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(Circulation. 1999;100:II-187.)
© 1999 American Heart Association, Inc.
Surgery for Congenital Heart Disease |
Impaired Glucose Transporter Activity in Pressure-Overload Hypertrophy Is an Early Indicator of Progression to Failure
From the Departments of Cardiac Surgery (I.F., C.S., K.T., H.C.-D., C.M.R., P.J.d.N.), Pediatric Cardiology (A.M.M., S.D.C.), and Anesthesiology (F.X.M.), The Children’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Pedro J. del Nido, MD, Department of Cardiac Surgery, Children‘s Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115. E-mail delnido{at}A1.tch.harvard.edu
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Abstract |
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Background—Severe hypertrophy and heart failure are important risk factors in cardiac surgery. Early adaptive changes in hypertrophy include increased ventricular mass-to-cavity volume ratio (M/V ratio) and increased dependence on glucose for energy metabolism. However, glucose uptake is decreased in the late stages of hypertrophy when ventricular dilatation and failure are present. We hypothesized that impaired glucose uptake would be evident early in the progression of hypertrophy and associated with the onset of ventricular dilatation.
Methods and Results—Ten-day-old rabbits underwent banding of the
descending aorta. Development of hypertrophy was followed
by transthoracic echocardiography to
measure left ventricular M/V ratio. Glucose uptake rate, as
determined by 31P-nuclear magnetic resonance spectroscopy
measuring 2-deoxyglucose conversion to 2-deoxyglucose-6-phosphate, was
measured in isolated perfused hearts obtained from banded rabbits when
M/V ratio had increased by 15% from baseline (compensated
hypertrophy) and by 30% from baseline (early-decompensated
hypertrophy). In age-matched control animals, the rate of
glucose uptake was 0.61±0.08 µmol · g of wet
weight-1 · 30 min-1 (mean±SEM). With
a 15% M/V ratio increase, glucose uptake rate remained at control
levels (0.6±0.05 µmol · g of wet
weight-1 · 30 min-1), compared with
hearts with 30% increased M/V ratios, where glucose uptake was
significantly lower (0.42±0.05 µmol · g of wet
weight-1 · 30 min-1;
P
0.05). Glucose transporter protein expression was the
same in all groups.
Conclusions—Glucose uptake rate is maintained during compensated hypertrophy. However, coinciding with severe hypertrophy, preceding ventricular dilatation, and glucose transporter protein downregulation, glucose uptake is significantly decreased. Because of the increased dependence of the hypertrophied hearts on glucose use, we speculate that this impairment may be a contributing factor in the progression to failure.
Key Words: hypertrophy • echocardiography • glucose • metabolism
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Introduction |
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One of the earliest events during adaptive remodeling in pressure-overload hypertrophy is an increase in ventricular muscle mass; this is considered an initial compensatory response to maintain normal wall stress. If pressure overload persists, progressive ventricular dilatation ensues, which then leads to increased wall stress, afterload mismatch, and decreased cardiac output.1 Several adaptive mechanisms occur during the development of hypertrophy; these include the multiplication of sarcomeres,2 a switch to immature isoforms of contractile proteins,3 and greater dependence on transsarcolemmal calcium influx for excitation-contraction coupling.4 In addition, an increase occurs in glucose use as a substrate for energy production.5 6 The transition from compensated to decompensated hypertrophy with ventricular dysfunction is poorly understood.
In mammalian cells, glucose is not freely permeable across the lipid bilayer; it enters the cells by facilitated diffusion. Specific membrane proteins that passively transport glucose down a concentration gradient achieve this process. In cardiac myocytes, 2 types of glucose transporters have been described (GLUT-1 and GLUT-4); they are responsible for most of the uptake of glucose under basal conditions and in response to insulin stimulation, respectively.7 8 9 10 11 12 13 14 We previously showed that the glucose uptake rate is impaired in hearts with decompensated pressure-overload hypertrophy when ventricular dilatation and contractile dysfunction have occurred in response to thoracic aortic banding.15
In light of the potential role of glucose metabolism in
maintaining contractile function during the progression of
pressure-overload hypertrophy, we hypothesized that
impaired glucose transport occurs early in the progression to
ventricular dilatation. In a rabbit model of thoracic
aortic banding, we monitored the progression of hypertrophy
using transthoracic echocardiography.
In previous work with this model, we observed that after aortic
banding, an initial increase occurs in the left ventricular
(LV) mass to LV volume ratio (M/V ratio), which reaches a plateau
30% above prebanding levels. At this point, the rate of LV cavity
volume increases faster than the rate of LV mass production,
resulting in a fall in M/V ratio.16 This progression
mimics the progression seen clinically with pressure
overload.17 To determine the relationship between glucose
uptake and progression of hypertrophy, we measured the
glucose uptake rate and glucose transporter expression in control and
aortic-banded rabbits during the early rise and the plateau phase of LV
M/V ratio after aortic banding.
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Methods |
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Pressure-overload hypertrophy was achieved by placing a 2-0 silk suture around the descending aorta just distal to the ligamentum arteriosum in 10-day-old New Zealand White rabbits, as previously described.15 Implanting a fixed constriction in an immature animal and allowing it to grow induced pressure-overload hypertrophy by 2 to 3 weeks of age in this model. The progression of LV hypertrophy was determined by weekly transthoracic echocardiography (Hewlett-Packard Sonos 1500 Cardiac Imager) with a 7.5-MHz transducer. During these procedures, the animals remained unsedated to avoid the influences of anesthetics on the results.
Echocardiography
Two-dimensional cross-sectional images and M-modes of the left
ventricle were obtained by echocardiography.
Simultaneous measurements of ECG and LV short-axis
dimensions by M-mode were recorded on hard copy at a paper speed of
100 mm/s. These examinations were started at 3 weeks of age and
performed at 1-week intervals. LV epicardial and endocardial surfaces
were traced by computer-aided offline analysis on a bit-mapped
digitizing tablet. End-diastolic (maximum dimension) and
end-systolic (minimum dimension) LV wall thicknesses were
determined using previously described methods.18 19 20 The
M/V ratio was calculated, and the serial evaluation of M/V ratio was
expressed as percent change from baseline.
2-Deoxyglucose Uptake
Glucose uptake rate was determined using
31P-nuclear magnetic resonance (NMR)
spectroscopy. Spectra were acquired in an 8.45 Tesla vertical Bruker
spectrometer operating at a proton frequency of 145 MHz. The
isolated heart in its perfusion chamber was positioned within a 20-mm
solenoid radiofrequency coil. During the stabilization period of 30
minutes, the magnetic field was optimized by shimming on the
free-induction decay of the proton signal from the heart and the
surrounding perfusate. Spectra were obtained by
signal-averaging 120 scans with a 2-s delay. Each spectrum took 4
minutes. Spectral peak areas were quantified by integration after
baseline correction with software provided by Bruker. The
determined areas were normalized to an external standard (using 500
µmol/L of dimethylene phosphonic acid) contained in a balloon
adjacent to the heart.
The animals were euthanized by intravenous injection of an overdose of ketamine (50 to 100 mg/kg); heparin (500 U/kg) was also given intravenously. The hearts were rapidly excised and placed in cold Krebs-Henseleit (KH) solution. After aortic cannulation, the hearts were perfused in the nonworking, nonrecirculating Langendorff mode at a perfusion pressure of 80 mm Hg with oxygenated KH solution containing (in mmol/L): NaCl 117, KCl 4.7, MgSO4 1.2, CaCl2 1.8, NaHCO3 23.7, and glucose 10 (37°C, pH 7.4). After a 30-minute stabilization period, the perfusate was switched to a modified KH solution containing 10 IU/L bovine insulin, a reduced glucose content (1 mmol/L), and a concentration of 3 mmol/L 2-deoxyglucose (2-DG; Sigma). 2-DG acts as a competitive inhibitor of glucose, and it is transported into the cell via the same mechanism (facilitative diffusion). Phosphorylation of 2-DG by hexokinase to 2-deoxyglucose-6-phosphate (2-DG-6-P) results in a distinct resonance peak. The rate of rise of this peak is proportional to glucose uptake by the cell and serves to quantify the rate of glucose uptake. The rate of degradation of 2-DG-6-P was determined in a separate group of hearts by perfusion with a KH buffer with 10 mmol/L glucose and 10 U/L insulin after the infusion of 2-DG and obtaining spectra for an additional 30 minutes. The rate of 2-DG accumulation (proportional to the rate of glucose uptake) was quantified by a second-order polynomial function.
Glucose Uptake With [2-3H]Glucose
Glucose utilization was determined using the
[2-3H]glucose method of Katz and
Dunn.21 This method is based on the measurement of
tritiated water (3H2O)
production from [2-3H]glucose.
3H2O was separated from
[2-3H]glucose by ion-exchange
chromatography on a borate form of AG-1X8 resin
(Bio-Rad Laboratories).22 Initially, the hearts were
perfused with tracer-free perfusate for a stabilization period
of 20 minutes; they were subsequently perfused in a nonrecirculating
mode with KH buffer containing 50 µCi of
[2-3H]glucose over a period of 30 minutes. The
rate of 3H2O release was
measured in the effluent withdrawn at 5-minute intervals, and 1 mL was
dissolved in Insta-Gel Plus/XF solution (Packard Bioscience).
Isotope counting was performed on a Beckman LS 6500 liquid
scintillation counter (Beckman Instruments Inc). Rates of glucose
uptake are reported as micromoles per grams of wet weight per minute
(µmol · g of wet weight-1 ·
min-1).
Hexokinase Activity
Hypertrophied and control hearts from separate groups of animals
were rapidly excised and perfused with modified KH solution for 5
minutes. The left ventricle was weighed, frozen in liquid nitrogen, and
homogenized in a buffer containing (in mmol/L):
TrisHCl 20, KCl 900, MgCl2 10, EDTA 2, and
glucose 10 and 0.5% Triton (Sigma). The assay was performed on the
homogenate in a buffer containing (in mmol/L): TrisHCl
40, KCl 100, MgCl2 20, EDTA 4, ATP 2,
NADP+ 0.25, and glucose 10 and 0.03 U of
glucose-6-phosphate dehydrogenase (Sigma). Control assays were
performed on a buffer solution in which glucose or
homogenate was omitted. The rate of reduction of
NADP+ with glucose-6-phosphate dehydrogenase was
measured spectrophotometrically at a wavelength of 340 nm. One
milliunit of hexokinase represents the amount of enzyme
activity that forms in 1 nmol of glucose-6-phosphate in 1
minute.23 24
Western Immunoblotting
Ventricular tissue from a separate set of
hypertrophied and age-matched littermates (control animals) was
homogenized in ice-cold buffer containing (in mmol/L):
TrisHCl 20, EDTA 2, EGTA 0.5, and PMSF 1, and 25 µg/mL leupeptin and
0.3 mol/L sucrose (pH 7.4); it was then centrifuged at
1000g for 20 minutes. The crude supernatant fraction was
stored at -80°C for later analysis. Gel electrophoresis with
10% SDS-PAGE gels was performed on samples of 25 µg of protein from
total homogenates in accordance with the method of
Laemmli.25 Proteins were then electrophoretically
transferred to nitrocellulose membranes. After transfer, the membranes
were incubated in 5% nonfat dry milk in 10 mmol/L TrisHCl (pH
7.5), 100 mmol/L NaCl, and 0.1% Tween 20 for 1 hour at room
temperature to block unspecific binding sites; they were then incubated
with antibodies.
GLUT-1 and GLUT-4 (Genzyme Diagnostics) were used as primary antibodies at a dilution of 1:1000; samples were then incubated with horseradish peroxidase-conjugated secondary antibody (Jackson Immuno Research Labs) at a dilution of 1:10000. The bound antibody was detected by the enhanced chemoluminescence method according to the manufacturer’s instructions (Amersham Life Science). This method depends on the production of light after the oxidation of luminol by horseradish peroxidase in the presence of H2O2. After exposure on films, quantitative protein analysis was undertaken by laser densitometry.
Statistical Analysis
Data are expressed as mean±SEM and were analyzed using
SigmaStat software (Jandel Scientific). Comparisons between groups were
made with 1-way ANOVA. Probability values were corrected by
Bonferroni’s post hoc correction. If normality and equal variance
testing were passed, a standard t test was used. For all
these tests, P0.05 was considered statistically
significant.
Animal Care
All animals received humane care in compliance with the
Principles of Laboratory Animal Care formulated by the
National Society for Medical Research and the Guide for the Care
and Use of Laboratory Animals prepared by the National Academy of
Sciences and published by the National Institutes of Health (NIH
Publication No. 86 to 23, revised 1985). The protocol was reviewed and
approved by the animal care committee at Children’s Hospital in
Boston.
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Results |
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Weekly measurements of LV M/V ratios demonstrated that after aortic banding, an initial rapid increase of LV wall thickness occurred, resulting in a rise in LV M/V ratio. This reached a plateau
30% above prebanding levels by 3 to 4 weeks of age. We termed the
phase leading up to this plateau "compensated
hypertrophy." By 4 to 5 weeks of age, a gradual decline
in M/V ratio occurred due to a more rapid increase in LV cavity volume
relative to LV mass, indicative of LV dilatation (decompensated phase).
Figure 1
shows
representative M-mode echocardiographic
images of a heart with compensated hypertrophy and an
age-matched control heart.
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On the basis of the echocardiographic findings, animals
with a 15% increase in M/V ratio from baseline (4 weeks of age,
compensated hypertrophy) and with a 30% rise in M/V
ratio (5 weeks of age, early-decompensated phase) were studied and
compared with age-matched control animals. Paralleling these
echocardiographic findings, the banded animals showed a
significant degree of hypertrophy, as estimated by LV
weight to body weight ratios, which were 3.4±0.4 (compensated phase)
and 3.3±0.4 (early-decompensated phase) in the hypertrophied groups
compared with 2.3±0.2 in controls. Body weights were not different
between the groups, and LV weight was 3.08±0.26 g in hearts with
compensated hypertrophy, 2.85±0.06 g in hearts with
early-decompensated hypertrophy, and 2.16±0.29 g in
control hearts (P0.05).
31P-NMR spectra before and after a 30-minute
infusion of 2-DG are shown in Figures 2A and 2B. Figure 2C depicts a
representative curve of the 2-DG-6-P peak during 2-DG
infusion and wash-out, indicating that 2-DG-6-P is not further
metabolized during the observation period, even after subsequent
wash-out with glucose-containing buffer.
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Figure 3A shows the rate of 2-DG-6-P
accumulation over a period of 30 minutes in the aortic-banded groups
and control animals. 2-DG accumulation was significantly lower in
hearts with early-decompensated hypertrophy (30%
increase of M/V ratio) than in control hearts (P0.05),
with a slower rate of rise and lower total accumulation after 30
minutes. Figure 3B shows the rate of glucose uptake measured by
cumulative tritiated water production from
[2-3H]glucose over a period of 30 minutes. In
aortic-banded animals at a 30% rise of M/V ratio, the
glucose-uptake rate was significantly lower compared with age-matched
control animals (P0.05).
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In a separate group of hearts (n=4 per group), myocardial protein was
obtained from the left ventricle of rabbits with compensated,
early-decompensated, and late-decompensated hypertrophy (6
weeks of age, M/V ratio beginning to fall). The GLUT-1 and GLUT-4
protein content from the myocardium of aortic-banded groups
and age-matched littermates, as determined by
immunoblotting, was not significantly different between
any of the groups. A representative
immunoblot of GLUT-4 is depicted in Figure 4A, and a summary of the densitometry
results is shown in Figure 4B.
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In a separate group of hearts perfused with KH solution containing
insulin and glucose, total hexokinase activity was the same in
hypertrophied and control hearts at a M/V ratio increase of 30%
(38.2±0.47 mU/mg protein compared with 42.8±1.62 mU/mg protein,
respectively).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, echocardiography was used to monitor the progression of LV hypertrophy and to determine the timing for the study of glucose uptake and glucose transporter protein content. The observations derived from this investigation reveal that a decrease in glucose uptake rate is evident early in the transition from compensated to decompensated pressure-overload hypertrophy, as determined by an index of LV M/V ratio. The defect in insulin-stimulated glucose uptake precedes the downregulation of sarcoplasmic reticulum Ca-ATPase (SERCA-2) and glucose transporter expression (GLUT-4 and GLUT-1).15 26
Under pathophysiological conditions such as hypertrophy or during ischemia and early reperfusion, a high rate of cardiac glucose metabolism may be crucial.27 28 29 Glucose transport is thought to be rate-limiting for glucose use. In the heart, 2 distinctive glucose transporters are responsible for glucose uptake across the plasma membrane. The GLUT-1 transporter, which is present in low levels in most tissues, is non-insulin–stimulated and is responsible for basal glucose use.11 12 GLUT-4 activity is regulated by insulin and is expressed in tissues in which glucose transport needs to be rapidly and markedly enhanced (adipocytes, skeletal and cardiac muscle).13 14 In the basal state, GLUT-1 is evenly distributed between the plasma membrane and low-density microsomal pools, whereas GLUT-4 is almost entirely stored in an intracellular pool.14 30 31 Insulin interacts with its receptor on the plasma membrane and stimulates the redistribution of GLUT-4 to the sarcolemma.32 33 When insulin levels fall, GLUT-4 is resequestered in intracellular vesicles.34 A decrease in GLUT-4 mRNA and protein is thought to be a mechanism for insulin resistance in various models of diabetes, and it has been associated with lower myocardial glucose uptake.14 35 36 37 38 In the present study, we did not find altered GLUT-4 protein expression, as determined by immunoblotting of LV myocardial tissue, which indicates that insulin signal transduction and/or glucose transporter activity is altered in hypertrophied hearts.
In the present study, we used the distinct 31P-NMR peak of 2-DG-6-P to investigate the glucose transport capacity of hypertrophied hearts. 2-Deoxy-D-glucose, a competitive inhibitor of D-glucose, is transported into the cell via the same mechanism as glucose, is phosphorylated by hexokinase, and accumulates as 2-DG-6-P, which is metabolized very slowly. The rate of 2-DG-6-P accumulation, therefore, reflects both transport across the plasma membrane and phosphorylation of glucose, and it is a useful tracer of glucose transport and phosphorylation in the isolated perfused heart.15 39 To confirm our findings with 2-DG uptake in hypertrophied hearts, we used a radioactive tracer technique; the same results were obtained.
In some models, 2-DG-6-P is further metabolized by incorporation to glycogen at low rates.40 The rate of 2-DG-6-P degradation is slow with respect to the rate of uptake; degradation rates ranging from 70 to 110 minutes have been previously reported.39 41 42 In the present study, 2-DG uptake reached a plateau after 30 minutes of perfusion, and little, if any, 2-DG-6-P was further metabolized during a wash-out period. Similar findings have been reported when hypertrophied and normal hearts were compared in a spontaneously hypertensive rat heart model.43 Therefore, we think that the use of 2-DG is a reliable method of glucose uptake determination in our model.
In the current study, in hearts with compensated
hypertrophy (15% rise in M/V ratio), glucose uptake in
response to insulin was still maintained at near-normal levels;
impaired glucose uptake was detected before progression from
compensated to decompensated hypertrophy at the peak M/V
ratio (30% above baseline). It is conceivable that the impaired
response of GLUT-4 to insulin stimulation (eg, defects in insulin
receptor signaling or alterations in GLUT-4-containing vesicle
trafficking) could contribute to the development of decompensated
cardiac hypertrophy. Similar defects in the
insulin-stimulation of glucose use and transport in the heart have been
demonstrated in animal models of diabetes and insulin
resistance.37 44 45 46 In the absence of insulin, glucose
transport is rate-limiting for glycolysis, as reported for isolated rat
cardiomyocytes.47 Therefore, an important
relationship may exist between the progression of
hypertrophy to failure and decreased glucose uptake because
a diminished rate of cardiac glucose use is thought to be detrimental
to heart function.48 We previously showed that severe
hypertrophy with impaired glucose transport has functional
significance with regard to impaired recovery after experimental
myocardial ischemia. Normalizing glucose transport with
vanadate significantly improved postischemic recovery in
the hypertrophied heart.15
Our data indicate that a decline of glucose uptake rate occurs in the hypertrophied heart and, concomitantly with the lack of glucose available for the myocardium, hypertrophy progresses to myocardial failure. Insulin insensitivity of the GLUT-4 transport system, a potential underlying mechanism, may play a significant role. Because GLUT-4 protein levels remain unchanged at this stage, we speculate that impaired insulin signaling is responsible for this defect. Strategies to overcome this defect by either direct bypass of insulin-dependent GLUT-4 activation or augmenting glucose transport to the myocytes by other means may improve myocardial function and prevent the progression of hypertrophied hearts to failure.
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Acknowledgments |
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This work was supported in part by grants from the American Heart Association (to P.J.d.N.) and the National Institutes of Health (HL 46207 to P.J.d.N. and HL 52589 to F.X.M.).
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