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(Circulation. 2001;103:1570.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
High-Energy Phosphate Metabolism and Creatine Kinase in Failing Hearts
A New Porcine Model
From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis.
Correspondence to Jianyi Zhang, MD, PhD, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Mayo Mail Code 508, UMHC, Minneapolis, MN 55455. E-mail zhang047{at}tc.umn.edu
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—This study aimed to create a pig model of heart failure secondary to severe aortic stenosis and to examine the relationship between the alterations in myocardial high-energy phosphate (HEP) metabolism and protein expression of creatine kinase (CK) isoforms.
Methods and Results—Sixteen pigs with left ventricular hypertrophy (LVH) secondary to ascending aortic banding and 10 normal pigs (N) were studied. Myocardial protein levels of CK isoforms (Western blot), HEP levels, and CK kinetics (31P MR spectroscopy) were measured under basal conditions. Nine of the 16 animals with LVH developed congestive heart failure (CHF), as evidenced by ascites (100 to 2000 mL). LV weight/body weight ratio (g/kg) was 2.18±0.15 in N hearts, 3.04±0.14 in hearts with LVH (P<0.01), and 4.23±0.36 in hearts with CHF (P<0.01 versus LVH). Right ventricle weight/body weight ratio and LV end-diastolic pressure were significantly higher in hearts with CHF (each P<0.01 versus N or LVH). Myocardial phosphocreatine/ATP ratios and the CK forward flux rates were decreased in LVH hearts, most severely in hearts with CHF. CK-M/ß-actin ratios were 2.21±12 (N), 1.69±0.15 (LVH), and 1.39±0.27 (CHF, P<0.05 versus N). CK-mitochondria (CK-Mt)/ß-actin ratios were 1.40±0.09 (N), 1.24±0.09 (LVH), and 1.02±0.08 (CHF, P<0.05 versus N or LVH). The severity of the reduction of CK flux rate was linearly related to the severity of the decrease of CK-Mt/ß-actin (r=0.68, P<0.01).
Conclusions—In this new model of heart failure/hypertrophy, the abnormal myocardial HEP metabolism is related to the decreased CK-Mt protein level, which in turn is related to the severity of the hypertrophy.
Key Words: heart failure • hypertrophy • creatine kinase • phosphates • spectroscopy
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Heart failure is associated with abnormal myocardial energy metabolism.1 2 The mechanisms of this abnormality and its contribution to the evolution from compensated left ventricular hypertrophy (LVH) to congestive heart failure (CHF) are not known.1 2 One difficulty in studying this important medical problem is the lack of a large-animal model that has significant clinical relevance and clearly exhibits the transition from compensated LVH to CHF.
In the heart, the contractile utilized ATP is synthesized
mainly in the mitochondria through oxidative
phosphorylation and transported to the contractile
apparatus, where it is consumed by myosin ATPase to
generate force.3 4
The creatine kinase (CK) system is postulated to play an important role
in myocardial energy metabolism by maintaining high ADP
levels at the site in mitochondria at which ATP is generated and low
levels at the site of ATP
utilization.3 4
These considerations are embodied in the CK shuttle hypothesis, which
postulates that the CK system acts to facilitate ATP
production, transportation, and utilization. A fetal shift of
the myocardial CK isoforms with a decreased mitochondrial CK (CK-Mt)
was found in hearts with LVH or CHF of different
species.2 4 5 6
In normal hearts, the fraction of CK-Mt in small animals is
28%2 ; this fraction is
only 10% in large-animal or human
hearts.2 5 6
Because of the low CK-Mt fraction, in hearts with cardiac
hypertrophy the reduction of CK-Mt might be the "weak
link" of the energy shuttle and consequently contribute to the
transition from compensated LVH to heart failure. In dogs with LVH
secondary to pressure overload produced by banding of the ascending
aorta, we found that myocardial high-energy phosphate (HEP) levels and
the phosphocreatine (PCr)/ATP ratio were significantly
decreased.7 These
abnormalities were proportional to the degree of
hypertrophy but were not the result of persistent
abnormalities of myocardial
perfusion.7 Whether these
abnormalities in HEP metabolism are related to the
decreased CK-Mt is not known. The present study was designed to
develop a new porcine model of CHF secondary to severe pressure
overload and to examine the relationship between the abnormal
steady-state myocardial HEP metabolism and changes in
protein levels of the CK isoform.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Studies were performed in accordance with the "Position of the American Heart Association on Research Animal Use," adopted November 11, 1984, and protocols were approved by the Animal Care Committee of the University of Minnesota.
Production of LVH
Sixteen Yorkshire pigs at 45 days of age were
anesthetized with sodium pentobarbital (25 to 30 mg/kg IV),
intubated, and ventilated with a respirator. A right thoracotomy was
performed in the third intercostal space, and the ascending aorta,
1.5 cm above the aortic valve, was mobilized and encircled with a
polyethylene band 2.5 mm in width. While LV and distal aortic
pressures were measured simultaneously, the band was
tightened until a 60 to 70 mm Hg peak systolic pressure
gradient was achieved across the narrowing. The chest was then closed,
the pneumothorax was evacuated, and the animals were allowed to
recover. LVH occurred progressively as the area of aortic constriction
remained fixed in the face of normal body growth. Two months after
banding, animals were returned to the laboratory for
study.
Experimental Preparation
Ten normal pigs and 16 pigs with LVH were
premedicated with morphine sulfate (l mg/kg SC) and
anesthetized with pentobarbital (30 mg/kg IV, followed by an
infusion of 4 mg · kg-1 ·
h-1). A smaller dose of pentobarbital
(20 mg/kg IV) was used for animals with CHF to prevent loss of
animals from general anesthesia. Animals were intubated and
ventilated with a respirator with supplemental oxygen;
arterial blood gases and pH were maintained within the
physiological range. A polyvinyl chloride catheter,
3.0-mm OD, filled with heparin-saline was introduced into the right
femoral artery and advanced into the ascending aorta. A left
thoracotomy was performed in the fifth intercostal space, and the heart
was suspended in a pericardial cradle. A heparin-saline–filled
catheter was introduced into the LV through the apical dimple and
secured with a purse-string suture. A similar catheter was placed into
the left atrium through the atrial appendage. An NMR surface coil was
sutured to the anterior LV wall overlying the region perfused by the
left anterior descending coronary artery. The pericardial
cradle was released, and the heart was allowed to assume its normal
position. The animals were then placed in a Lucite cradle and
positioned within the magnet.
Myocardial Blood Flow
Myocardial blood flow was measured with
microspheres, 15 µm in diameter, labeled with
141Ce, 51Cr,
95Nb, 85Sr, or
46Sc (NEN Corp) as previously
described.7
NMR Technique
The NMR technique has been described in
detail.7 8 9 10
Briefly, measurements were performed in a 40-cm-bore 4.7-T magnet
interfaced with a Spectroscopy Imaging Systems Corp console. The LV
pressure signal was used to gate NMR data acquisition to the cardiac
cycle, whereas respiratory gating was achieved by triggering the
ventilator to the cardiac cycle between data
acquisitions.7 8 9 10
Calculation of Myocardial Free ADP
Levels
The myocardial free ADP levels were calculated from
the CK equilibrium
expression11 with an
equilibrium constant of
1.66x109 and cytosolic
pH=7.1:
[ADP]=([ATP][CRfree])/([PCr][H+]Keq).
PCr and ATP values were obtained from the spectra calibrated by the
biopsy-measured ATP levels. Free creatine was calculated by subtracting
the PCr values from the biopsy-obtained measurement of total creatine
(Crtotal).
CK Kinetics Measured With
31P MR Spectroscopy Saturation Transfer
Technique
The applied 31P MR
spectroscopy magnetization saturation transfer technique was described
previously.12 13
Briefly, a Gaussian pulse train was used to saturate ATP-
resonance.
This Gaussian pulse train was applied repetitively to ensure the
complete saturation of ATP- resonance.
The CK kinetics was calculated with the magnetization
transfer method as previously
described.12 13
The forward rate of CK
(kf:
PCr>ATP-) and intrinsic longitudinal relaxation time for PCr
(T1) were calculated on the basis of the 2-site chemical exchange
model12 13 :
kf=(
M/M)/T*1
and 1/T1=1/T*1-kf, where
kf and
T1 represent the estimation of pseudo–first-order rate
constant and the intrinsic longitudinal relaxation time of PCr,
respectively;
M=M0-Minfinite,
where M0 and Minfinite
represent the magnetization at saturation zero and infinite
times, respectively; and T*1 is a time constant that fits the integral
of PCr magnetization decay as the time of saturation at ATP-
increased from 0 to infinite. The CK forward flux rate
(Fluxf) was calculated as the products of
kf and
myocardial PCr concentration
(Fluxf=kf[PCr]).
Hemodynamic
Measurements
Aortic and LV pressures were monitored with pressure
transducers positioned at mid chest level. LV pressure was recorded
at normal and high gain for measurement of end-diastolic
pressure.
Experimental Protocol
Aortic and LV pressures were measured with Spectramed
pressure transducers positioned at mid chest level and recorded on
an 8-channel direct writing recorder (Coulbourne Instrument Co). LV
pressure was recorded at normal and high gain for measurement of
end-diastolic pressure. Midway through the 10-minute MR
spectroscopy acquisition period, a microsphere injection was
performed for determination of myocardial blood
flow.
Tissue Preparation
At the end of the study, a drill biopsy was taken
from 5 normal, 4 LVH, and 4 CHF ventricles for subsequent
analysis of ATP content with a high-performance liquid
chromatography
technique.14 The animal was
then killed, the heart was excised, and a full-thickness myocardial
specimen 3 g in weight was taken and frozen (-70°C) for
subsequent determination of Crtotal content and
molecular
analysis.14 The
heart was then fixed in 10% buffered formalin for myocardial blood
flow measurement as
described.6 7
Myocardial CK Activity and Isozyme
Measurements
Specimens from 6 hearts of each group were studied to
examine myocardial protein levels of CK isoforms by Western blot as
previously
described.15
Western Blot Analysis
A parallel Western
blot15 analysis was
performed. The protein extracts were run on 12% SDS-PAGE gels for 3
hours at 180 V with the Protean Electrophoresis apparatus
(BioRad). Commercially prepared molecular weight standards and purified
proteins (CK-MM, CK-MB, CK-BB, and CK-Mt, all obtained from Aalto) were
run as controls. The protein subunits were transferred for 1 hour at
100 V in transfer buffer (25 mmol/L Tris, 192 mmol/L glycine,
20% methanol). Monoclonal mouse antibodies specific to the CK-M and
CK-B subunits (OEM Concepts Inc) and polyclonal rabbit antibodies
specific to CK-Mt (from Dr Strauss’ laboratory, Washington University,
St Louis, Mo) were sequentially directed against their respective
protein subunits bound to the membrane. Densitometry of the film
allowed for a relative quantification of the CK protein
subunits.
Total CK and CK Activity
Total CK activity was measured with a creatine kinase
diagnostic kit (CK-10) (Sigma
Diagnostics).16
Data Analysis
Data were analyzed with 1-way ANOVA with
replications. A value of
P<0.05 was required for
significance. When the ANOVA yielded a significant result, individual
comparisons were made by the method of Scheffé. Data are reported as
mean±SEM.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animal Model
The signs of cyanosis and ascites (peritoneal fluid >50 mL) were used to separate LVH hearts with and without CHF. Nine of the 16 pigs with aortic banding developed CHF, as evidenced by ascites (100 to 2000 mL). Two of these 9 pigs that also had cyanosis died during the instrumentation surgery. The other 7 pigs formed the CHF group. The remaining 7 pigs with aortic banding formed the LVH group. The anatomic data are summarized in Table 1
. The ratio of LV weight to body weight
(LVW/BW; g/kg) increased by 39% in hearts with LVH
(P<0.05) and increased by 94%
in hearts with CHF (P<0.01
versus LVH or normal). The ratio of RV weight to body weight (RVW/BW;
g/kg) increased by 112%
(P<0.01 versus LVH or normal)
only in hearts with CHF.
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Hemodynamic Data
Hemodynamic data are shown in
Table 2. LV systolic pressure was significantly
higher in hearts with LVH. LV end-diastolic pressure was
significantly increased only in CHF hearts
(P<0.01 versus LVH or normal,
Table 2).
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Myocardial Blood Flow
Myocardial blood flow data are summarized in
Table 3. The regional myocardial blood flow distribution
was not significantly different between the normal and LVH hearts
(Table 3).
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31P NMR
Measurements
The myocardial PCr/ATP ratio is summarized in
Table 4. The voxel labeled EPI was located over the outer
edge of the LV wall, whereas the voxel most distant from the coil,
labeled ENDO, was located over the subendocardium. The voxel labeled
MID was located over the mid myocardium. Spectra were
characterized by high PCr and ATP levels, whereas inorganic phosphate
(Pi) was too low to identify at the
signal-to-noise ratio of the spectra. Myocardial PCr/ATP was
significantly decreased in every layer across the LV wall of the LVH
hearts. The reduction of PCr/ATP was most severe in hearts with CHF
(Table 4).
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Biopsy and CK Kinetics Data
Myocardial ATP and Crtotal
content decreased by 29% and 26%, respectively, in hearts with CHF
(P<0.05,
Table 5). In hearts with compensated LVH, neither ATP nor
Crtotal level changed significantly
(Table 5). The calculated myocardial free ADP was
significantly increased in hearts with LVH or CHF (each
P<0.05 versus normal).
Myocardial PCr was significantly decreased in hearts with LVH, most
severely in hearts with CHF
(Table 5).
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The CK kinetics data are summarized in
Table 5
. Under basal conditions, the M/M ratio tended to
be lower in hearts with CHF
(P=0.06,
Table 5). The intrinsic longitudinal relaxation time of PCr
(T1) was not significantly different between normal and hypertrophied
hearts. The
kf,
however, was significantly decreased in hearts with CHF
(P<0.05,
Table 5). The calculated Fluxf was
decreased by 35% in LVH hearts
(P<0.05 versus normal) and by
60% in hearts with CHF
(P<0.01 versus
LVH).
The chemically measured total CK activity decreased by 48%
in hearts with CHF (P<0.05,
Table 5).
Alterations of CK Isoform Expression in the LVH
and CHF Hearts
The CK isoform protein levels normalized to ß-actin
from all hearts are summarized in
Figure 1. Myocardial ß-actin contents were not
significantly different among the 3 groups. Each isoform protein
expression level was normalized to the ß-actin. Therefore, only the
ratios of CK isoform to ß-actin from different groups are compared in
this figure. In human and large-animal models, the fractions of the
isoforms to the total CK were 90%, 3%, and 10% for CK-M,
CK-B, and CK-Mt,
respectively.2 5 6
The CK-M protein decreased by 23% and 36% in hearts with LVH and CHF,
respectively (each P<0.05
versus normal,
Figure 1A). The protein level of CK-B was not significantly
different among the 3 groups
(Figure 1B). The CK-Mt protein isoform decreased by 28% only
in hearts with CHF (P<0.05,
Figure 1C).
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Relationship Between HEP
Metabolism, CK Isoform Expression, and the Severity of
LVH
The decrease of myocardial PCr/ATP ratio and
protein levels of CK-Mt and CK-M are linearly related to the increase
of LVW/BW
(Figure 2). Significant correlations were observed between
the decrease of PCr/ATP ratio, CK flux rate, and protein level of CK-Mt
in hypertrophied hearts
(Figure 3). Thus, in hearts with LVH, the abnormal
myocardial HEP metabolism and CK kinetics are related to
the decreased protein level of CK-Mt, which is most severe in hearts
with CHF.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study was designed to develop a new porcine model of CHF secondary to pressure overload and to examine the relationship between alterations in myocardial HEP metabolism and changes in myocardial protein levels of CK isoforms. The main findings are that (1) in response to this level of aortic stenosis, 56% of the animals developed severe LVH and CHF, as evidenced by ascites; the remaining animals developed compensated LVH; and (2) in LVH hearts, the severity of the altered HEP metabolism is related to the reduction of the CK-Mt protein level, which is most severe in CHF hearts.
LVH and CHF Secondary to Pressure
Overload
In the present study, signs of ascites and cyanosis
were used to separate hypertrophied hearts with and without CHF. All
the CHF pigs had ascites; 2 of them also had cyanosis. The RVW/BW and
LV end-diastolic pressure were significantly higher only in
hearts with CHF
(Tables 1 and 2). Taken together, these data demonstrate
unequivocally that >50% of the animals developed heart failure in
response to this level of aortic stenosis.
Using a porcine model, Massie et
al17 found that an aortic
stenosis that produced a 25 mm Hg pressure gradient
across the narrowing resulted in an increase of LV mass by 38% in 6
months. No signs of heart failure were observed in these animals. Using
this animal model, they found that myocardial HEP
metabolism was not significantly different from that of
normal hearts either at basal or high cardiac work
states.17 In dogs at 8 weeks
of age, an aortic banding that produced a 25 mm Hg pressure
gradient across the narrowing resulted in an increase of LV mass by
100% in 12 months.7 Using
this dog model of compensated LVH, we found that myocardial HEP
metabolism was abnormal, which was linearly related with
the severity of myocardial hypertrophy but not related to
the persistent myocardial
ischemia.7 18
In the present study, we applied a more severe aortic
stenosis that produced an 70 mm Hg pressure gradient
across the narrowing. In small-animal models, aortic banding induced
severe LVH and heart failure has been reported in numerous
studies.2 The large-animal
model of LVH/CHF described in the present study is very useful to
examine the mechanism of heart failure, because the anatomy of
the porcine heart is closer to that of the human heart. More integrated
physiological experiments could also be performed
in this animal model.
Reduction of ATP Content
Recently, there has been an increasing volume of
evidence that myocardial ATP concentration is decreased in the failing
heart.19 20 The
underlying mechanism(s) of this abnormality is not defined. In the
present study, myocardial ATP level decreased by 29% in hearts
with CHF
(Table 5). The cause of the reduction of the ATP level in
CHF hearts is unknown. In dogs with rapid pacing–induced heart
failure, Shen et al19 found
that the myocardial total adenine nucleotide (TAN) pool and
ATP content decreased with a time course identical to that of LV
dysfunction, being progressively more severe during continuous rapid
pacing. The loss of the TAN pool itself could result in the reduction
of ATP, because the resynthesis of adenine nucleotide is a
slow and energy-costly process through de novo synthesis, in which
inosine monophosphate is produced from ribose-5-phosphate, which
utilizes 6 HEP
bonds.21
Loss of Myocardial
Crtotal Content
The myocardial Cr total
concentration is reduced in failing hearts
(Table 5).19 20 22
Recently, Neubauer et al22
found that in hearts with CHF, the decreased myocardial
Crtotal level may be caused by a significant
reduction of myocardial creatine transporter. As a result of the
decrease of the myocardial ATP/ADP ratio, myocardial free energy
release per unit ATP hydrolysis (G) is significantly
reduced.23 A reduced G
was previously shown to be related to the decreased LV contractile
performance.23 Shen
et al19 reported that in
dogs, during the progressive increase of the severity of LV dysfunction
in response to rapid pacing, the reduction of myocardial
Crtotal occurred earlier and faster than the
decrease of myocardial ATP/TAN levels. It was therefore hypothesized
that the loss of the Crtotal was to compensate
for the loss of the TAN pool and consequently to decrease the
myocardial free ADP and preserve the
G.19 In the present
study, myocardial ATP and Crtotal were
significantly lower only in hearts with CHF
(Table 5). It is interesting to note that the
Crtotal of the 2 pigs that had severe heart
failure and died on the surgery table was only 31 and 47 µmol/g dry
wt, respectively. This is only 50% of the mean value of the CHF
hearts and 33% of the normal values
(Table 5). This >60% decrease of
Crtotal would make the calculated free ADP level
normal, assuming that reduction of ATP was not >30%
(Table 5). These data support the concept that loss of the
Crtotal in the failing heart may serve as a
compensatory mechanism in response to the reduction of the TAN
pool19 and consequently
preserve myocardial free energy release per unit ATP
hydrolysis.19 23
Myocardial PCr/ATP Ratio, CK Energetics, and
Isoform Expression
Hearts with LVH are characterized by significant
decreases of myocardial PCr and PCr/ATP ratio
(Table 4, References 1818 to 20). In hearts with
postinfarction LV remodeling, we found that the decreased PCr/ATP ratio
in myocardium remote from LV scar was independent of the
myocardial
ischemia.20 The
decrease of PCr/ATP ratio indicates an alteration of oxidative
phosphorylation regulation and decrease of
G.2 23 24
In patients with dilated cardiomyopathy, the
PCr/ATP ratios also provided prognostic information and predicted
survival better than LV ejection fraction or New York Heart Association
class.25 All these data
indicate that the reduction of PCr/ATP is related to the severity of
LVH and LV dysfunction. Providing direct evidence to demonstrate a
causal factor, however, is a different matter. Data from the
present study indicate that the abnormal myocardial PCr/ATP ratio
is related to the reduced protein level of CK-Mt. Because CK-Mt is
located at the end point of the cascade of ATP production, the
reduction of this protein may limit the ATP production rate,
which could result in a lower PCr/ATP ratio.
The coupling of CK-Mt and the adenine nucleotide translocator (ANT) is important to maintain a normal mitochondrial oxidative phosphorylation regulation. The reduction of CK-Mt could result in an alteration of mitochondrial oxidative phosphorylation regulation, which could be manifested by a decreased PCr/ATP ratio. The uncoupling of CK-Mt with ANT could also result in a decreased ATP production rate and consequently a decreased steady-state PCr/ATP ratio.
Alterations in Myocardial Bioenergetics and
LV Dysfunction
How this reduction of myocardial HEP levels
(Table 5) contributes to the contractile performance
of the failing hearts is not known. It is not likely, however, that
this 30% decrease of myocardial ATP concentration would cause the
dysfunction of failing hearts. The fact that myocardial ATP
concentration is many times greater than the
Km
values of either the ATPase at the contractile apparatus or
sarcoplasmic reticulum calcium ATPase
(SERCA)2 26
makes it unlikely that this reduction would directly depress the
contractile performance of the LV.
A fetal shift of the CK enzyme system has been reported in several models of LVH/CHF hearts (for review see Reference 22 ). The CK system plays an important role in myocardial energy metabolism as an energy transport shuttle or energy buffer or by its function in enzyme-enzyme coupling with myosin ATPase.2 3 4 Creatine diffuses more readily than ADP in the myocyte, giving rise to the "CK/CP shuttle" hypothesis. In previous studies, a decreased contractile reserve was observed in hearts with a suppressed CK system induced by sulfhydryl inhibition,23 by guanidino substrate replacement,27 or by CK-M and CK-Mt gene knockout.28 Taken together, these observations suggest that a severely altered myocardial CK system could contribute to LV dysfunction of the CHF hearts.
CK-Mt and ANT are parts of the mitochondrial permeable
transition pore (mtPTP). A reduction of CK-Mt can induce the
accumulation of reactive oxygen species, which opens the mtPTP and
triggers myocardial
apoptosis.29 Perhaps
it is the decreased CK activity and energy state (as indicated by a
decrease of ATP/ADP ratio,
Table 5) and increase of reactive oxygen species that
contribute to the opening of mtPTP and initiate apoptosis,
which then contributes to the LV dysfunction. Whether the alteration of
CK-Mt contributes to apoptosis warrants future
studies.
Conclusions
Our findings indicate that in this new model of
pressure-overload LVH and failure, the abnormal myocardial HEP
metabolism is related to the reduced protein level of
mitochondrial
CK.
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Acknowledgments |
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This work was supported by US Public Health Service grants HL-50470 and HL-61353. Dr Zhang is the recipient of an Established Investigator Award from the American Heart Association. We thank Dr Arnold W. Strauss who kindly provided the antibody for CK-Mt.
|
Footnotes |
|---|
The first 2 authors contributed equally to this study.
Received August 10, 2000; revision received September 29, 2000; accepted October 6, 2000.
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