© 2000 American Heart Association, Inc.
Integrative Physiology |
Treatment With Dimethylthiourea Prevents Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction in Mice
Role of Oxidative Stress
From Cardiovascular Medicine (S.K., H.T., S.H., T.I., N.S., S.S., A.T.), Graduate School of Medical Sciences, and the Department of Biophysics (H.U.), Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Correspondence to Hiroyuki Tsutsui, MD, PhD, Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail prehiro{at}cardiol.med.kyushu-u.ac.jp
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Abstract |
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Abstract—Oxidative stress might play an important role in the progression of left ventricular (LV) remodeling and failure that occur after myocardial infarction (MI). We determined whether reactive oxygen species (ROS) are increased in the LV remodeling and failure in experimental MI with the use of electron spin resonance spectroscopy and whether the long-term administration of dimethylthiourea (DMTU), hydroxyl radical (·OH) scavenger, could attenuate these changes. We studied 3 groups of mice: sham-operated (sham), MI, and MI animals that received DMTU (MI+DMTU). Drugs were administered to the animals daily via intraperitoneal injection for 4 weeks. ·OH was increased in the noninfarcted myocardium from MI animals, which was abolished in MI+DMTU. Fractional shortening was depressed by 65%, LV chamber diameter was increased by 53%, and the thickness of noninfarcted myocardium was increased by 37% in MI. MI+DMTU animals had significantly better LV contractile function and smaller increases in LV chamber size and hypertrophy than MI animals. Changes in myocyte cross-sectional area determined with LV mid–free wall specimens were concordant with the wall thickness data. Collagen volume fraction of the noninfarcted myocardium showed significant increases in the MI, which were also attenuated with DMTU. Myocardial matrix metalloproteinase-2 activity, measured with gelatin zymography, was increased with MI after 7 and 28 days, which was attenuated in MI+DMTU. Thus, the attenuation of increased myocardial ROS and metalloproteinase activity with DMTU may contribute, at least in part, to its beneficial effects on LV remodeling and failure. Therapies designed to interfere with oxidative stress might be beneficial to prevent myocardial failure.
Key Words: antioxidant • radicals • heart failure • myocardial infarction • remodeling
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Introduction |
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Myocardial infarction (MI) frequently produces left ventricular (LV) dilatation and hypertrophy of the noninfarcted myocardium.1 These changes in LV geometry, referred to as remodeling, contribute to the development of depressed cardiac performance.2 Thus, surviving patients with MI are at an increased risk for occurrence of heart failure (HF), reinfarction, arrhythmia, and sudden cardiac death.2 LV remodeling is caused by the side-to-side slippage of cardiac myocytes at the infarcted region and the hypertrophic response of the noninfarcted myocytes, resulting in a progressive increase in the chamber diameter.3 The underlying mechanisms responsible for these processes have been attributed to hemodynamic stress as well as the activation of neurohumoral factors, including the renin-angiotensin system. However, the details of contributing factors in LV remodeling remain to be elucidated.
Reactive oxygen species (ROS) can produce myocardial contractile dysfunction and structural damage.4 There is growing evidence that ROS are increased in HF and may contribute to disease progression.5 6 Hill and Singal7 showed that antioxidant enzyme activities are decreased and that thiobarbituric acid reactive substances (TBARS) are increased in the failing myocardium due to MI. Further, recent study in isolated cardiac myocytes has shown that a subtle increase in ROS results in a phenotype characterized by hypertrophy and apoptosis,8 which play an important role in myocardial remodeling and failure.9 We recently demonstrated that ·OH is increased with the development of rapid pacing-induced HF with the use of electron spin resonance (ESR) spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO).6 In our studies, ·OH is generated from superoxide anion (·O2-) and H2O2 via metal-catalyzed Harber-Weiss reaction and Fenton reaction within the myocardial tissue. These observations have prompted the thought that oxidative stress can contribute to LV remodeling and HF after MI.
Several important questions remain to be answered. First, no direct evidence for the increased production of ROS has been obtained in post-MI hearts. Therefore, it should be determined whether our previous observations in rapid pacing–induced HF can be applicable to post-MI HF. Second, even though the direct demonstration of increased ROS in the failing myocardium should help to focus attention on the therapeutic value of antioxidants, it also raises the question of whether enhanced production of ROS is truly a mechanism of HF or merely a marker of the manifestation of the disease. Several previous studies have used antioxidant vitamins to address this question, in which, however, the changes of ROS production have not been rigorously examined concurrently with myocardial response.10 It is critically important to examine whether the administration of ROS scavengers can attenuate both ROS production and HF.
Previous studies have reported increased myocardial metalloproteinase (MMP) activity in experimental models, including rapid pacing–induced HF11 and post-MI,12 13 as well as in human end-stage HF.14 Recently, an MMP inhibitor was shown to limit early LV dilatation in a murine model of MI.15 Because MMP can be activated by ROS in vivo,16 one proposed mechanism of LV remodeling is the activation of MMP secondary to increased ROS production. We hypothesized that ROS production and myocardial elaboration of MMP activation are interdependent and that the effects of ROS scavengers on LV remodeling are related, at least in part, to the modulation of this axis.
Accordingly, the first goal of the present study was to examine whether the production of ROS is increased in the remodeled LV after MI; the second goal was to determine whether chronic inhibition of ·OH production could inhibit the progression of LV remodeling and failure. A pharmacological intervention that can be used to prevent ·OH-mediated injury should ideally be capable of entering myocardial cells rapidly to encounter the generation of reactive oxygen metabolites. It should also maintain sufficient levels of tissue concentrations to afford protection against low levels of ·OH. However, most ROS scavengers have serum half-lives on the order of minutes and do not readily cross cell membranes. Dimethylthiourea (DMTU) is an agent that is highly diffusible, has a long half-life, and is effective in scavenging hydrogen peroxide (H2O2) and ·OH.17 Therefore, DMTU is expected to be an effective antioxidant, especially when administered in vivo.
In the present study, we created MI in mice by ligating the left anterior descending coronary artery, and we assessed the production of ·OH by measuring the rate of reduction of hydroxy-TEMPO in the myocardial tissue by using ESR spectroscopy. Further, we examined whether chronic in vivo administration of DMTU into MI animals can attenuate the LV remodeling and HF. We also examined myocardial MMP activity by using gelatin zymography.
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Materials and Methods |
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Animal Models
The study was approved by our institutional animal research committee and conformed to the animal care guidelines of the American Physiological Society. MI was created in male CD-1 (Charles River) mice (6 to 8 weeks old, weight 30 to 40 g) by ligating the coronary artery according to the methods described by Michael et al.18
Experimental Protocol
MI mice were randomly grouped to receive either saline (MI
group) or DMTU (MI+DMTU group). DMTU (50 mg/kg in sterile saline) was
administered daily via intraperitoneal injection
beginning 6 hours after the creation of MI and throughout the study (4
weeks). This dose was chosen based on the previous studies of its
efficacy.19 20
Echocardiography and Hemodynamic
Evaluation
Serial echocardiographic measurements at
baseline and 3, 7, 14, and 28 days after surgery were made in all
groups of animals.21 After the
echocardiographic measurements, LV pressure was
measured according to the methods described by Williams et
al.22 One subset of investigators (S.H. and N.S.), who
were not informed of the experimental groups, performed in vivo LV
function studies that included echocardiography and
LV pressure measurements.
Experimental Protocol 1
Quantification of Myocardial ·OH by ESR
Spectroscopy
We quantified ·OH in the noninfarcted LV
myocardium according to the methods described
previously.6
Experimental Protocol 2
LV Morphology and Morphometry
A separate group of animals, treated identically as in protocol
1, was used to evaluate the effects of chronic DMTU administration on
LV chamber diameters. Infarct size in these hearts was determined
according to the method described by Pfeffer et al.23
Myocyte Size and Collagen Volume Fraction
Myocyte cross-sectional area and collagen volume fraction were
measured according to the methods described
previously.24
Experimental Protocol 3
Myocardial MMP Activity
MMP activity in the noninfarcted LV was measured with gelatin
zymography according to the methods described
previously.11 12
An expanded Materials and Methods section can be found in an online data supplement available at http://www.circresaha.org.
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Results |
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Animal Characteristics
Coronary artery ligation and a sham operation were performed in 84 and 32 mice, respectively. Eighty-one mice that survived 6 hours after coronary artery ligation were randomized to active treatment with DMTU (MI+DMTU; n=33) or no treatment (MI; n=48). During the follow-up period, 24 (30%) deaths occurred (6 mice receiving DMTU and 18 mice receiving no drugs; P=NS). All mice that died were confirmed to have MI on postmortem examination. All sham-operated animals survived until the end of the study period.
Echocardiography
Serial 2-dimensional and M-mode
echocardiography was performed in a group of
sham-operated (n=10), MI (n=10), and MI+DMTU (n=8) animals. Figure 1
demonstrates marked LV dilatation and
contractile impairment in the MI mouse. These changes were attenuated
in MI+DMTU mice. Figure 2 shows that LV
end-diastolic diameter increased and percent fractional
shortening (FS) decreased by day 3 after ligation of coronary
artery. They were significantly different from control values by days 3
to 28 of the control. DMTU significantly inhibited this LV diameter
increase and percent FS decrease in MI as early as 3 days, which was
maintained throughout the study period, indicating the persistent
attenuation of LV dilatation and failure with DMTU from the early phase
after MI.
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; n=10), MI (•; n=10),
and MI+DMTU (
; n=8) mice. Values are mean±SEM.
*P<0.01 for difference from the sham value at matched
time points. 
P<0.01 for difference from the MI value
at matched time points.The summarized data for echocardiographic measurements at baseline and after 4 weeks are presented in Table 1 online (data supplement available at http://www.circresaha.org). In comparison with sham-operated animals, MI animals showed a 38% decrease (P<0.01) in the thickness of the infarcted region and a 37% (P<0.05) increase in the thickness of the noninfarcted region. DMTU significantly attenuated the hypertrophy of the noninfarcted myocardium (P<0.01) but did not affect the thickness of the infarcted portion.
Hemodynamics and Organ Weights
Hemodynamic measurements could be obtained in a
group of MI (n=8), MI+DMTU (n=8), and sham-operated (n=7) animals
(Table 2 online; data supplement available at
http://www.circresaha.org). They had similar body weights
(P=NS). The MI mice tended to exhibit lower aortic blood
pressures than the sham group, which, however, did not reach
statistical significance (P=0.06). LV
end-diastolic pressure was significantly elevated and LV
+dP/dt was depressed in the MI group (P<0.01 for both),
which was attenuated with DMTU. Coincident with an increased LV
end-diastolic pressure, the ratio of lung weight to body
weight was significantly increased in the MI group versus the sham
group (9.1±1.5 versus 4.6±0.1 g/kg, P<0.01), which was
also attenuated with DMTU treatment (5.7±0.4 g/kg, P<0.01
versus MI).
ROS in the Noninfarcted LV
ESR signals of hydroxy-TEMPO reduced more rapidly in the presence
of homogenates from post-MI hearts compared with sham
(Figure 3A). There was a linear relation
in the semilogarithmic plot of peak signal intensity versus time,
indicating the first-order kinetics of the signal decay (Figure 3B). The rate constant of signal decay was significantly
(P<0.01) larger in MI than that in sham (Figure 3C)
animals. DMTU (50 mmol/L) added to the reaction mixture completely
abolished an increase of signal decay in MI, indicating that ROS indeed
contributed to the increase of signal decay rate in MI. Catalase (50
U/mL) plus superoxide dismutase (SOD; 50 U/mL) also attenuated an
increase in signal decay rate, which implies the contribution of
·O2- to the
production of ·OH.
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In the MI+DMTU group, the "DMTU-inhibitable" rate of signal decay
was normalized, which provided evidence that the chronic in vivo
administration of ·OH scavenger DMTU into MI animals completely
prevented the production of ·OH (Figure 4).
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LV Morphology and Morphometry
Figure 5 shows the transverse LV
sections (midcavity) stained with Masson’s trichrome. The sections
obtained from the MI mouse revealed an anteroapical infarct that
extends into the anterolateral wall (Figure 5B). The
interventricular septum was generally spared. Infarct size
was estimated to establish whether the scarred myocardium
was comparable between MI and MI+DMTU and to provide a basis of
comparison. Two MI and 2 MI+DMTU mice with an infarct size of <40%
were excluded from the analysis of LV morphology. Infarct size
was identical between MI (59±3%, range 42% to 70%; n=12) and
MI+DMTU (56±2%, range 49% to 66%; n=11) animals. Figure 6 illustrates MI size and LV chamber
diameter in all groups. Consistent with
echocardiographic data (Table 1 online; data supplement
available at http://www.circresaha.org), MI+DMTU animals had
significantly smaller LV chamber diameters and volume than MI
animals.
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Myocyte cross-sectional area was increased in MI, which was
significantly attenuated with DMTU treatment (Figure 7). These results are concordant with LV
wall thickness data obtained from echocardiography
(Table 1 online; data supplement available at
http://www.circresaha.org). Collagen volume fraction was also increased
in MI, which was inhibited with DMTU treatment (Figure 7).
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Myocardial MMP Activity
Figure 8 shows
representative gelatin zymography of the LV from sham,
MI, and MI+DMTU mice. There was minimal MMP activity in the sham group.
MI after 7 days markedly enhanced MMP-2 (62- and 58-kDa gelatinases)
activity in the noninfarcted LV. The increase in MMP-2 activity
persisted at day 28 after MI.12 13 There was a modest but
significant increase in MMP-1 activity (54 kDa) in MI at both days 7
and 28.12 13 With DMTU, there was significant attenuation
of MMP activities at 7 and 28 days after the induction of MI (Figure 8).
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Discussion |
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The present study demonstrates an increase of ROS in the noninfarcted myocardium, in association with LV remodeling (ie, the chamber dilatation and hypertrophy of the noninfarcted region). Despite the equal infarct size, chronic administration of DMTU into the MI animals results in a tendency toward normalization of LV size and contractile function. The changes in LV structure after DMTU treatment are associated with reduced myocyte hypertrophy and interstitial fibrosis, suggesting that they are responsible, at least in part, for post-MI LV remodeling and reverse remodeling with DMTU.
Increased ROS in the Post-MI Heart
The ESR method for the measurement of ROS in the myocardial tissue
used in the present study has been well validated in our previous
studies.5 6 This can provide a direct method to quantify
the generation of ROS within biological tissue.6 We
extended our earlier observations in rapid ventricular
pacing–induced HF by showing that the production of ·OH
was increased in the myocardium with remodeling and
dysfunction after MI. These results also confirm and extend previous
observations that lipid peroxidation products measured as TBARS are
increased in post-MI hearts.7 In addition, the present
study demonstrates that the addition of catalase plus SOD into the
reaction mixture significantly attenuates the increase of signal decay
(Figure 3C
). These findings indicate that as was shown in our
previous study,6 ·OH can be secondarily produced
from ·O2- through the
electron exchange between
·O2- and
H2O2 via Harber-Weiss
reaction and Fenton reaction.25
·O2- can be produced intracellularly through electron leakage from mitochondria during oxidative phosphorylation and through the activation of several cellular enzymes, including NADPH oxidase, xanthine oxidase, and nitric oxide synthase.8 We previously used ESR with the ·O2- spin trap, 5,5'-dimethyl-1-pyrroline-N-oxide, to show that formation of ·O2- was increased in submitochondrial particles from rapid pacing–induced HF.5 Even though the source of ROS was not determined in the present study due to the limited amount of available myocardial tissue, it is well expected that the same mechanism might be operative in this model.
Role of DMTU Administration on Post-MI Remodeling and
Failure
Previous studies have shown that ROS play an important role in the
pathogenesis of myocardial ischemia-reperfusion,26
doxorubicin-induced cardiomyopathy,27
and HF.5 6 ROS have been implicated as an important
contributing factor in LV remodeling after MI.7 However,
whether and to what degree ROS inhibition can attenuate the LV
remodeling process remain unexplored. This question is also important
to establish a cause-and-effect relationship between oxidative stress
and HF. We observed that DMTU prevented LV dilatation and
hypertrophy of noninfarcted LV in association with
contractile dysfunction. The beneficial effects of DMTU were not due to
its MI size-sparing effect because the administration was started 6
hours after coronary artery ligation and the resultant MI size
was not affected with DMTU (Figure 6A). DMTU has been shown to
readily enter myocardium, to have a long serum half-life of
43 hours, and to have no cardiac toxicity in intact
animals.28 These properties are thought to be effective in
accomplishing meaningful reduction in myocardial damage. Therefore, the
present study provided clear evidence that DMTU can modulate the
myocardial response to infarction and that increased ROS are
responsible, at least in part, for remodeling and failure.
Serial echocardiographic measurements demonstrated that
the beneficial effects of DMTU on LV remodeling could be identified at
the early phase of its process (Figure 2), indicating that ROS
are involved in the early remodeling after MI. Nevertheless, we could
not exclude the possibility that ROS are also involved in the late
phase. To clarify the mechanisms of DMTU-induced effects, it is
necessary to determine whether the protective ability of DMTU is due to
its capability to chelate metals with the use of desferrioxamine.
However, the chelation of iron with desferrioxamine produces
ferrioxamine, and the iron in ferrioxamine can be a redox reactant. In
fact, desferrioxamine has been shown to have a biphasic
antioxidant/pro-oxidant behavior29 and to amplify
oxidative damage through the generation of ·OH.30
Future studies that confirm whether the same effects could be observed
with the use of other antioxidants are warranted.
Dhalla et al10 have shown that the transition from hypertrophy to failure could be prevented with the antioxidant vitamin E in the guinea pig model of ascending aortic constriction. In addition, probucol has been shown to exert protective effects against adriamycin-induced cardiomyopathy.27 The present study extends the previous observation by demonstrating substantial reductions in LV dilation and hypertrophy after DMTU treatment in association with the improvement in contractile function. The changes in LV structure were associated with reduced myocyte hypertrophy and interstitial fibrosis, suggesting that they are responsible, at least in part, for post-MI LV remodeling and reverse remodeling with DMTU.
The present results suggest that increased myocardial ROS could contribute to the activation of MMP and thus to the development of LV remodeling after MI. It has been reported that MMPs are increased in the noninfarcted myocardium obtained from a rat model of MI.13 Further, an MMP inhibitor has been shown to limit the chamber dilatation in a murine model of MI.15 Sustained MMP activation might therefore influence the structural properties of the myocardium by providing an abnormal extracellular environment with which the myocytes interact.31 Importantly, the present study has demonstrated that DMTU inhibits the activation of MMP in association with the development of LV remodeling. These data raise the interesting possibility that increased ROS after MI can be a stimulus for myocardial MMP activation, which might play an important role in the development of HF. Although this concept warrants further exploration, there is recent evidence for the activation of vascular MMP by ROS in vivo.16 In addition, the beneficial effects of DMTU on LV failure may be related to its antiedema action because small increases in interstitial water content can greatly increase LV chamber stiffness.32
Moreover, ROS have direct effects on cellular structure and function and may be integral signaling intermediates in myocardial remodeling.33 Higher levels of ROS are known to cause direct damage to proteins and lipids, leading to myocyte death through necrosis or apoptosis.4 Further, more powerful pro-oxidant peroxynitrite can be produced, particularly when both ·O2- and nitric oxide are present.34 A recent study by Siwik et al8 demonstrated that a subtle increase in ROS caused by partial inhibition of SOD results in a phenotype characterized by hypertrophy and apoptosis in isolated cardiac myocytes, which appears to be present in the noninfarcted myocardium. ROS of mitochondrial origin may be particularly prone to trigger apoptosis.35
The demonstration of a preventive effect of DMTU on HF implies that
antioxidants could be of clinical relevance. Recently, carvedilol, a
ß-blocker with antioxidant activity, has been shown to be beneficial
in the treatment of patients with congestive HF.36 One
must take into account that this drug possesses additional properties,
including 
-adrenoceptor–blocking action and antiproliferative
activities. However, as in the settings of
ischemia-reperfusion, one might assume that the beneficial
effects of carvedilol on HF are also mediated, at least in part,
through the prevention of ROS-induced damage.
Study Limitations
There are several limitations that should be acknowledged in this
study. First, because the hemodynamic profile of DMTU
is incompletely described, we could not exclude the possibility that
the beneficial effects of DMTU might be due to hypothetical favorable
hemodynamic effects on systemic and coronary
circulation. However, this possibility might be less likely because
arterial pressure and heart rate were not influenced with
DMTU (Table 2 online; data supplement available at
http://www.circresaha.org). Second, we administered DMTU into the
animals for 4 weeks to allow sufficient time to identify changes in LV
morphology, because this study was designed to address the hypothesis
that ROS inhibition could attenuate long-term LV remodeling. Thus, the
present study does not preclude an additional effect if DMTU was
initiated at the time of coronary ligation or the effects on
coronary occlusion with reperfusion. Further studies in
genetically altered mice and other models will also improve
understanding of the role of oxidative stress in LV remodeling. Third,
in the present study, we examined the amount of ROS at the time
point after the development of LV remodeling. Significant changes in
ROS may also occur at the onset and during the development of
remodeling. Further studies that focus in the temporal changes of
oxidative stress may be necessary.
Conclusions
·OH radicals were increased within the post-MI hearts,
which might be involved in myocardial remodeling and failure. Therapies
designed to interfere with oxidative stress could be beneficial to
prevent the progression of HF.
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Acknowledgments |
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This work was supported in part by grants 07266220, 07670789, 08258221, and 09670724 from the Ministry of Education, Science and Culture.
Received March 21, 2000; revision received July 5, 2000; accepted July 10, 2000.
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