Metabolic
changes in cardiac hypertrophy
Christophe Montessuit, Nathalie Rosenblatt-Velin,
René Lerch
Cardiology Center, University Hospital, Geneva, Switzerland
Correspondence: Dr Christophe Montessuit, Cardiology Center, University Hospital,
24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. Tel: +41-22 372
72 16, fax: +41-22 372 72 29, email: christophe.montessuit@hcuge.ch
Myocardial hypertrophy
is associated with profound changes in the cardiomyocyte
phenotype, altering size, shape and function of the cells.
There is now substantial evidence that hypertrophy is associated
with changes in both regulation of substrate metabolism and
expression of control proteins of metabolism. This results
in increased glucose metabolism with reduced fatty acid oxidation.
These metabolic changes have features of both adaptation
and maladaptation, since although they are detrimental to
contractile function they may enable survival of the cardiomyocytes
in unfavorable conditions.
Introduction
Life critically depends on the beating of the heart, an energy-consuming process
fueled by hydrolysis of ATP to ADP. The energy required for the resynthesis
of ATP is in turn harnessed from the catabolic breakdown of metabolic substrates.
In order to maintain a continuous supply of ATP to the contractile machinery,
the heart has developed an omnivorous attitude and is able to use a wide
variety of circulating substrates, including fatty acids, glucose, lactate
and ketone bodies. However, substrate selection is not simply dictated by
their relative
abundance at a given time, but is submitted to regulation according to the
developmental, hormonal and pathophysiological status of the organism. Cardiac
hypertrophy is among the pathologies that modify myocardial substrate utilization.
Figure 1. (A) Simplified overview of substrate metabolism
in normal cardiac myocytes. CAT, carnitine acetyltransferase;
CPT-1, carnitine palmitoyltransferase-1; GLUT1, non-insulin-dependent
glucose transporter; GLUT4, insulin-dependent glucose transporter;
LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase;
LCAD, long-chain acyl-CoA dehydrogenase; MCAD, medium-chain
acyl-CoA dehydrogenase; SCAD, short-chain acyl-CoA dehydrogenase.
Overview of fatty acid and glucose
metabolism
Catabolic breakdown of glucose occurs in two stages (Figure 1A): glycolysis,
an anaerobic, cytoplasmic stage with low ATP yield, followed by aerobic oxidation
of glycolysis-derived pyruvate in the mitochondria (the Krebs cycle). Pyruvate
is first converted to acetyl-CoA by the action of pyruvate dehydrogenase (PDH),
the rate-limiting enzyme for glucose oxidation.
b-Oxidation of fatty acids also takes place in the mitochondria and generates
acetyl-CoA, which is further oxidized in the Krebs cycle. Reducing power used
for ATP resynthesis is extracted both at the b-oxidation and the Krebs cycle
stages.[1] Long-chain fatty acids (LCFA) cannot freely diffuse
into the mitochondria. They have first to be converted to acylcarnitine by
the carnitine palmitoyltranferase-1 (CPT-1) reaction, a rate-limiting step
for LCFA oxidation. b-Oxidation-derived acetyl-CoA inhibits the PDH and, consequently,
glucose oxidation, a feedback mechanism known as the Randle cycle.[2]
The fetal or neonatal myocardium relies mostly on glycolysis for energy production;
within a few days after birth, this substrate preference is shifted towards
oxidation of fatty acids.[3] This evolution is associated
with changes in the expression of genes coding for metabolic regulatory proteins.
After birth, the constitutively active glucose transporter isoform GLUT1 is
replaced by the insulin-sensitive, regulable isoform GLUT4.[4,5] Simultaneously,
expression of enzymes of fatty acid oxidation is increased. In addition to
changes in gene expression, allosteric regulation of several enzymes is involved
in the developmental maturation of fatty acid oxidation.[3]
Metabolism in cardiac hypertrophy
Despite the availability of methods allowing non-invasive, quantitative assessment
of myocardial metabolism in humans,[6] the bulk of information
on substrate metabolism in cardiac hypertrophy comes from experiments in isolated
perfused rodent hearts. This model allows for precise control of the substrate
supply, the hormonal milieu and the workload imposed on the heart. Cardiac
hypertrophy is induced in vivo within a few weeks by artificial generation
of a pressure-overload (i.e. aortic banding) or volume-overload (i.e. aortocaval
fistula) condition. Another widely used experimental model of left ventricular
hypertrophy is the spontaneously hypertensive rat (SHR).
Fatty acid metabolism
Several studies using isolated perfused hearts obtained from rats with cardiac
hypertrophy have documented a reduction of palmitate oxidation, associated
with reduced cardiac performance.[7–9] Reduction in fatty
acid oxidation is not due to systemic alterations of substrate metabolism,
since it persists in isolated cardiomyocytes.[10,11] Replacement
of palmitate with short-chain fatty acids that can freely diffuse into the
mitochondria ameliorates the performance of hypertrophied hearts, suggesting
that the b-oxidation pathway itself is not impaired in the heart with compensated
hypertrophy.[7] Instead, inhibition of LCFA oxidation has
been attributed to the reduced availability of l-carnitine in hypertrophied
hearts, leading to impaired transport of LCFA into the mitochondria (Figure
1B).
Figure 1. (B) Alterations of substrate metabolism
in hypertrophied cardiac myocytes. Red crosses denote impaired
steps or pathways.
Indeed, addition of l-carnitine or propionyl-l-carnitine,
a naturally occurring derivative of l-carnitine, to the culture
medium stimulates oxidation of palmitate in cardiomyocytes
isolated from hypertrophied hearts. Similarly, administration
of propionyl-l-carnitine in the drinking water during development
of hypertrophy in vivo restores both palmitate oxidation[12] and
contractile function during ex vivo perfusion.[13] However,
in some experiments,[13,14] l-carnitine replenishment
is not accompanied by increased LCFA oxidation. Rather, oxidative
metabolism of carbohydrates is stimulated,[14] possibly
by export of acetyl-CoA out of the mitochondrion, relieving
inhibition of PDH.
Fatty acid metabolism can also be (dys)regulated by alterations of expression
of the enzymes of the pathway. We[15] and others[16] have
observed downregulation of the mRNA coding for the medium-chain acyl-CoA dehydrogenase
(MCAD), a key enzyme of b-oxidation, during development of hypertrophy. Interestingly,
a deficiency in activity or protein content of this enzyme became apparent
only in the failing heart (Figure 1C). This confirms that, as mentioned above,
compensated hypertrophy is probably not associated with an impairment of b-oxidation.
Whether downregulation of enzymes of b-oxidation is a cause or a consequence
of heart failure remains to be investigated.
Figure 1. (C) Alterations of substrate metabolism
in failing cardiac myocytes. Red crosses denote impaired
steps or pathways.
Glucose metabolism
In parallel with defects of fatty acid metabolism, cardiac hypertrophy is associated
with alterations of glucose metabolism. The first stage of glucose catabolism,
anaerobic glycolysis, has been found to be stimulated in several models of
cardiac hypertrophy.[8,12,17] The mechanism
responsible for increased glycolytic flux is not well understood. In a model
of right ventricle hypertrophy, Do et al.[18] observed increased
activity of several glycolytic enzymes. Little is known, however, about the
activity of phosphofructokinase, the most important control element in glycolysis.
Another possible explanation for the activation of glycolysis is increased
glucose transport into cardiomyocytes. As mentioned above, the adult heart
mainly expresses the GLUT4 isoform of glucose transporters, the activity of
which is regulated in response to insulin and other factors. Hearts isolated
from SHR rats show augmented basal uptake of glucose, insulin resistance and
decreased GLUT4 expression,[19] similar to observations in
patients with cardiac hypertrophy.[20] Basal uptake of glucose
is mediated by the GLUT1 isoform, which is expressed at a low level in the
normal adult heart, but is increased in vivo during post-ischemic reperfusion[21]
during angiotensin II-induced hypertrophy[22] or in isolated
cardiomyocytes rendered hypertrophic in vitro.[23] Despite
the elevated basal uptake of glucose in hearts from SHR rats, no increase in
GLUT1 expression was observed,[19] suggesting that stimulation
of glucose uptake can occur without an augmentation of the GLUT’s density at
the cell surface.[24] Similarly, we observed in infarct-induced
hypertrophy that GLUT1 expression increased only during progression to heart
failure.[25]
Because of reduced fatty acid oxidation in hypertrophied hearts, we should
expect glucose oxidation to be elevated in comparison with normal hearts. This
has been observed in SHR rats[9] and in postinfarction left ventricular hypertrophy
(Rosenblatt-Velin, unpublished observations). In contrast, a reduction of glucose
oxidation has been observed in pressure- or volume-overload hypertrophy, despite
acceleration of glycolysis.[12,17] In these
studies, however, isolated hearts were perfused with high concentrations of
fatty acids (1.2 mM), which contribute to inhibition of glucose oxidation.[26] Consistently,
activity of PDH, the rate-limiting enzyme of glucose oxidation, was reduced
in hypertrophied myocardium, despite an unaffected total PDH content.[27] Inhibition
of PDH seems to be relieved by carnitine supplementation.
The dissociation between accelerated glycolysis and reduced or unchanged glucose
oxidation is likely to have detrimental consequences on cardiac function. The
reason is that when glycolysis is not coupled to glucose oxidation, production
of protons and lactate occurs, leading to intracellular acidosis, a major cause
of contractile dysfunction.
Resumption of fetal gene program
Both repression of MCAD and overexpression of GLUT1 are reminiscent of the
pattern of gene expression observed during fetal life. It is tempting to speculate
that a general resumption of the fetal gene program occurs during cardiac hypertrophy.
Other features of a return to a fetal program include a switch from expression
of muscle- or cardiac-specific isoforms of CPT-1, fatty acid binding protein,
or lactate dehydrogenase to expression of non-cardiac isoforms. Indeed, preliminary
findings from our laboratory suggest that these isoform switches occur in myocardial
hypertrophy (Rosenblatt-Velin, unpublished observations).
Interestingly, it seems that a common transcription factor, Sp1, governs expression
of MCAD[28] and GLUT1,[29] albeit in opposite directions.
Myocardial expression of Sp1 is downregulated after birth,[29] but
increases again in left ventricular hypertrophy.[28] Sp1
is therefore a candidate for a single molecular switch bringing the metabolic
phenotype back to a fetal pattern. Whether Sp1 is actually responsible for
overexpression of GLUT1 in hypertrophy is currently being investigated.
Metabolic changes: cause or consequence?
Because of their detrimental effect on contractile function, the changes in
glucose and fatty acid metabolism described above can be perceived as maladaptive
features of the hypertrophied heart. It is, however, possible that the augmentation
of glucose metabolism represents an adaptation to enhance the chances of survival.
First, stimulation of glycolysis is likely to help the myocytes withstand repetitive
episodes of ischemia and reperfusion,[30] which often occurs
in patients with cardiac hypertrophy. In particular, glycolytically produced
ATP appears to be critical to the restoration of ion homeostasis during reperfusion.[31,32] Second,
glucose uptake and glycolytic activity seem to participate in the protection
of cardiomyocytes against apoptosis.[33] Thus, enhanced glucose
metabolism in hypertrophy, though at the expense of fatty acid oxidation and
cardiac function, may protect cardiac myocytes against both necrotic and apoptotic
cell death.
Metabolic changes: or consequence?
Thus far, metabolic alterations observed in the hypertrophied heart have been
considered in this review as part of the phenotype, i.e. as a consequence of
the development of hypertrophy. However, some observations suggest the intriguing
possibility that disruption of normal glucose or fatty acid metabolism may
indeed be a primary factor responsible for the development of hypertrophy.
In particular, mice with a cardiac-specific deletion of the glucose transport
protein GLUT4 exhibit cardiac hypertrophy associated with increased basal glucose
uptake, cardiac insulin resistance and increased expression of GLUT1.[34] Peripheral
metabolism is normal in these animals. The mechanisms leading to development
of hypertrophy are unknown, but it is tempting to speculate that ablation of
cardiac GLUT4 was compensated by overexpression of GLUT1, resulting in increased
glucose metabolism somehow leading to the development of myocardial hypertrophy.
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Regulatory interactions between lipids
and carbohydrates: the glucose fatty acid cycle after 35
years.
Randle PJ.
Nuffield Department of Clinical Biochemistry, University of Oxford, Radcliffe
Infirmary, U.K.
Competition for respiration between substrates in animal tissues has been
known for at least 80 years. The most important interaction, quantitatively
is between glucose and fatty acids. The starting point in 1963 for the so
called Glucose Fatty Acid Cycle was the realisation that the metabolic relationship
between glucose and fatty acids is reciprocal and not dependent. Glucose
provision promotes glucose oxidation and glucose and lipid storage, and inhibits
fatty acid oxidation. Provision of free fatty acids promotes fatty acid oxidation
and storage, inhibits glucose oxidation and may promote glucose storage if
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with evidence in man in vivo. In the authors opinion the evidence for inhibitory
effects of fatty acids on whole body glucose utilization ad oxidation (predominantly
muscles) is decisive and enzyme mechanisms mediating these effects are well
established. There is also much evidence that fatty acid oxidation inhibits
glucose oxidation and stimulates glucose formation in liver and again enzyme
mechanism are known. A permissive role for fatty acids in the insulin secretory
response of islet beta-cells has now been firmly established and can be visualised
as a mechanism to protect continuing provision of respiratory substrate.
Longer term exposure of islet beta-cells to fatty acids impairs the insulin
secretory response to glucose and mechanisms are known. There is compelling
evidence that fatty acid oxidation may impair glucose oxidation in uncontrolled
Type 1 and Type 2 diabetes, but no convincing evidence that fatty acids have
a role in diminished glucose storage (glycogen deposition) in Type 2 diabetes.
The inhibition of glucose storage which may follow prolonged elevation of
plasma FFA in man and experimental animals is associated with glycogen repletion
whereas the inhibition of glucose storage in Type 2 diabetes is associated
with glycogen depletion. The precise role of fatty acids in disturbed carbohydrate
metabolism in Type 2 diabetes is an area where future progress is confidently
predicted.
Publication Types:
PMID: 10095997 [PubMed - indexed for MEDLINE]
-
Developmental regulation in the expression
of rat heart glucose transporters.
Wang C, Hu SM.
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Antibodies against human erythrocyte glucose transporters (GLUT-1) were used
to determine if the transporters of embryonic and adult rat hearts have similar
reactivity. On the basis of immunoblotting, these antibodies react more strongly
with embryonic transporters than with adult ones. To determine if this phenomenon
may be correlated with changes in the expression of transporter types during
development, RNA isolated from either the embryonic or the adult rat heart
was amplified by polymerase chain reaction (PCR) to identify the transporter
species. Both GLUT-1 and GLUT-4 fragments were obtained among the PCR products.
They were used for Northern blot analysis. The results indicate that the
embryonic heart is rich in GLUT-1 mRNA; whereas the adult heart contains
predominantly GLUT-4 mRNA. Thus, it appears that the major type of glucose
transporter in rat heart switches from GLUT-1 to GLUT-4 during development.
PMID: 1711843 [PubMed - indexed for MEDLINE]
-
Developmental regulation of GLUT-1 (erythroid/Hep
G2) and GLUT-4 (muscle/fat) glucose transporter expression
in rat heart, skeletal muscle, and brown adipose tissue.
Santalucia T, Camps M, Castello A, Munoz P, Nuel A,
Testar X, Palacin M, Zorzano A.
Departament de Bioquimica i Fisiologia, Facultat de Biologia, Universitat
de Barcelona, Spain.
The expression of GLUT-1 (erythroid/Hep G2) and GLUT-4 (muscle/fat) glucose
transporters was assessed during development in rat heart, skeletal muscle,
and brown adipose tissue. GLUT-4 protein expression was detectable in fetal
heart by day 21 of pregnancy; it increased progressively after birth, attaining
levels close to those of adults at day 15 post natal. In contrast, GLUT-4
messenger RNA (mRNA) was already present in hearts from 17 day-old fetuses.
GLUT-4 mRNA stayed low during early postnatal life in heart and brown adipose
tissue and only increased after day 10 post natal. The expression pattern
for GLUT-4 protein in skeletal muscle during development was comparable to
that observed in heart. In contrast to heart and skeletal muscle, GLUT-4
protein in brown adipose tissue was detected in high levels (30% of adult)
during late fetal life. During fetal life, GLUT-1 presented a very high expression
level in brown adipose tissue, heart, and skeletal muscle. Soon after birth,
GLUT-1 protein diminished progressively, attaining adult levels at day 10
in heart and skeletal muscle. GLUT-1 mRNA levels in heart followed a similar
pattern to the GLUT-1 protein, being very high during fetal life and decreasing
early in post natal life. GLUT-1 protein showed a complex pattern in brown
adipose tissue: fetal levels were high, decreased after birth, and increased
subsequently in post natal life, reaching a peak by day 9. Progesterone-induced
postmaturity protected against the decrease in GLUT-1 protein associated
with post natal life in skeletal muscle and brown adipose tissue. However,
GLUT-4 induction was not blocked by postmaturity in any of the tissues subjected
to study. These results indicate that: 1) during fetal and early post natal
life, GLUT-1 is a predominant glucose transporter isotype expressed in heart,
skeletal muscle, and brown adipose tissue; 2) during early post natal life
there is a generalized GLUT-1 repression; 3) during development, there is
a close correlation between protein and mRNA levels for GLUT-1, and therefore
regulation at a pretranslational level plays a major regulatory role; 4)
the onset of GLUT-4 protein induction occurs between days 20-21 of fetal
life; based on data obtained in rat heart and brown adipose tissue, there
is a dissociation during development between mRNA and protein levels for
GLUT-4, suggesting modifications at translational or posttranslational steps;
and 5) postmaturity blocks the decrease in GLUT-1 expression but not the
induction of GLUT-4, observed soon after birth.(ABSTRACT TRUNCATED AT 400
WORDS)
PMID: 1370797 [PubMed - indexed for MEDLINE]
6. Knuuti J. Myocardial substrate metabolism imaged by PET.
Heart Metab 1999; 5: 21–24.
-
Fatty acid oxidation and mechanical
performance of volume-overloaded rat hearts.
el Alaoui-Talibi Z, Landormy S, Loireau A, Moravec J.
Laboratorie d'Energetique et de Cardiologie Cellulaire, Institut National
de la Sante et de la Recherche Medicale, Faculte de Pharmacie, Dijon, France.
Chronic volume overload was induced in 2-mo-old rats by surgical opening
of the aortocaval fistula. Rats were killed 3 mo later and their hearts were
atrially perfused. During the perfusions with 1.2 mM palmitate, mechanical
performance of volume-overloaded hearts was significantly decreased both
under conditions of a moderate work load and, mainly, after the clamp of
the aortic outflow line. Respective O2 consumption rates as well as the rates
of 14CO2 production from [U-14C]palmitate were decreased to the same extent.
When 2.4 mM octanoate was used as the exogenous substrate, both the O2 consumption
rates and the rates of CO2 production of volume-overloaded hearts became
comparable to those of control hearts perfused with same substrate. Mechanical
activity of volume-overloaded hearts returned to control values and remained
stable during the entire perfusion period tested. Total tissue L-carnitine
was decreased by approximately 30% in volume-overloaded hearts, which may
suggest that palmitate oxidation has been limited at the level of carnitine-acylcarnitine
translocase. However, our polarographic studies of the respiratory activity
of isolated mitochondria indicated that the palmitoylcarnitine translocation
proceeds normally. On the other hand, state 3 respiration of the mitochondria
from volume-overloaded hearts supplemented with either palmitate or palmitate
and L-carnitine was significantly lower than that of control ones. This may
suggest that an alteration of the enzymes involved in long-chain fatty acid
activation and/or long-chain fatty acyl transfer to L-carnitine has developed
under conditions of chronic mechanical overloading of the heart.
PMID: 1533101 [PubMed - indexed for MEDLINE]
-
Contribution of oxidative metabolism
and glycolysis to ATP production in hypertrophied hearts.
Allard MF, Schonekess BO, Henning SL, English DR, Lopaschuk
GD.
Cardiovascular Research Laboratory, University of British Columbia, St. Paul's
Hospital, Vancouver, Canada.
The contribution of glycolysis and oxidative metabolism to ATP production
was determined in isolated working hypertrophied hearts perfused with Krebs-Henseleit
buffer containing 3% albumin, 0.4 mM palmitate, 0.5 mM lactate, and 11 mM
glucose. Glycolysis and glucose oxidation were directly measured by perfusing
hearts with [5-3H/U-14C]glucose and by measuring 3H2O and 14CO2 production,
respectively. Palmitate and lactate oxidation were determined by simultaneous
measurement of 3H2O and 14CO2 in hearts perfused with [9,10-3H]palmitate
and [U-14C]lactate. At low workloads (60 mmHg aortic after-load), rates of
palmitate oxidation were 47% lower in hypertrophied hearts than in control
hearts, but palmitate oxidation remained the primary energy source in both
groups, accounting for 55 and 69% of total ATP production, respectively.
The contribution of glycolysis to ATP production was significantly higher
in hypertrophied hearts (19%) than in control hearts (7%), whereas that of
glucose and lactate oxidation did not differ between groups. During conditions
of high work (120 mmHg aortic afterload), the extra ATP production required
for mechanical function was obtained primarily from an increase in the oxidation
of glucose and lactate in both groups. The contribution of palmitate oxidation
to overall ATP production decreased in hypertrophied and control hearts (to
40 and 55% of overall ATP production, respectively) and was no longer significantly
depressed in hypertrophied hearts. Glycolysis, on the other hand, was accelerated
in control hearts to rates seen in the hypertrophied hearts. Thus a reduced
contribution of fatty acid oxidation to energy production in hypertrophied
rat hearts is accompanied by a compensatory increase in glycolysis during
low work conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 8067430 [PubMed - indexed for MEDLINE]
-
Altered glucose and fatty acid oxidation
in hearts of the spontaneously hypertensive rat.
Christe ME, Rodgers RL.
Department of Pharmacology and Toxicology, University of Rhode Island, Kingston
02881.
Metabolic fuel oxidation may be altered in left ventricular hypertrophy (LVH),
but detailed characterizations are lacking. Although the spontaneously hypertensive
rat (SHR) is a widely used experimental model of LVH, its myocardial fuel
oxidation rates are unknown. The purpose of this study was to directly measure
glucose and fatty acid (FA) oxidation in the SHR heart ex vivo under controlled
loading conditions. Hearts from 15-week-old SHR and Sprague Dawley (SD) rats
were perfused in a recirculating system and indices of cardiac performance
were continuously monitored. The oxidation of glucose and palmitate were
determined simultaneously at low and high workloads by the addition of U-14C-glucose
and 9,10-3H-palmitate to the recirculating perfusate. The results demonstrate
that FA oxidation of SHR hearts is profoundly suppressed (60-80%) relative
to that of the normotensive SD strain, particularly at high workloads. Glucose
oxidation is also moderately elevated, yielding a marked (four-to-five-fold)
increase in the ratio of glucose/FA oxidation rates in the SHR hearts. Since
more ATP is generated per mole of oxygen consumed when glucose is the fuel
scource, these results are consistent with the hypothesis that a shift away
from FA use toward glucose contributes to the preservation of energetic economy
in stable, concentric LVH.
PMID: 7869397 [PubMed - indexed for MEDLINE]
-
Alterations in energy metabolism of
hypertrophied rat cardiomyocytes: influence of propionyl-L-carnitine.
Torielli L, Conti F, Cinato E, Ceppi E, Anversa P, Bianchi
G, Ferrari P.
Prassis-Sigma Tau Research Institute, Milan, Italy.
Alterations in energy metabolism, reduced fatty acid oxidation, and cardiac
carnitine content have been implicated in the evolution from compensated
to decompensated cardiac hypertrophy. We determined high-energy nucleotide
levels in hypertrophied quiescent cardiomyocytes isolated from rat hearts
4 weeks after banding of abdominal aorta. In hypertrophied quiescent cardiomyocytes,
a decrease in ATP content (p = 0.03), and ratios of ATP/total adenine nucleotides
and of ATP/ADP were observed, together with an increase in ADP. In addition,
palmitate, but not glucose oxidation, was markedly reduced in hypertrophied
myocytes. In the presence of 25 microM propionyl-L-carnitine (PLC) or L-carnitine
(LC), palmitate oxidation was significantly stimulated in hypertrophied myocytes.
The ATP/ADP ratio was significantly increased only with PLC. This effect
was not due to an enhanced PLC uptake, since total PLC uptake was 50% lower
than that of LC. Changes in the energy generating system of quiescent myocytes
occur early in pressure overload hypertrophy, and these alterations can be
attenuated by PLC.
PMID: 8583777 [PubMed - indexed for MEDLINE]
-
Palmitate oxidation by the mitochondria
from volume-overloaded rat hearts.
Christian B, El Alaoui-Talibi Z, Moravec M, Moravec
J.
Department de Physiologie, Universite Claude Bernard-Lyon I, Villeurbanne,
France.
In this work, an attempt was made to identify the reasons of impaired long-chain
fatty acid utilization that was previously described in volume-overloaded
rat hearts. The most significant data are the following: (1) The slowing
down of long-chain fatty acid oxidation in severely hypertrophied hearts
cannot be related to a feedback inhibition of carnitine palmitoyltransferase
I from an excessive stimulation of glucose oxidation since, because of decreased
tissue levels of L-carnitine, glucose oxidation also declines in volume-overloaded
hearts. (2) While, in control hearts, the estimated intracellular concentrations
of free carnitine are in the range of the respective Km of mitochondrial
CPT I, a kinetic limitation of this enzyme could occur in hypertrophied hearts
due to a 40% decrease in free carnitine. (3) The impaired palmitate oxidation
persists upon the isolation of the mitochondria from these hearts even in
presence of saturating concentrations of L-carnitine. In contrast, the rates
of the conversion of both palmitoyl-CoA and palmitoylcarnitine into acetyl-CoA
are unchanged. (4) The kinetic analyses of palmitoyl-CoA synthase and carnitine
palmitoyltransferase I reactions do not reveal any differences between the
two mitochondrial populations studied. On the other hand, the conversion
of palmitate into palmitoylcarnitine proves to be substrate inhibited already
at physiological concentrations of exogenous palmitate. The data presented
in this work demonstrate that, during the development of severe cardiac hypertrophy,
a fragilization of the mitochondrial outer membrane may occur. The functional
integrity of this membrane seems to be further deteriorated by increasing
concentrations of free fatty acids which gives rise to an impaired cooperation
between palmitoyl-CoA synthase and carnitine palmitoyltransferase I. In intact
myocardium, the utilization of the in situ generated palmitoyl-CoA can be
further slowed down by decreased intracellular concentrations of free carnitine.
PMID: 9546638 [PubMed - indexed for MEDLINE]
-
Control of oxidative metabolism in volume-overloaded
rat hearts: effect of propionyl-L-carnitine.
El Alaoui-Talibi Z, Guendouz A, Moravec M, Moravec J.
Departement de Physiologie, Universite Claude Bernard-Lyon I, Villeurbanne,
France.
The objective of the present work was the assessment of metabolic events
responsible for the improvement of hemodynamic function of volume-overloaded
hearts from rats receiving propionyl-L-carnitine. A severe cardiac hypertrophy
was induced in 2-mo-old rats by surgical opening of an aortocaval communication.
Three months later, during in vitro perfusions with 1.2 mM palmitate, 11
mM glucose, and 10 IU/l insulin, the mechanical performance and overall energy
turnover (myocardial O2 consumption) of hypertrophied rat hearts were significantly
decreased under conditions of moderate and high workloads. These changes
in cardiac energetics paralleled the decrease in total tissue carnitine content
and alterations in exogenous palmitate oxidation. The oxidative utilization
of glucose was also slightly depressed in volume-overloaded hearts while
steady-state glycolysis rates increased, especially in hearts subjected to
high mechanical loads. This slowing of metabolic pathways involved in acetyl-CoA
generation resulted in decreased NADH availability and in an apparent substrate
limitation of oxidative phosphorylation suggested by a failure of cytosolic
unbound ADP to drive respiration. Long-term administration of propionyl-L-carnitine
normalized the degree of reduction of mitochondrial pyridine nucleotides
and improved the kinetics of mitochondrial ATP production in volume-overloaded
hearts. The resulting acceleration of energy turnover was essentially related
to improved oxidative utilization of glucose, but steady-state palmitate
oxidation rates also increased in severely hypertrophied hearts. This concomitant
acceleration of glucose and palmitate oxidation may be related to the particular
experimental conditions (high exogenous palmitate concentrations, elevated
workloads) used in this study. We assume that the increase in intracellular
carnitine, together with a stimulation of acetyl-CoA demands related to high
workloads, creates conditions that are compatible with the simultaneous relief
of pyruvate dehydrogenase and carnitine palmitoyltransferase I. The resulting
increase in the rate of steady-state ATP production improves, in turn, the
mechanical activity of volume-overloaded hearts.
PMID: 9139943 [PubMed - indexed for MEDLINE]
-
-
Propionyl L-carnitine improvement of
hypertrophied rat heart function is associated with an
increase in cardiac efficiency.
Schonekess BO, Allard MF, Lopaschuk GD.
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Although propionyl L-carnitine improves contractile function of hypertrophied
rat hearts, the mechanism(s) by which it does this are not known. One postulated
mechanism is that propionyl L-carnitine reverses the alterations in energy
metabolism that occur secondary to the carnitine deficiency seen in hypertrophied
myocardium. This study determined the effects of chronic propionyl L-carnitine
administration on myocardial carnitine content and energy metabolism in hypertrophic
hearts from male Wistar Kyoto rats. Pressure-overload hypertrophy was produced
by constriction of the abdominal aorta in juvenile rats. Propionyl L-carnitine
was administered to the rats via the drinking water for an 8 week period
(60 mg.kg(-1).day-1). Myocardial function and metabolic analysis was determined
in isolated working hearts obtained from aortic-banded and sham-operated
(control) animals at the end of the 8 week study period. Carnitine content
was significantly decreased in hypertrophied hearts compared to control hearts,
but was normalized by propionyl L-carnitine treatment. Propionyl L-carnitine
treatment also prevented the decrease in cardiac work that occurred in hypertrophied
hearts compared to control hearts. The primary change in energy substrate
use in hypertrophied hearts was a decrease in fatty acid oxidation rates.
Glucose and lactate oxidation were similar in control and hypertrophied hearts.
While glycolytic rates were slightly higher at moderate workloads, this was
not seen at high workloads. Surprisingly, propionyl L-carnitine treatment
did not reverse the depression of fatty acid oxidation seen in hypertrophied
rat hearts. In fact, a further significant decrease in fatty acid oxidation
occurred, such that the contribution of fatty acid oxidation to ATP production
decreased from 35 to 26%. Since propionyl L-carnitine treatment increased
cardiac work in hypertrophied hearts despite an overall decrease in ATP production
rates, an increase in cardiac efficiency was seen. In treated vs. untreated
hypertrophied hearts efficiency (cardiac work/ATP produced) increased from
0.23 to 0.40 ml.mm Hg.mumol ATP-1.g dry weight at high workloads. These data
suggest that the beneficial effect of propionyl L-carnitine on mechanical
function in the hypertrophied heart does not result from a normalization
of fatty acid oxidation, but rather from an increase in the efficiency of
translating ATP production into cardiac work.
PMID: 8605952 [PubMed - indexed for MEDLINE]
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Propionyl L-carnitine improvement of
hypertrophied heart function is accompanied by an increase
in carbohydrate oxidation.
Schonekess BO, Allard MF, Lopaschuk GD.
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Propionyl L-carnitine (PLC) is a naturally occurring derivative of L-carnitine
that can improve hemodynamic function of hypertrophied rat hearts. The mechanism(s)
responsible for the beneficial effects of PLC is not known, although improvement
of myocardial energy metabolism has been suggested. In this study, we determined
the effect of PLC on carbohydrate and fatty acid metabolism in hypertrophied
rat hearts. Myocardial hypertrophy was produced by partial occlusion of the
suprarenal aorta of juvenile rats. Over a subsequent 8-week period, a mild
hypertrophy developed, resulting in a 17% increase in heart weight in these
animals compared with the sham-operated control animals. Myocardial carnitine
was decreased in hypertrophied hearts compared with hearts from sham-operated
animals (4155 +/- 383 versus 5924 +/- 570 nmol.g dry wt-1, respectively;
P < or = .05). Perfusion of isolated working hearts for 60 minutes with
buffer containing 1 mmol/L PLC increased carnitine content in hypertrophied
hearts from 4155 +/- 383 to 7081 +/- 729 nmol.g dry wt-1 (P < or = .05).
In the presence of 1.2 mmol/L palmitate, fatty acid oxidation rates were
not decreased in the hypertrophied hearts compared with control hearts. PLC
treatment did not alter rates of fatty acid oxidation in control hearts but
did result in a small increase in rates in the hypertrophied hearts.(ABSTRACT
TRUNCATED AT 250 WORDS)
PMID: 7554119 [PubMed - indexed for MEDLINE]
15. Remondino-Müller A, Rosenblatt-Velin N, Montessuit C Alterations
of mRNA expression of regulatory proteins of metabolism in remote myocardium
following infarction [abstract]. J Mol Cell Cardiol 1997; 29: A85.
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Fatty acid oxidation enzyme gene expression
is downregulated in the failing heart.
Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly
DP.
Department of Medicine, Washington University School of Medicine, St Louis,
Mo, USA.
BACKGROUND: During the development of heart failure (HF), the chief myocardial
energy substrate switches from fatty acids to glucose. This metabolic switch,
which recapitulates fetal cardiac energy substrate preferences, is thought
to maintain aerobic energetic balance. The regulatory mechanisms involved
in this metabolic response are unknown. METHODS AND RESULTS: To characterize
the expression of genes involved in mitochondrial fatty acid beta-oxidation
(FAO) in the failing heart, levels of mRNA encoding enzymes that catalyze
the first and third steps of the FAO cycle were delineated in the left ventricles
(LVs) of human cardiac transplant recipients. FAO enzyme and mRNA levels
were coordinately downregulated (> 40%) in failing human LVs compared
with controls. The temporal pattern of this alteration in FAO enzyme gene
expression was characterized in a rat model of progressive LV hypertrophy
(LVH) and HF [SHHF/Mcc-facp (SHHF) rat]. FAO enzyme mRNA levels were coordinately
downregulated (> 70%) during both the LVH and HF stages in the SHHF rats
compared with controls. In contrast, the activity and steady-state levels
of medium-chain acyl-CoA dehydrogenase, which catalyzes a rate-limiting step
in FAO, were not significantly reduced until the HF stage, indicating additional
control at the translational or post-translational levels in the hypertrophied
but nonfailing ventricle. CONCLUSIONS: These findings identify a gene regulatory
pathway involved in the control of cardiac energy production during the development
of HF.
PMID: 8941110 [PubMed - indexed for MEDLINE]
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-
Glycogen metabolism in the aerobic hypertrophied
rat heart.
Allard MF, Henning SL, Wambolt RB, Granleese SR, English
DR, Lopaschuk GD.
Cardiovascular Research Laboratory, University of British Columbia, Vancouver,
Canada. mallard@prl.pulmonary.ubc.ca
BACKGROUND: Rates of glycolysis from exogenous glucose are accelerated in
hypertrophied hearts. In this study, we determined whether alterations in
the metabolism of glycogen, an endogenous storage form of glucose, also occur
in hypertrophied hearts. METHODS AND RESULTS: Rates of glycolysis ([3H]H2O
production) and oxidation ([14C]CO2 production) from exogenous glucose and
glycogen were measured in isolated working hearts from control and aortic-banded
rats. Hearts in which glycogen was prelabeled with [5-(3)H]- or [U-(14)C]glucose
were perfused with buffer containing 11 mmol/L [5-(3)H]- or [U-(14)C]glucose
(different from the isotope used to prelabel glycogen), 0.4 mmol/L palmitate,
0.5 mmol/L lactate, and 100 microU/mL insulin. Rates of glycolysis from exogenous
glucose were greater (3471+/-114 versus 2665+/-194 nmol glucose x min(-1)
x g dry wt(-1), P<.05, n=4 to 6, mean+/-SEM) and rates of exogenous glucose
oxidation (445+/-36 versus 619+/-16 nmol glucose x min(-1) x g dry wt(-1),
P<.05, n=4 to 6) were lower in hypertrophied hearts than in control hearts.
Rates of glycolysis and oxidation from glycogen were not different between
hypertrophied and control hearts. A greater proportion of glycogen was oxidized
(80% to 100%) than the proportion of exogenous glucose oxidized (13% to 24%)
in both groups. Additionally, 10.5+/-1.4 and 12.3+/-1.0 micromol/g dry wt
of glycogen was synthesized in hypertrophied and control hearts, respectively,
indicating that simultaneous synthesis and degradation (ie, glycogen turnover)
occurred in both groups. CONCLUSIONS: Thus, aerobic myocardial glycogen metabolism
in the hypertrophied heart is similar to that observed in the normal heart
even though exogenous glucose metabolism is altered in the hypertrophied
heart.
PMID: 9244242 [PubMed - indexed for MEDLINE]
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-
Energy metabolism in normal and hypertrophied
right ventricle of the ferret heart.
Do E, Baudet S, Verdys M, Touzeau C, Bailly F, Lucas-Heron
B, Sagniez M, Rossi A, Noireaud J.
Laboratory of Cellular & Molecular Physiopathology &, Pharmacology,
CJF INSERM 96-01, Grenoble, France.
Using an isolated ferret heart preparation (Langendorff perfusion, perfusion
pressure 90 mmHg), energy metabolism has been characterized in right and
left ventricles from control and hypertrophied hearts. Hypertrophy was induced
by pulmonary artery clipping for 30-45 days (right ventricle wall weight/body
weight ratio increased by 70%). Myocardial contents of high energy phosphate
compounds, glycogen and lactate, and the activities of some enzymes were
biochemically measured in perfused hearts and also after ischemic arrest
(30 min global ischemia). In hypertrophied right ventricles, PCr (-46%),
Cr (-34%) levels, creatine kinase activity (-18%) were significantly decreased
compared with control. ATP and Pi levels were not affected by hypertrophy.
The adenylate energy charges were similar (0.85-0.86) in both types of heart.
The activities of hexokinase (+26%), aldolase (+212%), pyruvate kinase (+14%)
and glucose 6-phosphate dehydrogenase (+107%) were increased by hypertrophy.
The LDH isozyme pattern was significantly changed such that LDH3 was decreased
by 11%, and LDH4 and LDH5 were increased by a factor 1.4 and 2.9 respectively
in hypertrophy. After 30 min of global ischemia, PCr level was decreased
by 89 and 79% in control and hypertrophied ventricles respectively. ATP level
was depressed by 41 in control and only by 21% in hypertrophied muscles.
Altogether, the present data suggested that, in the adult ferret heart, the
capacity for the ATP synthesis could be maintained during hypertrophy by
the enhancement of the glycolytic pathway. The smaller decline of ATP after
ischemia in hypertrophied tissue could be explained by a lower consumption
of ATP in the hypertrophied compared to the control heart during the earliest
period of ischemia.
PMID: 9236144 [PubMed - indexed for MEDLINE]
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-
Decreased GLUT-4 mRNA content and insulin-sensitive
deoxyglucose uptake show insulin resistance in the hypertensive
rat heart.
Paternostro G, Clarke K, Heath J, Seymour AM, Radda
GK.
Department of Biochemistry, University of Oxford, UK.
OBJECTIVES: Insulin resistance in skeletal muscle and adipose tissue often
accompanies hypertension; however, it has not been shown that heart muscle
is similarly affected. The aims of this study were to determine whether basal
and insulin-stimulated glucose transport and glucose transporter mRNA content
are altered in the spontaneously hypertensive rat (SHR) heart. METHODS: Hearts
from 16-18-month-old SHRs were compared to their normotensive (WKY) controls.
The accumulation of 2-deoxyglucose-6-phosphate (2DG6P), detected using 31P
nuclear magnetic resonance spectroscopy, was used to assess glucose uptake
before and during insulin stimulation in the isolated perfused heart. The
mRNA levels of both the insulin-sensitive glucose transporter (GLUT-4) and
the transporter responsible for basal glucose uptake (GLUT-1) were quantified
by Northern blot analysis. RESULTS: The hypertensive rat hearts exhibited
hypertrophy in that the heart/body weight ratio was increased by 59%. In
these hearts, the basal rate of glucose uptake was 3-fold greater and hexokinase
activity was 1.6 fold greater than that of the control rat hearts. On exposure
to insulin, accumulation of 2DG6P increased 5-fold in the control hearts,
but only 1.4-fold in the SHR hearts. Thus, in the presence of insulin, the
rate of glucose uptake by the hypertensive rat heart was significantly (P < 0.05)
reduced, being 82% of control. GLUT-4 mRNA content was decreased was no significant
difference in the GLUT-1 mRNA content. CONCLUSION: We have demonstrated insulin
resistance in the hypertrophied heart of the hypertensive rat that may have
a molecular basis in a lower GLUT-4 content.
PMID: 7585807 [PubMed - indexed for MEDLINE]
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Comment in:
Insulin resistance in patients with cardiac hypertrophy.
Paternostro G, Pagano D, Gnecchi-Ruscone T, Bonser RS,
Camici PG.
MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital,
London, UK.
OBJECTIVE: Animal studies suggest that left ventricular hypertrophy might
be associated with insulin resistance and alterations in glucose transporters.
We have previously demonstrated myocardial insulin resistance in patients
with post-ischemic heart failure. The aim was to investigate whether myocardial
insulin resistance could be demonstrated in human cardiac hypertrophy in
the absence of hypertension, diabetes and coronary artery disease. METHODS:
Eleven normotensive nondiabetic patients with cardiac hypertrophy due to
aortic stenosis and angiographically normal coronary arteries were compared
to 11 normal volunteers. Myocardial glucose uptake (MGU) was measured with
positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose during fasting
(low insulinemia) or during euglycemic-hyperinsulinemic clamp (physiologic
hyperinsulinemia). Myocardial biopsies were obtained in order to investigate
changes in insulin-independent (GLUT-1) and insulin-dependent (GLUT-4) glucose
transporters. RESULTS: During fasting, plasma insulin (7 +/- 1 vs. 6 +/-
1 mU/l) and MGU (0.12 +/- 0.05 vs. 0.11 +/- 0.04 mumol/min/g) were comparable
in patients and controls. By contrast, during clamp, MGU was markedly reduced
in patients (0.48 +/- 0.02 vs. 0.70 +/- 0.03 mumol/min/g, p < 0.01) despite
similar plasma insulin levels (95 +/- 6 vs. 79 +/- 6 mU/l). A decreased GLUT-4/GLUT-1
ratio was shown by Western blot analysis in patients. CONCLUSIONS: Insulin
resistance seems to be a feature of the hypertrophied heart even in the absence
of hypertension, coronary artery disease and diabetes and may be explained,
at least in part, by abnormalities in glucose transporters.
PMID: 10435017 [PubMed - indexed for MEDLINE]
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-
Effect of transient ischemia on the
expression of glucose transporters GLUT-1 and GLUT-4 in
rat myocardium.
Tardy-Cantalupi I, Montessuit C, Papageorgiou I, Remondino-Muller
A, Assimacopoulos-Jeannet F, Morel DR, Lerch R.
Department of Internal Medicine, University Hospital, Geneva, Switzerland.
A number of observations indicate that myocardial glucose utilization is
increased late during post-ischemic reperfusion. The present study was designed
to examine whether transient ischemia elicits altered expression of glucose
transporters GLUT-1 and GLUT-4. In rats, the left anterior descending coronary
artery was occluded for 20 min followed by reperfusion for 1, 3 or 7 days.
Regional myocardial uptake and phosphorylation of glucose was determined
based on myocardial accumulation of 2-deoxy-D-[2, 6-3H]glucose-6-phosphate.
In hearts from fasted rats, after 3 days of reperfusion, myocardial uptake
and phosphorylation of glucose was 48% higher in the reperfused region compared
to a remote control region. No regional difference in myocardial glucose
uptake and phosphorylation was detectable in hearts from fed rats. After
1 day of reperfusion, expression of myocardial glucose transporter GLUT-1
mRNA was increased to 195+/-24% (mean+/-SEM) of the value measured in the
remote region and the expression of GLUT-4 mRNA was decreased to 58+/-7%.
After 3 days of reperfusion both mRNA and protein of GLUT-1 were higher in
the reperfused region, averaging 133+/-23% and 249+/-36%, respectively. The
corresponding values for GLUT-4 mRNA and protein were 77+/-7% and 62+/-6%,
respectively. The results indicate that a short period of ischemia alters
the expression of glucose transporter isoforms GLUT-1 and GLUT-4. Observed
changes may be involved in the mechanisms underlying late changes of substrate
metabolism during reperfusion. Copyright 1999 Academic Press.
PMID: 10336852 [PubMed - indexed for MEDLINE]
22. Rosenblatt-Velin N, Brink M, Delafontaine P Angiotensin
II increases GLUT-1 mRNA gene expression in rat myocardium [abstract]. Eur
Heart J 1999; 20: S600.
-
Transcriptional activation of the glucose
transporter GLUT1 in ventricular cardiac myocytes by hypertrophic
agonists.
Montessuit C, Thorburn A.
Department of Oncological Sciences, Program in Human Molecular Biology and
Genetics, Departments of Oncological Sciences, Human Genetics, and Internal
Medicine, University of Utah, Salt Lake City, Utah 84112, USA. christophe.montessuit@hci.utah.edu
Myocardial hypertrophy is associated with increased basal glucose metabolism.
Basal glucose transport into cardiac myocytes is mediated by the GLUT1 isoform
of glucose transporters, whereas the GLUT4 isoform is responsible for regulatable
glucose transport. Treatment of neonatal cardiac myocytes with the hypertrophic
agonist 12-O-tetradecanoylphorbol-13-acetate or phenylephrine increased expression
of Glut1 mRNA relative to Glut4 mRNA. To study the transcriptional regulation
of GLUT1 expression, myocytes were transfected with luciferase reporter constructs
under the control of the Glut1 promoter. Stimulation of the cells with 12-O-tetradecanoylphorbol-13-acetate
or phenylephrine induced transcription from the Glut1 promoter, which was
inhibited by cotransfection with the mitogen-activated protein kinase phosphatases
CL100 and MKP-3. Cotransfection of the myocytes with constitutively active
versions of Ras and MEK1 or an estrogen-inducible version of Raf1 also stimulated
transcription from the Glut1 promoter. Hypertrophic induction of the Glut1
promoter was also partially sensitive to inhibition of the phosphatidylinositol
3-kinase pathway and was strongly inhibited by cotransfection with dominant-negative
Ras. Thus, Ras activation and pathways downstream of Ras mediate induction
of the Glut1 promoter during myocardial hypertrophy.
PMID: 10085148 [PubMed - indexed for MEDLINE]
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-
Post-ischemic stimulation of 2-deoxyglucose
uptake in rat myocardium: role of translocation of Glut-4.
Montessuit C, Papageorgiou I, Remondino-Muller A, Tardy
I, Lerch R.
Cardiology, Department of Internal Medicine, University Hospital of Geneva,
Switzerland.
Myocardial ischemia elicits translocation of the insulin-sensitive glucose
transporter GLUT-4 from intracellular membrane stores to the sarcolemma.
Because glucose metabolism is of crucial importance for post-ischemic recovery
of the heart, myocardial uptake of [3H]-labeled 2-deoxyglucose and subcellular
localization of GLUT-4 were determined during reperfusion in isolated rat
hearts perfused with medium containing 0.4 mm palmitate and 8 mm glucose.
Hearts were subjected to 20 min of no-flow ischemia, followed by reperfusion
for up to 60 min. Subcellular localization of GLUT-4 was determined by cell
fractionation followed by immunoblotting. After 15 and 60 min of reperfusion
uptake of 2-deoxyglucose was significantly higher (91+/-9 and 96+/-8 nmol/min/g
wet weight, respectively) as compared to control values (65+/-1 nmol/min/g
wet weight). Ischemia elicited translocation of GLUT-4 to the sarcolemma,
which persisted after 15 min of reperfusion. However, after 60 min of reperfusion
the subcellular distribution of GLUT-4 was similar to control hearts. In
conclusion, reversal of ischemia-induced translocation of GLUT-4 to the sarcolemma
is rather slow, possibly facilitating glucose uptake early during reperfusion.
However, myocardial uptake and phosphorylation of 2-deoxyglucose remains
enhanced late during reperfusion, when pre-ischemic distribution of GLUT-4
is almost completely restored, indicating that additional mechanisms are
likely to be involved in post-ischemic stimulation of glucose uptake.Copyright
1998 Academic Press Limited.
PMID: 9515016 [PubMed - indexed for MEDLINE]
25. Rosenblatt-Velin N, Papageorgiou I, Terrand J Progression
from hypertrophy to heart failure is associated with upregulation of GLUT1
[abstract]. J Mol Cell Cardiol 1999; 31: A77.
-
Substrate competition in postischemic
myocardium. Effect of substrate availability during reperfusion
on metabolic and contractile recovery in isolated rat hearts.
Tamm C, Benzi R, Papageorgiou I, Tardy I, Lerch R.
Cardiology Center, University Hospital, Geneva, Switzerland.
Normal myocardium can derive energy for contraction and relaxation from oxidative
metabolism of a variety of substrates. This investigation examined the influence
of substrate availability early during reperfusion on the substrate pattern
of oxidative metabolism and recovery of contractile function. For this purpose,
isovolumically beating isolated rat hearts, perfused retrogradely with erythrocyte-supplemented
buffer containing 0.4 mmol/L palmitate and 11 mmol/L glucose, were subjected
to 40 minutes of no-flow ischemia. Hearts were reperfused with medium containing
selected concentrations of palmitate and glucose. The substrate pattern for
oxidative metabolism was determined on the basis of myocardial release of
14CO2 after equilibration of the hearts during the initial 15 minutes of
reperfusion with either [1-14C]palmitate or [U-14C]glucose. In continuously
perfused control hearts, glucose oxidation was largely inhibited by palmitate.
During postischemic reperfusion, oxidation of glucose was increased by 59%
(P < .05) and 467% (P <.01) in hearts reperfused after the ischemic
period with 11 mmol/L glucose plus 0.4 or 1.2 mmol/L palmitate, respectively.
Oxidation of palmitate was concomitantly reduced during reperfusion at low
(0.4 mmol/L) but not at high (1.2 mmol/L) palmitate concentration. Compared
with hearts reperfused with medium containing 0.4 mmol/L palmitate as sole
substrate, hearts reperfused with medium containing 11 mmol/L glucose with
0.4 mmol/L palmitate exhibited lower left ventricular diastolic pressure
(69 +/- 5 versus 90 +/- 3 mm Hg [mean +/- SEM], P < .05), less release
of creatine kinase (31 +/- 5 versus 59 +/- 7 U/g wet wt, P < .05), and
better recovery of left ventricular pressure development (26 +/- 9 versus
6 +/- 4 mm Hg, P < .05). Omission of palmitate or increasing the palmitate
concentration to 1.2 mmol/L did not significantly alter postischemic myocardial
contracture and enzyme release. The findings support the view that glucose
oxidation early during reperfusion may be crucial for functional recovery.
The results further indicate that interaction of substrates of oxidative
metabolism is altered in severely injured postischemic myocardium. Inhibition
of glucose oxidation by fatty acids was partially reversed during reperfusion.
PMID: 7955147 [PubMed - indexed for MEDLINE]
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-
The effects of hypertrophy and diabetes
on cardiac pyruvate dehydrogenase activity.
Seymour AM, Chatham JC.
Department of Biological Sciences, University of Hull, Cottingham Road, Hull,
HU6 7RX, UK.
Alterations in substrate selection and utilisation are characteristics of
heart failure of different etiologies and these changes may be involved in
the development of contractile dysfunction. Regulation of pyruvate dehydrogenase
(PDH) is crucial in determining the relative contribution of glucose oxidation
to energy production; however, the role of PDH in the development of heart
failure has not been clarified. In this study, we present a reliable and
simple method for assaying both the active and total forms of PDH (PDHa and
PDHt respectively) in cardiac tissue, and have compared the effects of pressure
overload hypertrophy and diabetes on PDH activity. PDHa and PDHt were measured
in extracts of hypertrophied hearts after 5 weeks of pressure overload or
in hearts after 7 weeks following induction of diabetes. There was no significant
change in PDHt in the hypertrophied group, but the fraction of PDH in the
active form significantly decreased from 61+/-1% in controls to 36+/-1% (P<0.05).
Following diabetes, there was a decrease in the ratio of PDHa:PDHt from 60+/-3%
to 11+/-1% (P<0.0001) and PDHt activity -6.2+/-0.9 to 2.7+/-0.4 micromol/min/g
wet weight (P<0.02)]. This study reports for the first time that (i) concomitant
with the development of compensated hypertrophy, there is a decrease in the
fraction of PDH in the active form; and (ii) in the diabetic heart, there
is marked decrease in total PDH activity in addition to a decrease in the
fraction of PDH in the active form. These results indicate that myocardial
substrate delivery to the mitochondria may be impaired in both hypertrophy
and diabetes, which may lead to the energy depleted state observed in heart
failure. Copyright 1997 Academic Press Limited.
PMID: 9344771 [PubMed - indexed for MEDLINE]
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A role for Sp and nuclear receptor transcription
factors in a cardiac hypertrophic growth program.
Sack MN, Disch DL, Rockman HA, Kelly DP.
Department of Medicine, Washington University School of Medicine, St. Louis,
MO 63110, USA.
During cardiac hypertrophy, the chief myocardial energy source switches from
fatty acid beta-oxidation (FAO) to glycolysis-a reversion to fetal metabolism.
The expression of genes encoding myocardial FAO enzymes was delineated in
a murine ventricular pressure overload preparation to characterize the molecular
regulatory events involved in the alteration of energy substrate utilization
during cardiac hypertrophy. Expression of genes involved in the thioesterification,
mitochondrial import, and beta-oxidation of fatty acids was coordinately
down-regulated after 7 days of right ventricular (RV) pressure overload.
Results of RV pressure overload studies in mice transgenic for the promoter
region of the gene encoding human medium-chain acyl-CoA dehydrogenase (MCAD,
which catalyzes a rate-limiting step in the FAO cycle) fused to a chloramphenicol
acetyltransferase reporter confirmed that repression of MCAD gene expression
in the hypertrophied ventricle occurred at the transcriptional level. Electrophoretic
mobility-shift assays performed with MCAD promoter fragments and nuclear
protein extracts prepared from hypertrophied and control RV identified pressure
overload-induced protein/DNA interactions at a regulatory unit shown previously
to confer control of MCAD gene transcription during cardiac development.
Antibody "supershift" studies demonstrated that members of the
Sp (Sp1, Sp3) and nuclear hormone receptor [chicken ovalbumin upstream promoter
transcription factor (COUP-TF)/erbA-related protein 3] families interact
with the pressure overload-responsive unit. Cardiomyocyte transfection studies
confirmed that COUP-TF repressed the transcriptional activity of the MCAD
promoter. The DNA binding activities and nuclear expression of Sp1/3 and
COUP-TF in normal fetal mouse heart were similar to those in the hypertrophied
adult heart. These results identify a transcriptional regulatory mechanism
involved in the reinduction of a fetal metabolic program during pressure
overload-induced cardiac hypertrophy.
PMID: 9177236 [PubMed - indexed for MEDLINE
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-
Factors involved in GLUT-1 glucose transporter
gene transcription in cardiac muscle.
Santalucia T, Boheler KR, Brand NJ, Sahye U, Fandos
C, Vinals F, Ferre J, Testar X, Palacin M, Zorzano A.
Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Diagonal
645, Universitat de Barcelona, Barcelona 08028, Spain.
Glucose constitutes a major fuel for the heart, and high glucose uptake during
fetal development is coincident with the highest level of expression of the
glucose transporter GLUT-1 during life. We have previously reported that
GLUT-1 is repressed perinatally in rat heart, and GLUT-4, which shows a low
level of expression in the fetal stage, becomes the main glucose transporter
in the adult. Here, we show that the perinatal expression of GLUT-1 and GLUT-4
glucose transporters in heart is controlled directly at the level of gene
transcription. Transient transfection assays show that the -99/-33 fragment
of the GLUT-1 gene is sufficient to drive transcriptional activity in rat
neonatal cardiomyocytes. Electrophoretic mobility shift assays demonstrate
that the transcription factor Sp1, a trans-activator of GLUT-1 promoter,
binds to the -102/-82 region of GLUT-1 promoter during the fetal state but
not during adulthood. Mutation of the Sp1 site in this region demonstrates
that Sp1 is essential for maintaining a high transcriptional activity in
cardiac myocytes. Sp1 is markedly down-regulated both in heart and in skeletal
muscle during neonatal life, suggesting an active role for Sp1 in the regulation
of GLUT-1 transcription. In all, these results indicate that the expression
of GLUT-1 and GLUT-4 in heart during perinatal development is largely controlled
at a transcriptional level by mechanisms that might be related to hyperplasia
and that are independent from the signals that trigger cell hypertrophy in
the developing heart. Furthermore, our results provide the first functional
insight into the mechanisms regulating muscle GLUT-1 gene expression in a
live animal.
PMID: 10364200 [PubMed - indexed for MEDLINE]
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Rate of glycolysis during ischemia determines
extent of ischemic injury and functional recovery after
reperfusion.
Vanoverschelde JL, Janier MF, Bakke JE, Marshall DR,
Bergmann SR.
Cardiovascular Division, Washington University School of Medicine, St. Louis,
Missouri 63110.
The efficacy of increasing glycolysis during ischemia for enhancing the salutary
effects of reperfusion was evaluated in isolated perfused rabbit hearts subjected
to low-flow ischemia followed by reperfusion. Control hearts were perfused
with buffer containing 0.4 mM palmitate, 5 mM glucose, and 70 mU/l insulin.
Additional groups of hearts were perfused with double glucose/insulin and
1 mM dichloroacetate or were subjected to substrate priming to increase preischemic
glycogen content. Ischemic contracture was completely prevented in hearts
perfused with high glucose/insulin and was delayed markedly by either dichloroacetate
or enhanced preischemic glycogen [45 +/- 14 and 31 +/- 20 min, respectively;
P < 0.01 each vs. control (11 +/- 10 min)] and inversely related to the
rate of lactate production. With reperfusion, recovery of developed pressure
was 56 +/- 23% of baseline in control hearts, 90 +/- 8% in hearts receiving
high glucose/insulin, 92 +/- 5% in hearts receiving dichloroacetate, and
79 +/- 19% in hearts with increased glycogen (P < 0.05 each vs. control
hearts). Creatine kinase release was reduced by > 55% in treated hearts.
Thus enhancement of glycolysis by diverse mechanisms during ischemia decreased
ischemic damage and improved the recovery of contractile function with reperfusion.
PMID: 7977809 [PubMed - indexed for MEDLINE]
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Relation between glycolysis and calcium
homeostasis in postischemic myocardium.
Jeremy RW, Koretsune Y, Marban E, Becker LC.
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md.
This study examined the hypothesis that glycolysis is required for functional
recovery of the myocardium during reperfusion by facilitating restoration
of calcium homeostasis. [Ca2+]i was measured in isolated perfused rabbit
hearts by using the Ca2+ indicator 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic
acid (5F-BAPTA) and 19F nuclear magnetic resonance spectroscopy. In nonischemic
control hearts, inhibition of glycolysis with iodoacetate did not alter [Ca2+]i.
In hearts subjected to 20 minutes of global zero-flow ischemia, [Ca2+]i increased
from 260 +/- 80 nM before ischemia to 556 +/- 44 nM after 15 minutes of ischemia
(p less than 0.05). After reperfusion with 5 mM pyruvate as a carbon substrate,
[Ca2+]i increased further in hearts with intact glycolysis to 851 +/- 134
nM (p less than 0.05 versus ischemia) during the first 10 minutes of reperfusion,
before returning to preischemic levels. In contrast, inhibition of glycolysis
during the reperfusion period resulted in persistent severe calcium overload
([Ca2+]i, 1,380 +/- 260 nM after 15 minutes of reperfusion, p less than 0.02
versus intact glycolysis group). Furthermore, despite the presence of pyruvate
and oxygen, inhibition of glycolysis during early reperfusion resulted in
greater impairment of functional recovery (rate/pressure product, 3,722 +/-
738 mm Hg/min) than did reperfusion with pyruvate and intact glycolysis (rate/pressure
product, 9,851 +/- 590 mm Hg/min, p less than 0.01). Inhibition of glycolysis
during early reperfusion was also associated with a marked increase in left
ventricular end-diastolic pressure during reperfusion (41 +/- 5 mm Hg) compared
with hearts with intact glycolysis (16 +/- 2 mm Hg, p less than 0.01). The
detrimental effects of glycolytic inhibition during early reperfusion were,
however, prevented by initial reperfusion with a low calcium solution ([Ca]o,
0.63 mM for 30 minutes, then 2.50 mM for 30 minutes). In these hearts, the
rate/pressure product after 60 minutes of reperfusion was 12,492 +/- 1,561
mm Hg/min (p less than 0.01 versus initial reflow with [Ca]o of 2.50 mM).
These findings indicate that the functional impairment observed in postischemic
myocardium is related to cellular Ca2+ overload. Glycolysis appears to play
an important role in restoration of Ca2+ homeostasis and recovery of function
of postischemic myocardium.
PMID: 1576739 [PubMed - indexed for MEDLINE]
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-
The functional recovery of post-ischemic
myocardium requires glycolysis during early reperfusion.
Jeremy RW, Ambrosio G, Pike MM, Jacobus WE, Becker LC.
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD
21205.
Glycolysis normally provides only a small fraction of myocardial ATP production,
but ATP from glycolysis may be preferentially used to support membrane activities
such as ion pumping. Since ion homeostasis is disturbed during ischemia,
glycolysis may be particularly important in the recovery of postischemic
myocardium. This hypothesis was investigated in isovolumic, isolated rabbit
hearts, perfused with 16 mM glucose, 5 mM pyruvate or 5 mM acetate. Global
left ventricular function (rate-pressure product, RPP) and unidirectional
ATP synthesis rate (P(i)-->ATP flux, 31P NMR) were measured before and
after 20 min global ischemia. Control hearts with intact glycolysis were
compared with hearts which had glycolysis inhibited by iodoacetate (150 microM),
2-deoxyglucose (10 mM) or prior glycogen depletion. In normal hearts, inhibition
of glycolysis had no effect on function when pyruvate or acetate was present
as as a carbon substrate. In post-ischemic hearts, reperfusion with glucose
(n = 7) resulted in moderate recovery of function to about 65% of pre-ischemic
levels after 1 h reperfusion. Administration of iodoacetate at the onset
of reperfusion to hearts receiving pyruvate or acetate resulted in much worse
functional recovery and a marked rise in left ventricular end-diastolic pressure
(LVEDP). With pyruvate (n = 7), RPP recovered to 27% of pre-ischemic levels,
while mean LVEDP increased to 34 mmHg (vs 16 mmHg with glucose); with acetate
(n = 6), RPP returned to 31% of pre-ischemic levels, while mean LVEDP rose
to 32 mmHg. The ratio of P(i)-->ATP flux to atoms of oxygen consumed (P:O
ratio) was 2.14 +/- 0.36 in hearts reperfused with iodoacetate and pyruvate,
consistent with partial mitochondrial uncoupling. However, if inhibition
of glycolysis with iodoacetate was delayed until after 30 min reperfusion,
recovery of hearts reperfused with pyruvate was similar to hearts perfused
with glucose, and there was no evidence of mitochondrial uncoupling (P:O
ratio = 2.95 +/- 0.33). Inhibition of glycolysis during reperfusion with
2-deoxyglucose yielded results similar to reperfusion with iodoacetate. The
worst recovery was observed in hearts with combined glycolytic inhibition
by pre-ischemic glycogen depletion and iodoacetate during reperfusion (RPP
= 13% of pre-ischemic levels). These findings indicate that glycolysis plays
a crucial role during early reperfusion in the functional and metabolic recovery
of post-ischemic myocardium.
PMID: 8510169 [PubMed - indexed for MEDLINE]
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Glucose uptake and glycolysis reduce
hypoxia-induced apoptosis in cultured neonatal rat cardiac
myocytes.
Malhotra R, Brosius FC 3rd.
Department of Internal Medicine, Division of Nephrology, University of Michigan
Medical Center and the Ann Arbor Veterans Affairs Medical Center, Ann Arbor,
Michigan 48109, USA.
Myocardial ischemia/reperfusion is well recognized as a major cause of apoptotic
or necrotic cell death. Neonatal rat cardiac myocytes are intrinsically resistant
to hypoxia-induced apoptosis, suggesting a protective role of energy-generating
substrates. In the present report, a model of sustained hypoxia of primary
cultures of Percoll-enriched neonatal rat cardiac myocytes was used to study
specifically the modulatory role of extracellular glucose and other intermediary
substrates of energy metabolism (pyruvate, lactate, propionate) as well as
glycolytic inhibitors (2-deoxyglucose and iodoacetate) on the induction and
maintenance of apoptosis. In the absence of glucose and other substrates,
hypoxia (5% CO2 and 95% N2) caused apoptosis in 14% of cardiac myocytes at
3 h and in 22% of cells at 6-8 h of hypoxia, as revealed by sarcolemmal membrane
blebbing, nuclear fragmentation, and chromatin condensation (Hoechst staining),
terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)
staining, and DNA laddering. This was accompanied by translocation of cytochrome
c from the mitochondria to the cytosol and cleavage of the death substrate
poly(ADP-ribose) polymerase. Cleavage of poly(ADP-ribose) polymerase and
DNA laddering were prevented by preincubation with the caspase inhibitors
benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl
ketone (zDEVD-fmk), indicating activation of caspases in the apoptotic process.
The caspase inhibitor zDEVD-fmk also partially inhibited cytochrome c translocation.
The presence of as little as 1 mM glucose, but not pyruvate, lactate, or
propionate, before hypoxia prevented apoptosis. Inhibiting glycolysis by
2-deoxyglucose or iodoacetate, in the presence of glucose, reversed the protective
effect of glucose. This study demonstrates that glycolysis of extracellular
glucose, and not other metabolic pathways, protects cardiac myocytes from
hypoxic injury and subsequent apoptosis.
PMID: 10212235 [PubMed - indexed for MEDLINE]
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Cardiac hypertrophy with preserved contractile
function after selective deletion of GLUT4 from the heart.
Abel ED, Kaulbach HC, Tian R, Hopkins JC, Duffy J, Doetschman
T, Minnemann T, Boers ME, Hadro E, Oberste-Berghaus C,
Quist W, Lowell BB, Ingwall JS, Kahn BB.
Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center
and Harvard Medical School, Boston, Massachusetts 02215, USA. dabel@caregroup.harvard.edu
Glucose enters the heart via GLUT1 and GLUT4 glucose transporters. GLUT4-deficient
mice develop striking cardiac hypertrophy and die prematurely. Whether their
cardiac changes are caused primarily by GLUT4 deficiency in cardiomyocytes
or by metabolic changes resulting from the absence of GLUT4 in skeletal muscle
and adipose tissue is unclear. To determine the role of GLUT4 in the heart
we used cre-loxP recombination to generate G4H(-/-) mice in which GLUT4 expression
is abolished in the heart but is present in skeletal muscle and adipose tissue.
Life span and serum concentrations of insulin, glucose, FFAs, lactate, and
beta-hydroxybutyrate were normal. Basal cardiac glucose transport and GLUT1
expression were both increased approximately 3-fold in G4H(-/-) mice, but
insulin-stimulated glucose uptake was abolished. G4H(-/-) mice develop modest
cardiac hypertrophy associated with increased myocyte size and induction
of atrial natriuretic and brain natriuretic peptide gene expression in the
ventricles. Myocardial fibrosis did not occur. Basal and isoproterenol-stimulated
isovolumic contractile performance was preserved. Thus, selective ablation
of GLUT4 in the heart initiates a series of events that results in compensated
cardiac hypertrophy.
PMID: 10606624 [PubMed - indexed for MEDLINE]
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