
Spinale FG, Tomita M, Zellner JL, Cook JC, Crawford FA,
Zile MR. Collagen remodeling and changes in LV function during
development and recovery from supraventricular
tachycardia. Am J Physiol. 1991;261:H308–H318.
15.
Komamura K, Shannon RP, Ihara T, Shen YT, Mirsky I,
Bishop SP, Vatner SF. Exhaustion of the Frank-Starling mechanism in
conscious dogs with heart failure. Am J Physiol. 1993;265:H1119–H1131.
16.
Weber KT, Pick R, Silver MA, Moe GW, Janicki JS,
Zucker IH, Armstrong PW. Fibrillar collagen and remodeling of dilated
canine left ventricle. Circulation. 1990;82:1387–1401.
17.
Weber KT, Janicki JS, Shroff S. Collagen remodeling of
the pressure-overloaded, hypertrophied nonhuman primate
myocardium. Circ Res. 1988;62:757–765.
18. Woessner FJ. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991;5:2145–2154.[Abstract]
19. Stetler-Stevenson WG. Dynamics of matrix turnover during pathologic remodeling of the extracellular matrix. Am J Pathol. 1996;148:1345–1350.[Medline] [Order article via Infotrieve]
20.
Lee E, Vaughan DE, Parikh SH, Grodzinsky AJ, Libby P,
Lark MW, Lee RT. Regulation of matrix metalloproteinases and
plasminogen activator inhibitor-1
synthesis by plasminogen in cultured human vascular smooth
muscle cells. Circ Res. 1996;78:44–49.
21. Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem. 1997;378:151–160.
22.
Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E,
Unemori EN, Lark MW, Amento E, Libby P. Cytokine stimulated
human vascular smooth muscle cells synthesize a complement of enzymes
required for extracellular matrix digestion. Circ Res. 1994;75:181–189.
23. Werb Z, Alexander CM. Proteinases and matrix degradation. In: Kelley WN, Harris ED, Ruddy S, Sledge CB, eds. Textbook of Rheumatology. Philadelphia, PA: WB Saunders Co Inc; 1993:248–268.
24.
Dollery CM, McEwan JR, Henney AM. Matrix
metalloproteinases and cardiovascular disease.
Circ Res. 1995;77:863–868.
25. Janicki JS, Henegar JR, Campbell SE, Tyagi SC. Myocardial collagenase activity in experimental dilated cardiomyopathy. In: Weber KT, ed. Wound Healing Responses in Cardiovascular Diseases. New York, NY: Futura Press; 1995:73–81.
26.
Thomas CV, Coker ML, Zellner JL, Handy JR, Crumbley
AJ, Spinale FG. Increased matrix metalloproteinase activity and
selective upregulation in LV myocardium from patients with
end-stage dilated cardiomyopathy.
Circulation. 1998;97:1708–1715.
27. Gunja-Smith A, Morales AR, Romanelli R, Woessner JF. Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy. Am J Pathol. 1996;148:1639–1648.[Abstract]
28.
Spinale FG, Fulbright BM, Mukherjee R, Tanaka R, Hu J,
Crawford FA, Zile MR. Relationship between ventricular and
myocyte function with tachycardia induced
cardiomyopathy. Circ Res. 1992;71:174–187.
29. Spinale FG, Holzgrefe HH, Mukherjee R, Hird RB, Walker JD, Arnim AE, Powell JR, Koster WH. Angiotensin converting enzyme inhibition and the progression of congestive cardiomyopathy: effects on left ventricular and myocyte structure and function. Circulation. 1995;92;562–568.
30. Ye QZ, Johnson LL, Hupe DJ, Baragi V. Purification and characterization of the human stromelysin catalytic domain expressed in Escherichia coli. Biochemistry. 1992;31:11231–11235.[Medline] [Order article via Infotrieve]
31. Ye QZ, Johnson LL, Nordan I, Hupe D, Hupe L. A recombinant human stromelysin catalytic domain identifying tryptophan derivatives as human stromelysin inhibitors. J Med Chem. 1994;37:206–209.[Medline] [Order article via Infotrieve]
32. Ye QZ, Johnson LL, Yu AE, Hupe D. Reconstructed 19 kDa domain of gelatinase A is an active proteinase. Biochemistry. 1995;34:4702–4708.[Medline] [Order article via Infotrieve]
33. Bunning P, Homquist B, Riordan JF. Substrate specificity and kinetic characteristics of angiotensin converting enzyme. Biochemistry. 1983;22:103–110.[Medline] [Order article via Infotrieve]
34.
Shipp MA, Vijayaraghavan J, Schmidt EV, Masteller EL,
D'Adamio L, Hersh LB, Reinherz EL. Common acute lymphoblastic leukemia
antigen (CALLA) is active neutral endopeptidase 24.11
(enkephalinase): direct evidence by cDNA transfection analysis.
Proc Natl Acad Sci U S A. 1989;86:297–301.
35. Ahn K, Sisneros A, Herman SB, Pan SM, Hupe D, Lee C, Nikam S, Cheng XM, Doherty AM, Schroeder RL, Haleen SJ, Kaw S, Emoto N, Yanagisawa M. Novel selective quinazoline inhibitors of endothelin converting enzyme-1. Biochem Biophys Res Commun. 1995;243:184–190.
36. Welker P, Lippert U, Nurnberg W, Kruger-Krasagakes S, Moller A, Czarnetzki B. Glucocorticoid induced modulation of cytokine secretion from normal and leukemic human myelomonocytic cells. Int Arch Allergy Immunol. 1996;109:110–115.[Medline] [Order article via Infotrieve]
37. Benedict CR, Weiner DH, Johnstone DE, Bourassa MG, Ghali JK, Nicklas J, Kirlin P, Greenberg B, Quinones MA, Yusuf S for the SOLVD investigators. Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: results of the Studies of Left Ventricular Dysfunction (SOLVD) Registry. J Am Coll Cardiol. 1993;22:146A–153A.
38.
Swedberg K, Eneroth P, Kjekshus J, Willhelmsen L,
for the CONCENSUS trial study group: hormones regulating
cardiovascular function in patients with severe
congestive heart failure and their relation to mortality.
Circulation. 1990;82:1730–1736.
39.
Zellner JL, Spinale FG, Eble DM, Hewett KW, Crawford
FA. Alterations in myocyte shape and basement membrane attachment with
tachycardia induced heart failure. Circ Res. 1991;69:590–600.
40.
Tomita M, Spinale FG, Crawford FA, Zile MR.
Changes in left ventricular volume, mass, and function
during development and regression of supraventricular
tachycardia-induced cardiomyopathy:
disparity between recovery of systolic vs diastolic
function. Circulation. 1991;83:635–644.
41.
Spinale FG, Tempel GE, Mukherjee R, Eble DM, Brown R,
Vacchiano C, Zile MR. Cellular and molecular changes in the
ß-adrenergic receptor system with supraventricular
tachycardia induced cardiomyopathy.
Cardiovasc Res. 1994;28:1243–1250.
42.
Gaasch WH, Zile MR, Hoshino PK, Apstein CS, Blaustein
AS. Stress-shortening relations and myocardial blood flow in
compensated and failing canine hearts with pressure-overload
hypertrophy. Circulation. 1989;79:872–883.
43.
Shimizu G, Zile MR, Blaustein AS, Gaasch WH. Left
ventricular chamber filling and midwall fiber lengthening
in patients with left ventricular hypertrophy:
overestimation of fiber velocities by conventional midwall
measurements. Circulation. 1985;71:266–272.
44. Colan SD, Borrow KM, Neuman A. Left ventricular end-systolic wall stress-velocity of fiber shortening relation: a load independent index of myocardial contractility. J Am Coll Cardiol. 1984;4:715–724.[Abstract]
45. Gaasch WH, Freeman GL. Functional properties of normal and failing hearts. In: McCall D, Rahimtoola SH, eds. Heart Failure. New York, NY: Chapman and Hall; 1995:14–29.
46. Morgan DE, Tomlinson CW, Qayumi AK, Toleikis PM, McConville B, Jamieson WRE. Evaluation of ventricular contractility indexes in the dog with left ventricular dysfunction induced by rapid atrial pacing. J Am Coll Cardiol. 1989;14:489–495.[Abstract]
47. Janicki JS, Matsubara BB. Myocardial collagen and left ventricular diastolic dysfunction. In: Gaasch WH, LeWinter MM, eds. Left Ventricular Diastolic Dysfunction and Heart Failure. Philadelphia, Pa: Lea and Febiger; 1994:125–140.
48.
Kato S, Spinale FG, Tanaka R, Johnson W, Cooper G, Zile
MR. Inhibition of collagen cross-linking: effects on fibrillar collagen
and left ventricular diastolic function.
Am J Physiol. 1995;269:H863–H868.
49.
Solomon SB, Nikolic SD, Glantz SA, Yellin EL. Left
ventricular diastolic function of remodeled
myocardium in dogs with pacing-induced heart failure.
Am J Physiol. 1998;274:H945–H954.
50.
Wolff MR, de Tombe PP, Yasuhiko H, Burkhoff D, Bier S,
Hunter WC, Gertstenblith G, Kass DA. Alterations in left
ventricular mechanics, energetics, and contractile reserve
in experimental heart failure. Circ Res. 1992;70:516–529.
51. Komamura K, Shannon RP, Pasipoularides A, Ihara T, Lader AS, Patrick TA, Bishop SP, Vatner SF. Alterations in left ventricular diastolic function in conscious dogs with pacing induced heart failure. J Clin Invest. 1992;89:1825–1838.
52. Whittaker P, Kloner RA, Boughner DR, Pickering JG. Quantitative assessment of myocardial collagen with picosirius red staining and circularly polarized light. Basic Res Cardiol. 1994;89:397–410.[Medline] [Order article via Infotrieve]
53. Morodomi T, Ogata Y, Sasaguri Y, Morimatsu M, Nagase H. Purification and characterization of matrix metalloproteinase 9 from U937 monocytic leukemia and HT1080 fibrosarcoma cells. Biochem J. 1992;285:603–611.
54.
Barletta J, Angella G, Balch K, Dimova H, Stern G,
Moser M, Setten G, Schultz G. Inhibition of pseudomonal ulceration in
rabbit corneas by a synthetic matrix metalloproteinase
inhibitor. Invest Ophthalmol Vis Sci. 1996;37:20–28.
55. Grobelny D, Poncz L, Galardy R. Inhibition of human skin fibroblast collagenase, thermolysin, and Pseudomonas aeruginosa elastase by peptide hydroxamic acids. Biochemistry. 1992;31:7152–7154.[Medline] [Order article via Infotrieve]
56. Robinson TF, Cohen-Gould L, Factor SM. Skeletal framework of mammalian heart muscle: arrangement of inter- and pericellular connective tissue structures. Lab Invest. 1983;49:482–498.[Medline] [Order article via Infotrieve]
57. Spinale FG. The extracellular matrix with the development and regression from dilated cardiomyopathy. In: Weber KT, ed. Wound Healing Responses in Cardiovascular Diseases. Armonk, NY: Futura Press, Inc; 1995:83–98.
58. Baker KM, Booz GW, Dostal DE. Cardiac actions of angiotensin II: role of an intracardiac renin-angiotensin system. Annu Rev Physiol. 1992;54:227–241.[Medline] [Order article via Infotrieve]
59. Takahashi S, Barry AC, Factor SM. Collagen degradation in ischemic rat hearts. Biochem J. 1990;265:233–241.[Medline] [Order article via Infotrieve]
60.
Eble DM, Walker JD, Mukherjee R, Samarel AM, Spinale
FG. Myosin heavy chain synthesis is increased in a rabbit model of
heart failure. Am J Physiol. 1997;272:H969–H978.
61. Kajstura J, Zhang X, Liu Y, Szoke E, Cheng W, Olivetti G, Hintze TH, Anversa P. The cellular basis of pacing induced cardiomyopathy: myocyte cell loss and myocyte cellular reactive hypertrophy. Circulation. 1995;92;2306–2317.
62. Nagase H, Enghild JJ, Suzuki K, Salvesen G. Stepwise activation mechanisms of the precursor of matrix metalloproteinase 3 (stromelysin) by proteinases and (4-aminophenyl)mercuric acetate. Biochemistry. 1990;29;5783–5789.
63. Perreault CL, Shannon RP, Komamura K, Vatner SF, Morgan JP. Abnormalities in intracellular calcium regulation and contractile function in myocardium from dogs with pacing induced heart failure. J Clin Invest. 1992;89:932–938.
This article has been cited by other articles:
 |
|
 |
|
  J. Zheng, Y. Chen, B. Pat, L. A. Dell'Italia, M. Tillson, A. R. Dillon, P. C. Powell, K. Shi, N. Shah, T. Denney, et al. Microarray Identifies Extensive Downregulation of Noncollagen Extracellular Matrix and Profibrotic Growth Factor Genes in Chronic Isolated Mitral Regurgitation in the Dog Circulation, April 21, 2009; 119(15): 2086 - 2095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. T. Weber, W. B. Weglicki, and R. U. Simpson Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium Cardiovasc Res, February 15, 2009; 81(3): 500 - 508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Jaber, C. Maniu, J. Krysiak, B. P. Shapiro, D. M. Meyer, W. A. Linke, and M. M. Redfield Titin Isoforms, Extracellular Matrix, and Global Chamber Remodeling in Experimental Dilated Cardiomyopathy: Functional Implications and Mechanistic Insight Circ Heart Fail, September 1, 2008; 1(3): 192 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kelly, S. Q. Khan, M. Thompson, G. Cockerill, L. L. Ng, N. Samani, and I. B. Squire Plasma tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9: novel indicators of left ventricular remodelling and prognosis after acute myocardial infarction Eur. Heart J., September 1, 2008; 29(17): 2116 - 2124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Yan, R. T. Yan, F. G. Spinale, R. Afzal, H. R. Gunasinghe, R. E. Stroud, R. S. McKelvie, and P. P. Liu Relationships between plasma levels of matrix metalloproteinases and neurohormonal profile in patients with heart failure Eur J Heart Fail, February 1, 2008; 10(2): 125 - 128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kelly, S. Khan, G. Cockerill, L.L. Ng, M. Thompson, N.J. Samani, and I.B. Squire Circulating Stromelysin-1 (MMP-3): A novel predictor of LV dysfunction, remodelling and all-cause mortality after acute myocardial infarction Eur J Heart Fail, February 1, 2008; 10(2): 133 - 139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Lionetti, L. Guiducci, A. Simioniuc, G. D. Aquaro, C. Simi, D. De Marchi, S. Burchielli, L. Pratali, M. Piacenti, M. Lombardi, et al. Mismatch between uniform increase in cardiac glucose uptake and regional contractile dysfunction in pacing-induced heart failure Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2747 - H2756. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. V. Hojilla, I. Kim, Z. Kassiri, J. E. Fata, H. Fang, and R. Khokha Metalloproteinase axes increase beta-catenin signaling in primary mouse mammary epithelial cells lacking TIMP3 J. Cell Sci., March 15, 2007; 120(6): 1050 - 1060. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Saliaris, L. C. Amado, K. M. Minhas, K. H. Schuleri, S. Lehrke, M. St. John, T. Fitton, C. Barreiro, C. Berry, M. Zheng, et al. Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and beta-adrenergic hyporesponsiveness in heart failure Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1328 - H1335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Lee, T. H. Everett IV, D. Rahmutula, J. M. Guerra, E. Wilson, C. Ding, and J. E. Olgin Pirfenidone Prevents the Development of a Vulnerable Substrate for Atrial Fibrillation in a Canine Model of Heart Failure Circulation, October 17, 2006; 114(16): 1703 - 1712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L. Brower, J. D. Gardner, M. F. Forman, D. B. Murray, T. Voloshenyuk, S. P. Levick, and J. S. Janicki The relationship between myocardial extracellular matrix remodeling and ventricular function. Eur. J. Cardiothorac. Surg., October 1, 2006; 30(4): 604 - 610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Hudson, P. W. Armstrong, W. Ruzyllo, J. Brum, L. Cusmano, P. Krzeski, R. Lyon, M. Quinones, P. Theroux, D. Sydlowski, et al. Effects of Selective Matrix Metalloproteinase Inhibitor (PG-116800) to Prevent Ventricular Remodeling After Myocardial Infarction: Results of the PREMIER (Prevention of Myocardial Infarction Early Remodeling) Trial J. Am. Coll. Cardiol., July 4, 2006; 48(1): 15 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Morita, S. Khanal, S. Rastogi, G. Suzuki, M. Imai, A. Todor, V. G. Sharov, S. Goldstein, T. P. O'Neill, and H. N. Sabbah Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2522 - H2527. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Paolocci, B. Tavazzi, R. Biondi, Y. A. Gluzband, A. M. Amorini, C. G. Tocchetti, M. Hejazi, P. M. Caturegli, J. Kajstura, G. Lazzarino, et al. Metalloproteinase Inhibitor Counters High-Energy Phosphate Depletion and AMP Deaminase Activity Enhancing Ventricular Diastolic Compliance in Subacute Heart Failure J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 506 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Gavira, J. Herreros, A. Perez, M. J. Garcia-Velloso, J. Barba, F. Martin-Herrero, C. Canizo, A. Martin-Arnau, J. M. Marti-Climent, M. Hernandez, et al. Autologous skeletal myoblast transplantation in patients with nonacute myocardial infarction: 1-year follow-up J. Thorac. Cardiovasc. Surg., April 1, 2006; 131(4): 799 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Vanhoutte, M. Schellings, Y. Pinto, and S. Heymans Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: A temporal and spatial window Cardiovasc Res, February 15, 2006; 69(3): 604 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Janicki, G. L. Brower, J. D. Gardner, M. F. Forman, J. A. Stewart Jr., D. B. Murray, and A. L. Chancey Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload Cardiovasc Res, February 15, 2006; 69(3): 657 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Menon, M. Singh, R. S. Ross, J. N. Johnson, and K. Singh {beta}-Adrenergic receptor-stimulated apoptosis in adult cardiac myocytes involves MMP-2-mediated disruption of {beta}1 integrin signaling and mitochondrial pathway Am J Physiol Cell Physiol, January 1, 2006; 290(1): C254 - C261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. M. Greer, D. P. Ware, and D. J. Lefer Myocardial infarction and heart failure in the db/db diabetic mouse Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H146 - H153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Blom, R. Mukherjee, J. J. Pilla, A. S. Lowry, W. M. Yarbrough, J. T. Mingoia, J. W. Hendrick, R. E. Stroud, J. E. McLean, J. Affuso, et al. Cardiac Support Device Modifies Left Ventricular Geometry and Myocardial Structure After Myocardial Infarction Circulation, August 30, 2005; 112(9): 1274 - 1283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Ikonomidis, J. R. Barbour, Z. Amani, R. E. Stroud, A. R. Herron, D. M. McClister Jr, S. E. Camens, M. L. Lindsey, R. Mukherjee, and F. G. Spinale Effects of Deletion of the Matrix Metalloproteinase 9 Gene on Development of Murine Thoracic Aortic Aneurysms Circulation, August 30, 2005; 112(9_suppl): I-242 - I-248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Nagaya, K. Kangawa, T. Itoh, T. Iwase, S. Murakami, Y. Miyahara, T. Fujii, M. Uematsu, H. Ohgushi, M. Yamagishi, et al. Transplantation of Mesenchymal Stem Cells Improves Cardiac Function in a Rat Model of Dilated Cardiomyopathy Circulation, August 23, 2005; 112(8): 1128 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Vellaichamy, M. L. Khurana, J. Fink, and K. N. Pandey Involvement of the NF-{kappa}B/Matrix Metalloproteinase Pathway in Cardiac Fibrosis of Mice Lacking Guanylyl Cyclase/Natriuretic Peptide Receptor A J. Biol. Chem., May 13, 2005; 280(19): 19230 - 19242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Lindsey, D. K. Goshorn, C. E. Squires, G. P. Escobar, J. W. Hendrick, J. T. Mingoia, S. E. Sweterlitsch, and F. G. Spinale Age-dependent changes in myocardial matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles and fibroblast function Cardiovasc Res, May 1, 2005; 66(2): 410 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Banfi, V. Cavalca, F. Veglia, M. Brioschi, S. Barcella, L. Mussoni, L. Boccotti, E. Tremoli, P. Biglioli, and P. Agostoni Neurohormonal activation is associated with increased levels of plasma matrix metalloproteinase-2 in human heart failure Eur. Heart J., March 1, 2005; 26(5): 481 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Yan, R. T. Yan, and P. P. Liu Narrative Review: Pharmacotherapy for Chronic Heart Failure: Evidence from Recent Clinical Trials Ann Intern Med, January 18, 2005; 142(2): 132 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Heymans, F. Lupu, S. Terclavers, B. Vanwetswinkel, J.-M. Herbert, A. Baker, D. Collen, P. Carmeliet, and L. Moons Loss or Inhibition of uPA or MMP-9 Attenuates LV Remodeling and Dysfunction after Acute Pressure Overload in Mice Am. J. Pathol., January 1, 2005; 166(1): 15 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Ikonomidis, J. W. Hendrick, A. M. Parkhurst, A. R. Herron, P. G. Escobar, K. B. Dowdy, R. E. Stroud, E. Hapke, M. R. Zile, and F. G. Spinale Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H149 - H158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Bachetti, L. Comini, E. Pasini, and R. Ferrari Anti-cytokine therapy in chronic heart failure: new approaches and unmet promises Eur. Heart J. Suppl., November 1, 2004; 6(suppl_F): F16 - F21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Xie, M. Singh, and K. Singh Differential Regulation of Matrix Metalloproteinase-2 and -9 Expression and Activity in Adult Rat Cardiac Fibroblasts in Response to Interleukin-1{beta} J. Biol. Chem., September 17, 2004; 279(38): 39513 - 39519. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Moriwaki, A. Stempien-Otero, M. Kremen, A. E. Cozen, and D. A. Dichek Overexpression of Urokinase by Macrophages or Deficiency of Plasminogen Activator Inhibitor Type 1 Causes Cardiac Fibrosis in Mice Circ. Res., September 17, 2004; 95(6): 637 - 644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Jayasankar, Y. J. Woo, L. T. Bish, T. J. Pirolli, M. F. Berry, J. Burdick, R. C. Bhalla, R. V. Sharma, T. J. Gardner, and H. L. Sweeney Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy Circulation, September 14, 2004; 110(11_suppl_1): II-180 - II-186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Villars, S. K. Hamlin, A. D. Shaw, and J. T. Kanusky Role of Diastole in Left Ventricular Function, I: Biochemical and Biomechanical Events Am. J. Crit. Care., September 1, 2004; 13(5): 394 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sundstrom, J. C. Evans, E. J. Benjamin, D. Levy, M. G. Larson, D. B. Sawyer, D. A. Siwik, W. S. Colucci, P. W.F. Wilson, and R. S. Vasan Relations of plasma total TIMP-1 levels to cardiovascular risk factors and echocardiographic measures: the Framingham heart study Eur. Heart J., September 1, 2004; 25(17): 1509 - 1516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yamamoto, Y. Takahashi, T. Mano, Y. Sakata, N. Nishikawa, J. Yoshida, Y. Oishi, M. Hori, T. Miwa, S. Inoue, et al. N-Methylethanolamine attenuates cardiac fibrosis and improves diastolic function: inhibition of phospholipase D as a possible mechanism Eur. Heart J., July 2, 2004; 25(14): 1221 - 1229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sundstrom, J. C. Evans, E. J. Benjamin, D. Levy, M. G. Larson, D. B. Sawyer, D. A. Siwik, W. S. Colucci, P. Sutherland, P. W.F. Wilson, et al. Relations of Plasma Matrix Metalloproteinase-9 to Clinical Cardiovascular Risk Factors and Echocardiographic Left Ventricular Measures: The Framingham Heart Study Circulation, June 15, 2004; 109(23): 2850 - 2856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sakata, K. Yamamoto, T. Mano, N. Nishikawa, J. Yoshida, M. Hori, T. Miwa, and T. Masuyama Activation of Matrix Metalloproteinases Precedes Left Ventricular Remodeling in Hypertensive Heart Failure Rats: Its Inhibition as a Primary Effect of Angiotensin-Converting Enzyme Inhibitor Circulation, May 4, 2004; 109(17): 2143 - 2149. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. KJAeR Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading Physiol Rev, April 1, 2004; 84(2): 649 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Diwan, Z. Dibbs, S. Nemoto, G. DeFreitas, B. A. Carabello, N. Sivasubramanian, E. M. Wilson, F. G. Spinale, and D. L. Mann Targeted Overexpression of Noncleavable and Secreted Forms of Tumor Necrosis Factor Provokes Disparate Cardiac Phenotypes Circulation, January 20, 2004; 109(2): 262 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Tonduangu, L. Hittinger, B. Ghaleh, P. Le Corvoisier, L. Sambin, S. Champagne, T. Badoual, F. Vincent, A. Berdeaux, B. Crozatier, et al. Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs Circulation, January 6, 2004; 109(1): 114 - 119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Chapman and F. G. Spinale Extracellular protease activation and unraveling of the myocardial interstitium: critical steps toward clinical applications Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H1 - H10. [Full Text] [PDF]
|
|
|
|
|
|
K. Kameda, T. Matsunaga, N. Abe, H. Hanada, H. Ishizaka, H. Ono, M. Saitoh, K. Fukui, I. Fukuda, T. Osanai, et al. Correlation of oxidative stress with activity of matrix metalloproteinase in patients with coronary artery disease: Possible role for left ventricular remodelling Eur. Heart J., December 2, 2003; 24(24): 2180 - 2185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Lindsey, J. Yoshioka, C. MacGillivray, S. Muangman, J. Gannon, A. Verghese, M. Aikawa, P. Libby, S. M. Krane, and R. T. Lee Effect of a Cleavage-Resistant Collagen Mutation on Left Ventricular Remodeling Circ. Res., August 8, 2003; 93(3): 238 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Boixel, V. Fontaine, C. Rucker-Martin, P. Milliez, L. Louedec, J.-B. Michel, M.-P. Jacob, and S. N. Hatem Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat J. Am. Coll. Cardiol., July 16, 2003; 42(2): 336 - 344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Menasche Skeletal muscle satellite cell transplantation Cardiovasc Res, May 1, 2003; 58(2): 351 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Al Attar, C. Carrion, S. Ghostine, I. Garcin, J.-T. Vilquin, A. A. Hagege, and P. Menasche Long-term (1 year) functional and histological results of autologous skeletal muscle cells transplantation in rat Cardiovasc Res, April 1, 2003; 58(1): 142 - 148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. M. Yarbrough, R. Mukherjee, T. A. Brinsa, K. B. Dowdy, A. A. Scott, G. P. Escobar, C. Joffs, D. G. Lucas, F. A. Crawford Jr, and F. G. Spinale Matrix metalloproteinase inhibition modifies left ventricular remodeling after myocardial infarction in pigs J. Thorac. Cardiovasc. Surg., March 1, 2003; 125(3): 602 - 610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Nishikawa, K. Yamamoto, Y. Sakata, T. Mano, J. Yoshida, T. Miwa, H. Takeda, M. Hori, and T. Masuyama Differential activation of matrix metalloproteinases in heart failure with and without ventricular dilatation Cardiovasc Res, March 1, 2003; 57(3): 766 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. King, M. L. Coker, A. Goldberg, J. H. McElmurray III, H. R. Gunasinghe, R. Mukherjee, M. R. Zile, T. P. O'Neill, and F. G. Spinale Selective Matrix Metalloproteinase Inhibition With Developing Heart Failure: Effects on Left Ventricular Function and Structure Circ. Res., February 7, 2003; 92(2): 177 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Mukherjee, T. A. Brinsa, K. B. Dowdy, A. A. Scott, J. M. Baskin, A. M. Deschamps, A. S. Lowry, G. P. Escobar, D. G. Lucas, W. M. Yarbrough, et al. Myocardial Infarct Expansion and Matrix Metalloproteinase Inhibition Circulation, February 4, 2003; 107(4): 618 - 625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kashem, S. Hassan, D. L. Crabbe, D. B. Melvin, and W. P. Santamore Left ventricular reshaping: Effects on the pressure-volume relationship J. Thorac. Cardiovasc. Surg., February 1, 2003; 125(2): 391 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Briest, A. Holzl, B. Rassler, A. Deten, H. A Baba, and H.-G. Zimmer Significance of matrix metalloproteinases in norepinephrine-induced remodelling of rat hearts Cardiovasc Res, February 1, 2003; 57(2): 379 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Qun Gao, G. Sawicki, W. L Suarez-Pinzon, T. Csont, M. Wozniak, P. Ferdinandy, and R. Schulz Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction Cardiovasc Res, February 1, 2003; 57(2): 426 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Baicu, J. D. Stroud, V. A. Livesay, E. Hapke, J. Holder, F. G. Spinale, and M. R. Zile Changes in extracellular collagen matrix alter myocardial systolic performance Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H122 - H132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E. J. M. Creemers, J. N. Davis, A. M. Parkhurst, P. Leenders, K. B. Dowdy, E. Hapke, A. M. Hauet, P. G. Escobar, J. P. M. Cleutjens, J. F. M. Smits, et al. Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H364 - H371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. Bradham Jr, H. Gunasinghe, J. R. Holder, M. Multani, D. Killip, M. Anderson, D. Meyer, W. H. Spencer III, G. Torre-Amione, and F. G. Spinale Release of matrix metalloproteinases following alcohol septal ablation in hypertrophic obstructive cardiomyopathy J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2165 - 2173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Manabe, T. Shindo, and R. Nagai Gene Expression in Fibroblasts and Fibrosis: Involvement in Cardiac Hypertrophy Circ. Res., December 13, 2002; 91(12): 1103 - 1113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Reinhardt, H H Sigusch, J Hensse, S C Tyagi, R Korfer, and H R Figulla Cardiac remodelling in end stage heart failure: upregulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP Heart, December 1, 2002; 88(5): 525 - 530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pauschinger, K. Chandrasekharan, J. Li, W. Poller, M. Noutsias, C. Tschope, and H.-P. Schultheiss Inflammation and extracellular matrix protein metabolism: two sides of myocardial remodelling Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I49 - I53. [Abstract] [PDF]
|
|
|
|
|
|
D. Li, V. Williams, L. Liu, H. Chen, T. Sawamura, T. Antakli, and J. L. Mehta LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1795 - H1801. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Schwartzkopff, M. Fassbach, B. Pelzer, M. Brehm, and B. E. Strauer Elevated serum markers of collagen degradation in patients with mild to moderate dilated cardiomyopathy Eur J Heart Fail, August 1, 2002; 4(4): 439 - 444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G.F Bronzwaer, C. Zeitz, C. A Visser, and W. J Paulus Endomyocardial nitric oxide synthase and the hemodynamic phenotypes of human dilated cardiomyopathy and of athlete's heart Cardiovasc Res, August 1, 2002; 55(2): 270 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nakamura, K. Egashira, Y. Machida, S. Hayashidani, M. Takeya, H. Utsumi, H. Tsutsui, and A. Takeshita Probucol Attenuates Left Ventricular Dysfunction and Remodeling in Tachycardia-Induced Heart Failure: Roles of Oxidative Stress and Inflammation Circulation, July 16, 2002; 106(3): 362 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Stroud, C. F. Baicu, M. A. Barnes, F. G. Spinale, and M. R. Zile Viscoelastic properties of pressure overload hypertrophied myocardium: effect of serine protease treatment Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2324 - H2335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Thompson and I. B. Squire Matrix metalloproteinase-9 expression after myocardial infarction: physiological or pathological? Cardiovasc Res, June 1, 2002; 54(3): 495 - 498. [Full Text] [PDF]
|
|
|
|
|
|
Y. Iwanaga, T. Aoyama, Y. Kihara, Y. Onozawa, T. Yoneda, and S. Sasayama Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats J. Am. Coll. Cardiol., April 17, 2002; 39(8): 1384 - 1391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. Bradham, G. Moe, K. A. Wendt, A. A. Scott, A. Konig, M. Romanova, G. Naik, and F. G. Spinale TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1288 - H1295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Zile and D. L. Brutsaert New Concepts in Diastolic Dysfunction and Diastolic Heart Failure: Part II: Causal Mechanisms and Treatment Circulation, March 26, 2002; 105(12): 1503 - 1508. [Full Text] [PDF]
|
|
|
|
|
|
F. G. Spinale Matrix Metalloproteinases: Regulation and Dysregulation in the Failing Heart Circ. Res., March 22, 2002; 90(5): 520 - 530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Zile and D. L. Brutsaert New Concepts in Diastolic Dysfunction and Diastolic Heart Failure: Part I: Diagnosis, Prognosis, and Measurements of Diastolic Function Circulation, March 19, 2002; 105(11): 1387 - 1393. [Full Text] [PDF]
|
|
|
|
|
|
P. W.M. Fedak, R. D. Weisel, T. M. Yau, D. A.G. Mickle, and R.-K. Li Cell transplantation, ventricular remodeling, and the extracellular matrix J. Thorac. Cardiovasc. Surg., March 1, 2002; 123(3): 584 - 585. [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
T. Walther, A. Schubert, V. Falk, C. Binner, A. Kanev, S. Bleiziffer, C. Walther, N. Doll, R. Autschbach, and F. W. Mohr Regression of Left Ventricular Hypertrophy After Surgical Therapy for Aortic Stenosis Is Associated With Changes in Extracellular Matrix Gene Expression Circulation, September 18, 2001; 104 (2009): I-54 - I-58. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Etoh, C. Joffs, A. M. Deschamps, J. Davis, K. Dowdy, J. Hendrick, S. Baicu, R. Mukherjee, M. Manhaini, and F. G. Spinale Myocardial and interstitial matrix metalloproteinase activity after acute myocardial infarction in pigs Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H987 - H994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sivasubramanian, M. L. Coker, K. M. Kurrelmeyer, W. R. MacLellan, F. J. DeMayo, F. G. Spinale, and D. L. Mann Left Ventricular Remodeling in Transgenic Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor Circulation, August 14, 2001; 104(7): 826 - 831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E.J.M. Creemers, J. P.M. Cleutjens, J. F.M. Smits, and M. J.A.P. Daemen Matrix Metalloproteinase Inhibition After Myocardial Infarction: A New Approach to Prevent Heart Failure? Circ. Res., August 3, 2001; 89(3): 201 - 210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Coker, J. R. Jolly, C. Joffs, T. Etoh, J. R. Holder, B. R. Bond, and F. G. Spinale Matrix metalloproteinase expression and activity in isolated myocytes after neurohormonal stimulation Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H543 - H551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Dolgilevich, F. M. Siri, S. A. Atlas, and C. Eng Changes in collagenase and collagen gene expression after induction of aortocaval fistula in rats Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H207 - H214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Peterson, H. Hallak, L. Johnson, H. Li, P. M. O'Brien, D. R. Sliskovic, T. M. A. Bocan, M. L. Coker, T. Etoh, and F. G. Spinale Matrix Metalloproteinase Inhibition Attenuates Left Ventricular Remodeling and Dysfunction in a Rat Model of Progressive Heart Failure Circulation, May 8, 2001; 103(18): 2303 - 2309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
P. Libby and R. T. Lee Matrix Matters Circulation, October 17, 2000; 102(16): 1874 - 1876. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
Y. Y. Li, C. F. McTiernan, and A. M. Feldman Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling Cardiovasc Res, May 1, 2000; 46(2): 214 - 224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G Spinale, M. L Coker, B. R Bond, and J. L Zellner Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target Cardiovasc Res, May 1, 2000; 46(2): 225 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, H. Simon, T. M.A. Bocan, and J.T. Peterson MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect of ACE- and MMP-inhibition Cardiovasc Res, May 1, 2000; 46(2): 298 - 306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.T. Peterson, H. Li, L. Dillon, and J. W. Bryant Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat Cardiovasc Res, May 1, 2000; 46(2): 307 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Lindsey, J. Gannon, M. Aikawa, F. J. Schoen, E. Rabkin, L. Lopresti-Morrow, J. Crawford, S. Black, P. Libby, P. G. Mitchell, et al. Selective Matrix Metalloproteinase Inhibition Reduces Left Ventricular Remodeling but Does Not Inhibit Angiogenesis After Myocardial Infarction Circulation, February 12, 2002; 105(6): 753 - 758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||