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From the Departments of Pathology*
and
Pharmacology,
Cardiovascular Research
Institute Maastricht, Universiteit Maastricht, The Netherlands; and the
Center for Transgene Technology and Gene
Therapy,
Katholieke Universiteit
Leuven, Leuven, Belgium
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MI was induced surgically by permanent ligation of the main left coronary artery as recently described.7 Tissue processing and architectural measurements were adapted from the same study.
Infusion of 5'-Bromo-2'-Deoxyuridine (BrdU)
To label DNA-synthesizing cells, all animals in the 2-week post-MI and sham group received BrdU (Serva, Heidelberg, Germany; infusion rate 13 mg/kg/day) from an osmotic minipump (Alzet 2001, Alza Corp., Palo Alto, CA), 7 days before sacrifice.
Immunohistochemistry
Immunohistochemistry was performed on the 1-, 2-, and 5-week
groups, using conventional methods to identify macrophages (moma-2
monoclonal antibody),8
endothelial cells (biotin-labeled
lectin from Bandeiraea simplicifolia, Sigma Chemicals, St.
Louis, MO),9
smooth muscle cells and myofibroblasts
(monoclonal anti-
-smooth muscle cell actin (-sma), DAKO,
Danmark), laminin (polyclonal anti-mouse laminin),10
and
DNA synthesis (monoclonal anti-BrdU, Harlan Sera-Lab, Loughborough,
UK). For quantification of DNA synthesis, the total labeling fraction
(LF; number of BrdU-positive/total numbers of counted nuclei x
100%) of BrdU-positive cells was calculated per 0.1
mm2
in the center and border zones of the
infarcts and in the non-infarcted septum. Apoptosis was studied in the
2-week postsurgery groups by means of the Terminal Transferase dUTP
nick end labeling (TUNEL) assay as described by Kockx et
al.11
For quantification of apoptotic cells, total numbers
of nuclei and percentage of TUNEL-positive nuclei were counted in the
whole infarcted area. DNA synthesis and apoptosis were studied in the
2-week postsurgery groups.
Myocardial MMP Extraction and Zymography
A separate group of animals (6 Plg-/-, 4 Plg+/+) was sacrificed 2 weeks after surgery for myocardial MMP activity analysis. The hearts were perfused with saline and the LV free walls were rapidly frozen in liquid nitrogen and stored at -80°C. The frozen tissue was cut into small pieces, washed with cold saline, and incubated in 100 µl extraction buffer (10 mmol/L cacodylic acid, pH 5.0, 0.15 mmol/L NaCl, 1 µmol/L ZnCl2, 20 mmol/L CaCl2, 1.5 mmol/L NaN3, and 0.01% Triton X-100) per 10 mg wet weight at 4°C with continuous agitation for 24 hours. This step was repeated with fresh buffer. The extraction buffer was collected and pH raised to 7.5 by addition of 1 mol/L Tris, pH 8.0. MMP activity was visualized using the zymography technique.12 In short, 10 µg of myocardial protein extracts were loaded per lane onto electrophoretic gels (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) containing gelatin (0.66 mg/ml). After electrophoresis, gels were washed twice for 15 minutes with 2.5% Triton X-100 and incubated overnight at 37°C in substrate buffer (50 mmol/L Tris-HCl, pH 8.0, 5 mmol/L CaCl2, 0.02% sodium nitrate). After incubation, gels were stained for 30 minutes in 0.05% Coomassie brilliant blue R250 in acetic acid:methanol:water (1:4:5) and destained in the same solvent. In each gel a reference sample was used to normalize scanned lytic activities between gels.
Hemodynamic Measurements
Cardiac output (CO) was evaluated in sham-operated and infarcted mice 2 weeks after surgery. In short, an electromagnetic flow-probe (1.2 mm; Skalar, Delft, The Netherlands) was placed on the ascending aorta, adjacent to its exit from the heart and connected to a Skalar MDL400 sine-wave flowmeter. An abdominal aorta catheter was connected to a pressure transducer (microswitch, model 156PC 156 WL, Honeywell, Amsterdam, The Netherlands). Signals were sampled at a rate of 2 kHz and fed into a personal computer for off-line analysis. After collecting baseline values of cardiac output (COrest) for 15 minutes, a rapid intravenous infusion (2.5 ml in 1 minute) of a warm (37°C) Ringer’s solution was started. This procedure increased CO to a plateau value. In a pilot study in Swiss mice, we observed an increase in CO from 7.9 ± 0.4 to 21.1 ± 0.7 ml/minute in sham-operated mice and from 5.7 ± 0.4 to 15 ± 1.4 ml/minute in MI mice.
For pressure measurements, a separate group of animals (n = 5–6 per group) were anesthesized with urethane (2.1 mg/g body weight, subcutaneously, Sigma). A 1.4 French high-fidelity catheter tip micromanometer (SPR-671; Millar Instruments, Houston, TX) was inserted through the right carotid artery in the left ventricular cavity. After hemodynamic stabilization, left ventricular pressure was sampled with a computer at a rate of 2 kHz, and stored for analysis of left ventricular systolic pressure (LVSP), end-diastolic pressure (LVEDP), and maximal positive (dP/dtmax) rate of pressure development. Increasing amounts of dobutamine (0.5, 1.0, 1.5, 2, and 3 ng/g/minute; Dobutrix, Lilly, Brussels, Belgium) were administered for 2 minutes each by continuous infusion in the left external jugular vein, via a catheter connected to a Harvard microinjection pump (Harvard Apparatus Inc., Holliston, MA). Pressure measurements were performed after 90 seconds’ dobutamine infusion.
Statistics
All above described parameters were measured without knowledge of the treatment group. Data are expressed as means ± SE. Means between groups were compared by the use of the Mann-Whittney U test. A P value <0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Histological examination of the Plg-/- infarcts demonstrated a
complete absence of cardiac wound healing and the persistence of
necrotic cardiomyocytes in the center of the Plg-/- infarcts, which
remained present as ghost cells until at least 5 weeks after MI (Figure 1, a and b)
. In both Plg-/- and Plg+/+
infarcts, 1 to 2 cell layers of cardiomyocytes in endocardium and
epicardium survived the MI. The basement membranes that surrounded the
cardiomyocytes were still visible in the Plg-/- infarcts, as
demonstrated by laminin immunohistochemistry 1, 2, and 5 weeks after MI
(Figure 1, c and d)
. The intensity of the laminin staining around the
necrotic cardiomyocytes in Plg-/- infarcts was slightly decreased in
time when compared to normal cardiomyocytes. The absent wound healing
in the Plg-/- mice was associated with a lack of influx of
macrophages into the infarct. Also, myofibroblasts and endothelial
cells were scarcely present in the center of 2- and 5-week-old Plg-/-
infarcts.
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, endothelial cells (lectin
staining, data not shown), and -smooth muscle actin-positive cells
(eg, myofibroblast-like cells and smooth muscle cells; Figure 2, c and d
).
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Sirius red staining demonstrated extensive collagen deposition in
Plg+/+ infarcts, but not in Plg-/- infarcts, 2 weeks after surgery
(Figure 3, a and b)
. Quantification
revealed relative collagen positive areas of 48.0 ± 12.1% in the
center of Plg+/+ infarcts and greatly reduced collagen deposition in
Plg-/- infarcts (0.7 ± 0.3%, P = 0.002, Figure 4
), and comparable to that in the
sham-operated animals. The border zones of Plg-/- infarcts revealed
some collagen deposition, although much less than in the Plg+/+
infarcts. In situ hybridization using a type I collagen
probe13
demonstrated diffuse collagen expression
throughout the entire Plg+/+ infarct. Type I collagen mRNA expression
was restricted to the border zones and the endo- and epicardial layers
in Plg-/- infarcts (Figure 3, c and d)
.
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Total cell numbers were lower in the center of 2-week Plg-/-
infarcts (180 ± 130 cells per 0.1 mm2) than
of Plg+/+ infarcts (910 ± 160 cells, P = 0.004,
Figure 5
). Measurement of DNA synthesis
by BrdU labeling (Figure 2, e and f)
yielded similar percentages of
BrdU-positive nuclei in the Plg-/- (23 ± 7%) and Plg+/+
(26 ± 5%, P = 0.33) infarcts, indicating that
the proliferative capacity of the Plg-/- cells is not reduced. Also,
the percentage of apoptotic cells, measured by the TUNEL staining
technique, was not significantly different in the Plg+/+ (0.4 ±
0.2%) and Plg-/- (0.4 ± 0.3%, P = 0.64)
infarcts, 2 weeks after MI (Figure 5)
. Thus, the absent wound healing
in Plg-/- mice is the consequence of abolished cell migration, not of
cell turnover.
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The occurrence of architectural changes shortly after the onset of
MI are well established: the infarcted left ventricle dilates, the
infarcted wall becomes thinner, and the non-infarcted septum undergoes
hypertrophy. These cardiac adaptations are normal compensatory
mechanisms after infarction to maintain stroke volume at an adequate
level.14
In the present study, all these architectural
changes were observed 2 and 5 weeks after MI, in both the Plg-/- and
Plg+/+ infarcted hearts (Table 1)
.
Infarct sizes, left ventricular lumen areas (measure for LV
dilatation), and septum thicknesses were not significantly
different between the two infarct groups. However, the infarcted wall
of the Plg-/- hearts remained thicker than that of Plg+/+ hearts
(0.45 ± 0.06 vs. 0.23 ± 0.03 mm,
P = 0.004), as clearly shown in Figure 6
. These thicker infarcted walls of the
Plg-/- mice probably account for the increased heart weights,
observed in the Plg-/- infarcts (Table 1)
.
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Gelatin zymography on murine left ventricular tissue reveals four
distinct proteins with gelatinase activity (Figure 7)
. The identity of these gelatinolytic
bands in mouse tissue extracts has been described by
others.15
The top band (~97 kd) represents MMP-9. Three
bands with molecular weights of ~72, ~66, and ~60 kd represent,
respectively, the proenzyme form, intermediate form, and active forms
of MMP-2. Quantification of the intensities of the bands demonstrated a
down-regulation in the activity of MMP-9 (77%) and active MMP-2 (49%)
in 2-week-old Plg-/- infarcted hearts (Figure 7)
. We observed no
differences in the intensity of the 66-kd band between the two strains
and a 40% decrease in the activity of the 72-kd band in the Plg-/-
mice. No differences in MMP activity were seen between sham-operated
Plg-/- and Plg+/+ mice.
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Cardiac function was evaluated 2 weeks after surgery by measuring
the rate of pressure development in the hearts
(dP/dtmax) and cardiac output levels (CO). Under
basal conditions, contractility (dP/dtmax) was
similar in the infarcted Plg+/+ and Plg-/- hearts. However, after
inotropic stimulation by dobutamine, dP/dtmax was
blunted in the Plg-/- infarcted hearts as compared to the wild-types
(Figure 8)
. Heart rate responses to
dobutamine were similar in all groups (data not shown).
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. We therefore maximally
challenged the hearts by a rapid intravenous fluid load. In rats, it
has previously been shown that volume overload elevates cardiac output
(CO) to maximal values during the last 10 to 15 seconds of a 1-minute
fluid load and that infarction blunts the increase in CO proportional
to the degree of heart failure.14,16
After volume
overload in Plg-/- and Plg+/+ mice, CO levels were comparably blunted
in both infarct groups when compared to the shams
(n = 3–5 per group, Table 2
). Taken together,
these measurements demonstrate impaired function in the Plg-/-
infarcted hearts during mild stimulation and equalization of cardiac
output in the two strains at extreme loads.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Early events of tissue repair after MI include migration of inflammatory cells into the wound and degradation of the extracellular matrix and necrotic cardiomyocytes.12 Inflammatory cells migrate into the wound by degrading the extracellular matrix surrounding the cardiomyocytes, using proteinases such as plasmin, MMPs, and cathepsins.17 In the present study, the infiltration of macrophages, (myo)fibroblasts, and endothelial cells was found to be abolished in the absence of plasminogen for at least 5 weeks after MI. This indicates that plasmin is required for cellular infiltration into the infarct, either directly by extracellular matrix proteolysis, or indirectly through activation of MMPs. In fact, decreased activity of MMP-9 and active MMP-2 was found in the Plg-/- infarcts compared to the wild-types. The intensity of the latent MMP-2 band was suppressed to a smaller extent in Plg-/- infarcts. This indicates that de novo synthesis of MMP-2 is barely affected. The small effect of Plg deficiency on the amount of latent MMP-2 suggest that MMP-2 activity is decreased due to inhibited activation of pro-MMP-2, rather than to a reduced synthesis. This indicates also that the effect of plasmin on infarct healing is at least partly mediated by activation of MMP-9 and MMP-2. This is supported by the finding that mice deficient in MMP-9 showed a reduction in the infiltration of leukocytes into the infarct and were protected against cardiac rupture.2 In the present study, we were unable to investigate the role of plasminogen in the development of left ventricular rupture, because cardiac rupture did not take place in Plg-/- and in only one Plg+/+ infarct.
The role of plasminogen in cardiac wound healing as shown here is consistent with its role in dermal and vascular wound healing.18,19 However, the effects on cardiac healing are more pronounced, in that vascular wound healing was delayed, but not completely abolished in plasminogen-deficient mice.18 Dermal wound healing in Plg-/- mice was associated with impaired keratinocyte migration, but an intact inflammatory response.19 In conclusion, impaired cardiac wound healing in both Plg-/- and u-PA-/- mice2 indicate that plasmin proteolysis is needed for the normal repair process of the heart after infarction. The plasmin-mediated ECM degradation is initiated by enhanced activity of uPA. Although plasmin cannot directly degrade interstitial collagens, it can initiate collagenolysis by activation of latent MMPs.
LV Architecture and Performance in the Absence of Infarct Healing
Despite the absence of cardiac wound healing, architectural changes of the LV were comparable in Plg-/- infarcts and wild-type infarcts, except the less pronounced thinning of the infarcted wall in Plg-/- mice. This might be explained by the persistent presence of necrotic cardiomyocytes in the Plg-/- infarcts, which have larger volumes than the collagen fibers in the Plg+/+ infarcts. Larger heart weights in the Plg-/- infarcts cannot be explained by a hypertrophic response of the noninfarcted myocardium, since septum thicknesses are not different between the Plg-/- and Plg+/+ infarcts. The increased heart weights are more likely explained by the reduction in infarct thinning in the Plg-/- mice. Another remarkable observation was that left ventricular dilatation was not increased in the absence of healing, suggesting that the infarcted wall of the Plg-/- hearts, with its large number of necrotic cells, has a similar tensile strength as the infarcted wall of Plg+/+ hearts, where fibrous tissue is deposited to restore the structural integrity. The suggested maintenance of tensile strength in the infarcted Plg-/- wall may be due to preservation of the extracellular matrix and/or to the 1 to 2 cell layers of surviving cardiomyocytes in both endo- and epicardium.
The impact of impaired healing on left ventricular function was evaluated by measuring cardiac output and left ventricular pressure development. Both parameters provide information on global cardiac function. An impaired function was observed in the Plg-/- infarct group after submaximal stimulation (dobutamine). However, extreme challenge (volume overload) resulted in equalization of cardiac output between the two groups. The reduced response to dobutamine does not depend on differences in ß-adrenoceptor signaling, since heart rates were similar in all groups. There is no a priori reason to assume a difference in contractility of cardiomyocytes in the non-infarcted myocardium between Plg-/- and Plg+/+ animals. The observed reduction of the response to dobutamine in the knockouts is compatible, however, with the observed structural changes in the infarcted area. In Plg-/- infarcts, reduced collagen deposition when compared to the wild-type infarcts, and the presence of necrotic cardiomyocytes increase the compliance of the infarct zone. This may result in mechanical disadvantages compared to the wild-types, where collagen deposition produces a virtually inextensible infarct.20 However, at extreme volume loads, both infarcts are stretched to a maximum and stiffness of the two infarct types is no longer different. Under these conditions, pump function will exclusively be determined by the healthy part of the myocardium, which apparently is comparable between the two infarct types.
In conclusion, this study provides direct proof that plasmin-mediated proteolysis plays a central role in cardiac wound healing after myocardial infarction in mice.
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Acknowledgements |
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Footnotes |
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Supported by the Netherlands Heart Foundation (grant 94.012).
Accepted for publication March 3, 2000.
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