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Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
1Correspondence: Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, P.O. Box 616, 6200 MD Maastricht, the Netherlands. E-mail: Karin.vdLee{at}FYS.Unimaas.NL
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, but not to PPAR
, acted as inducers of
cardiomyocyte UCP-2 expression. It is concluded that fatty acids
promote UCP-2 expression in neonatal cardiomyocytes, which might
explain the rapid increase in UCP-2 mRNA in the postnatal heart.
However, UCP-2 mRNA levels in the adult heart appear to be insensitive
to changes in cardiac fatty acid handling under various pathological
conditions.—van der Lee, K. A. J. M., Willemsen,
P. H. M., van der Vusse, G. J., van Bilsen, M. Effects
of fatty acids on uncoupling protein-2 expression in the rat heart.
Key Words: cardiomyocytes • metabolism • UCP • gene expression
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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have shown that fatty acids increase cardiac oxygen
consumption for the same amount of external work when applied to the
isolated perfused rat heart. This indicates uncoupling of mitochondrial
respiratory chain activity and ATP production. Later studies
demonstrated progressive uncoupling in heart mitochondria when rats
were fed a lipid-enriched diet (2)
.
The uncoupling protein (UCP) is known to uncouple oxidative
phosphorylation by moving protons across the mitochondrial inner
membrane toward the mitochondrial matrix (reviewed in ref
3
). Whereas the first uncoupling protein (UCP-1) was
reported two decades ago, two other members of the family (i.e., UCP-2
and -3) have recently been cloned (4
5
6)
. UCP-3 is
expressed mainly in brown adipose tissue and skeletal muscle, whereas
UCP-2 is more ubiquitously distributed. Since expression of UCP-2 is
relatively high in heart tissue (4
, 5)
, it is feasible
that UCP-2 mediates the fatty acid-induced uncoupling effects observed
in this organ. Indeed, fatty acids have been demonstrated to enhance
the uncoupling activity of UCP (7)
. Therefore, we propose
a close functional relationship between fatty acid handling and
uncoupling proteins in cardiac tissue.
Recently we demonstrated in neonatal cardiomyocytes that fatty acids
regulate the expression of genes encoding proteins involved in fatty
acid transport and metabolism (8)
. Other studies suggested
that fatty acids may also be implicated in the regulation of UCP-2
expression. For instance, skeletal muscle UCP-2 mRNA levels in rat and
human were found to increase during fasting, a condition associated
with a rise in plasma fatty acid levels (9
10
11)
.
Subsequent refeeding of rats resulted in a decline in plasma fatty acid
levels and a concomitant decrease in skeletal muscle UCP-2 expression
(11)
.
The first aim of the present study was to investigate whether
cardiac UCP-2 mRNA levels change during heart development and under
(patho)physiological conditions associated with changes in fatty acid
utilization in the adult heart, i.e., fasting, diabetes and cardiac
hypertrophy. Second, it was determined whether UCP-2 expression is
up-regulated in cultured neonatal cardiomyocytes and embryonic rat
heart-derived H9c2 cells after exposure to fatty acids and/or after
stimulation with the 1-adrenergic agonist
phenylephrine or the thyroid hormone triiodothyronine (T3). Finally,
the possible involvement of peroxisome proliferator-activated receptors
(PPARs), transcription factors known to be activated by fatty acids
(12
, 13)
, in neonatal cardiomyocyte UCP-2 expression was
explored.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Heart, soleus, extensor digitorum longus (EDL), and gastrocnemius muscles were dissected from adult (10-wk-old) Wistar Kyoto rats. Hearts were also obtained at birth (day 0) and at 2, 6, and 21 days. Hearts from fetal rats were obtained by killing pregnant rats, on day 21 of pregnancy (day 1).
Insulin-dependent diabetes was evoked in 3-month-old male Wistar rats
(Winkelmann, Borchen, Germany) by a single intravenous (i.v.) injection
of streptozotocin (55 mg/kg body weight) as described elsewhere
(14)
. Rats were killed after 3 wk, when body weight had
decreased by 27% and plasma glucose levels had increased from 7.0
± 0.7 mM to 22.5 ± 2.7 mM (14)
.
Cardiac hypertrophy was induced by suprarenal aorta banding as
described previously (15)
. After anesthetization of 6- or
7-wk-old male Lewis rats with pentobarbital (0.06 mg/g body weight
i.p.), a lateral abdominal incision was made. In the experimental
group, a ligature was tightened suprarenally around the abdominal
aorta. In sham-operated animals, the aorta was only dissected free. The
abdomen was closed and the rats were allowed to recover. After 4 wk
animals were killed and mean heart to body weight ratio had increased
by 24%.
Hearts of 6-wk-old male Sprague-Dawley rats, either fasted for 46 h or fed ad libitum, were a generous gift from Dr. S. Samec
and Dr. A. Dulloo, University of Geneva, Switzerland. In the serum of
fasted rats, fatty acid levels had increased threefold (1.33±0.25 mM
vs. 0.45±0.13 mM) at the time of death (16)
.
Rats subjected to the different treatments were killed by cervical dislocation, except for rats previously subjected to sham or aorta banding operations whose hearts were excised after anesthesia with pentobarbital (0.06 mg/g body weight i.p.). After excision, tissues were immediately frozen in liquid nitrogen and stored at -80°C until further analysis.
Cell culture
Primary cultures of ventricular myocytes from 0- to 3-day-old
neonatal rats were prepared as described previously (17)
.
Cardiomyocytes were plated at low density (40,000
cells/cm2) in tissue culture dishes coated with
1% gelatin type B (Sigma, St. Louis Mo.) in a 4:1 mixture of DMEM
(Life Technologies, Inc.-BRL, Gaithersburg, Md.) and M199 (Life
Technologies) supplemented with 10% horse serum (Life Technologies),
5% newborn calf serum (Sera-Lab, Sussex, U.K.), and antibiotics (P/S;
penicillin 100 IU/ml and streptomycin 0.1 mg/ml, Life Technologies).
Cells were incubated overnight in this serum-rich medium.
H9c2 cells (ATCC CRL-1446; Rockville, Md.) were maintained in a growth medium composed of DMEM supplemented with 10% fetal bovine serum (Life Technologies). Medium was changed every 3 to 4 days. H9c2 cells were plated at a density of 2000 cells/cm2 and allowed to proliferate in growth medium until reaching confluency.
Experiments with neonatal cardiomyocytes as well as H9c2 cells started
with a 24 h incubation in serum-free medium of a 4:1 mixture of
DMEM/M199, containing P/S and 10 mM glucose as the sole substrate.
Subsequently, substrate-free medium (4:1 mixture of DMEM and M199 with
P/S) containing 0.25 mM L-carnitine and 0.25 mU/ml insulin
was applied to the cells. This medium was supplemented with different
substrates or a combination of substrates. The first experimental group
received only glucose (final concentration, 10 mM) as substrate. Bovine
serum albumin (BSA 0.15 mM; Sigma) was also added to the medium to
allow for a proper comparison between the glucose group and the
experimental groups, which received medium containing the fatty
acid/BSA complex. The second group received a mixture of palmitic acid
(C16:0) and oleic acid (C18:1) (0.25 mM each, complexed to 0.15 mM BSA
as described elsewhere; ref 17
). The third group received
a combination of both substrates: glucose (10 mM) and C16:0/C18:1 (0.25
mM each). Cells were harvested after 48 h.
To induce in vitro hypertrophy, neonatal cardiac myocytes were stimulated with 10 µM phenylephrine (PE; Sigma). In addition, neonatal cardiomyocytes were stimulated with 10 nM triiodothyronine (T3; Sigma). Both agents were added to the medium 48 h before harvesting.
Furthermore, 100 µM Wy-14,643 (Biomol, Plymouth Meeting, Pa.) or 10
µM ciglitazone (Biomol), specific ligands for PPAR and PPAR,
respectively, were added to neonatal cardiomyocytes 48 h prior to
harvesting. The cardiomyocytes were cultured in medium containing
glucose as the sole substrate. Both compounds were dissolved in DMSO to
obtain a 1000x stock solution.
Northern analysis
Total RNA was isolated with TRIzol reagent (Life Technologies).
Ten or 20 µg total RNA was size-fractionated on a denaturing gel (1%
agarose, 5% formaldehyde, 1x MOPS), transferred to a nylon membrane
(Hybond-N, Amersham, Slough, U.K.) by capillary transfer, and fixed
using standard techniques. After prehybridization, the filters were
probed with a 0.9 kb EcoRI-SacI fragment of rat
UCP-2 cDNA (kindly provided by Dr. D. Riquier, Center National de la
Recherche Scientifique, Meudon, France), a 0.5 kb
KpnI-BamHI fragment of mouse muscle-type
carnitine palmitoyl transferase 1 (mCPT1; a gift of Dr. F. van de Leij,
Rijksuniversiteit Groningen, the Netherlands), or a 1.5 kb
XhoI-NcoI fragment of rat hexokinase II (HKII;
kindly provided by Dr. E. Wilson, Michigan State University, East
Lansing, Mich.). The cDNA probes were labeled with
[-32P]dCTP (3000 Ci/mmol; Amersham) by
random priming (Radprime, Life Technologies) to a specific activity of
>0.5 x 109 cpm/µg DNA. To correct for
possible differences in transfer and loading, the filters were also
hybridized with 32P-labeled ribosomal 18S probe.
After hybridization, filters were washed at the appropriate stringency
to remove nonspecific binding. The filters were exposed to phosphor
imaging screens, subsequently scanned with a PhosphorImager (Molecular
Dynamics, Sunnyvale, Calif.), and quantified using ImageQuant
software (Molecular Dynamics).
Protein content and cell area
Total protein content of neonatal cardiomyocytes was quantified
using the micro BCA method (Pierce, Rockford, Ill.) with BSA as
standard. Cell area was assessed using Scion Image Software
(http://scioncorp.com/) after monitoring with a CCD camera.
Statistics
Results are presented as mean percentage of the control
group ± SD. Comparison between two groups was
performed with a two-tailed Student’s t test for unpaired
data. Comparison between multiple groups was performed with one-way
analysis of variance (ANOVA). In case the F ratio obtained indicated
that significant differences between groups were present, the
Student’s t test was carried out, applying Bonferroni’s
adjustment for multiple comparison (18)
. Differences were
considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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shows that expression of UCP-2 is relatively low in each of the
skeletal muscle types examined, which are the fast-twitch glycolytic
EDL, the slow-twitch oxidative soleus, and the fast-twitch
glycolytic-oxidative gastrocnemius muscles. In contrast, expression of
UCP-2 in cardiac muscle far exceeds UCP-2 mRNA levels in skeletal
muscle, confirming that UCP-2 is abundantly expressed in the heart.
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Second, UCP-2 mRNA levels in heart tissue were determined during and
after the perinatal period (Fig. 2
). In the fetal heart, expression of UCP-2 was rather low. At birth,
when plasma fatty acid levels rise and cardiac fatty acid utilization
increases (19)
, UCP-2 mRNA levels increased threefold.
Plateau levels were reached within 3 wk thereafter. In the adult heart,
UCP-2 mRNA levels were approximately five times higher than before
birth.
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UCP-2 expression in the adult heart under (patho)physiological
conditions
In the adult heart, fatty acid utilization changes under different
(patho)physiological conditions. Whereas cardiac fatty acid utilization
increases during fasting and diabetes (20
, 21)
, it
decreases during cardiac hypertrophy (22)
. To examine
whether these changes are accompanied by alterations in the expression
of UCP-2, UCP-2 mRNA levels were determined in hearts of fasted,
diabetic, and aorta-banded rats. Fasting and streptozotocin-induced
diabetes did not significantly alter the mRNA content of UCP-2 in the
rat heart (Table 1
). Furthermore, in hypertrophied hearts of aorta-banded rats, expression
of UCP-2 remained unchanged compared to hearts of sham-operated
animals. To ascertain that the (patho)physiological conditions do
affect the expression of genes involved in cardiac metabolism, the mRNA
levels of the muscle-type carnitine palmitoyl transferase 1 (mCPT1) and
hexokinase II (HKII) were also determined (Table 1)
. Indeed, mCPT1 gene
expression was increased during fasting and tended to decrease during
cardiac hypertrophy (P<0.07), whereas HKII mRNA levels were
significantly decreased or tended to decrease in all three conditions.
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Fatty acid-induced expression of the UCP-2 gene in
vitro
To examine whether expression of UCP-2 can be regulated by fatty
acids, rat neonatal cardiomyocytes and embryonic rat heart-derived H9c2
cells were used as in vitro cardiac model systems. Neonatal
rat ventricular myocytes and H9c2 cells were cultured in the presence
of glucose, fatty acids (palmitic acid and oleic acid), or a
combination of both for 48 h. When neonatal cardiomyocytes were
exposed to fatty acids, either in the absence or presence of glucose,
UCP-2 expression increased >eightfold as compared to cells receiving
glucose as the sole substrate (Fig. 3
). In H9c2 cells, UCP-2 mRNA levels were also increased (>fourfold) in
the presence of fatty acids. As in vivo data suggested a
relationship between serum insulin levels and UCP2 expression in white
adipose tissue (23)
and insulin was routinely added to the
culture medium, it was also checked whether insulin affected fatty
acid-induced UCP-2 expression in neonatal cardiomyocytes. In the
absence and presence of different levels of insulin (0.025 and 0.25
mU/ml), fatty acids gave rise to a comparable increase (7- to 10-fold)
of the UCP-2 mRNA content (data not shown).
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Effects of phenylephrine and triiodothyronine on UCP-2 expression
in vitro
To investigate whether an in vitro effect on UCP-2
expression could be found under hypertrophic conditions, neonatal
cardiomyocytes were stimulated with the
1-adrenergic agonist PE in the presence or
absence of fatty acids for 48 h. Administration of PE (10 µM)
resulted in a 1.45 ± 0.06 fold rise in cellular protein content.
Mean cell area of ventricular myocytes increased from 91.3 ± 15.0
µm2 to 129.6 ± 15.1 µm2. UCP-2 mRNA
levels, however, were not affected by PE stimulation, irrespective of
the substrate composition of the culture medium (Fig. 4
). In contrast, stimulation of the cells with the thyroid hormone T3 (10
nM) resulted in a twofold increased UCP-2 expression, though only in
the presence of fatty acids.
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Effects of PPAR ligands on UCP-2 expression in vitro
Next it was examined whether PPAR could be involved in the fatty
acid-induced up-regulation of UCP-2 in neonatal cardiomyocytes. To this
end, neonatal rat ventricular myocytes receiving glucose as the only
substrate were exposed to either the PPAR specific ligand Wy-14,643
(100 µM) or the PPAR specific ligand ciglitazone (10 µM) for
48 h. Figure 5
demonstrates that the presence of the PPAR ligand, but not the
PPAR ligand, dramatically increases UCP-2 gene expression. Addition
of Wy-14,643 and ciglitazone in various concentrations (1.0–1000 µM
and 0.1–100 µM respectively; not shown) demonstrated that Wy-14,643
had already induced UCP-2 gene expression at a dose of 1.0 µM and was
maximally effective at 100 µM, whereas ciglitazone did not affect
UCP-2 expression even at the highest dose applied.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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UCP-2 expression in adult rat heart
During fasting and insulin-dependent diabetes, both plasma fatty
acid levels and cardiac fatty acid oxidation increase in rats
(20
, 21
, 24)
. These conditions are associated with changes
in the expression of various genes involved in cardiac metabolism, as
reported previously for heart-type fatty acid binding protein
(25
, 26)
and demonstrated for mCPT1 and HKII (see Table 1
). In this respect, the absence of changes in cardiac UCP-2 mRNA
levels is remarkable. In addition, cardiac hypertrophy, a condition
associated with a decreased cardiac fatty acid oxidation
(22)
and concomitant down-regulation of the expression of
genes involved in fatty acid metabolism (27)
, does not
affect UCP-2 expression either. The current findings are in line with
recent observations by Hidaka and colleagues (28)
, who
demonstrated that both fasting and streptozotocin-induced diabetes
results in enhanced UCP-3, but not UCP-2 mRNA levels, in the rat heart.
From the literature, the picture emerges that the regulation of
UCP-2 expression in response to various stimuli is highly tissue
dependent. Previously Samec et al. (16)
reported that
46 h of fasting, which was associated with a threefold rise in
serum fatty acid levels, led to increases in UCP-2 and UCP-3 expression
in gastrocnemius, soleus, and tibialis anterior skeletal muscles.
Likewise, liver UCP-2 mRNA levels are highly responsive to changes in
diet (29)
. Apparently, conditions that are associated with
changes in plasma fatty acid levels and/or fatty acid utilization by
the adult heart have no modulatory effect on adult cardiac UCP-2
expression. At present no satisfactory explanation can be provided for
the behavior of UCP in different tissues. As for the heart, in which
the expression of UCP-2 is very pronounced, it has been suggested
(28)
that the promoter of the UCP-2 gene is so active
under basal conditions that an increase in its activity can hardly be
detected. However, this notion is hard to reconcile with the
observation that in vivo administration of T3 and cold
exposure both increase cardiac UCP-2 expression in the rat (9
, 30)
. Furthermore, it does not explain why down-regulation of
UCP-2 expression is never observed, for instance, under conditions that
are associated with a reduction in cardiac fatty acid utilization, like
cardiac hypertrophy.
UCP-2 expression increases in the perinatal period
Perinatally, a substantial rise in cardiac UCP-2 mRNA content was
observed. In brown adipose tissue of mice, a marked increase of UCP-2
mRNA levels at birth has also been demonstrated (31)
.
However, in contrast to the UCP-2 expression pattern in the heart,
UCP-2 mRNA levels in brown adipose tissue returned to fetal levels
within 2 wk of birth (31)
. It was suggested that the
postnatal rise in UCP-2 expression might be caused by cold exposure of
the newborn animal when delivered to the extra-uterine environment. The
postnatal rise in circulating thyroid hormone levels (19)
might also be responsible for the increase in UCP-2 expression after
birth, since UCP-2 expression has been shown to be T3 responsive in
isolated neonatal cardiomyocytes (see below; ref 32
) and
in the adult heart (30)
. However, it should be kept in
mind that nutritional factors also change during the perinatal period.
Whereas the fetal diet consists mainly of carbohydrates, fat is the
main component of the diet of suckling newborn animals (reviewed in ref
19
). During this period the heart also switches from
carbohydrates to fatty acids as the main energy source
(33)
. Accordingly, it is tempting to speculate that the
exposure to increased plasma fatty acid levels may be directly
responsible for the increased UCP-2 mRNA levels. The current
observation that fatty acids are able to enhance UCP-2 expression in
neonatal cardiomyocytes seems to support this notion. On the other
hand, manipulation of the diet directly after birth did not affect
UCP-2 expression in skeletal muscle of mice (34)
. In view
of the tissue-specific behavior of uncoupling proteins, however, it
remains to be established whether this also applies to UCP-2 gene
expression in rat cardiac tissue.
Fatty acids enhance UCP-2 expression in vitro
Fatty acids were able to stimulate UCP-2 gene expression to a
significant extent (up to 10-fold) in primary cultures of neonatal rat
ventricular myocytes and in embryonic heart-derived H9c2 cells. To our
knowledge such a direct effect of fatty acids on cardiac UCP-2
expression has never been demonstrated before. The fact that fatty
acids are able to enhance the expression of the UCP-2 gene, as well as
genes like heart-type fatty acid binding protein, acyl-CoA synthetase,
mCPT1, or long-chain acyl-CoA dehydrogenase in neonatal cardiomyocytes
(35
36
37)
, suggests a common mechanism. The exact mechanism
by which fatty acids modulate UCP-2 expression is, however, unknown.
Since fatty acids are able to activate PPARs (12
, 13)
,
these transcription factors may be involved in fatty acid-induced gene
expression. Indeed, cardiac expression of the fatty acid-responsive
mCPT1 gene has been demonstrated to be regulated by PPAR (37
, 38)
. When Wy-14,643, a specific activator of PPAR, was added
to neonatal cardiomyocytes the expression of UCP-2, as well as that of
various genes involved in cardiac fatty acid transport and metabolism
(36)
increased dramatically. In contrast, the
PPAR-specific ligand ciglitazone, a thiazolidinedione (TZD), did not
affect UCP-2 expression. The fact that TZDs are able to enhance UCP-2
expression in a variety of other cell types, including adipocytes and
the rat skeletal muscle cell line L6 (39
, 40)
, most likely
reflects differences in the tissue distribution of the corresponding
PPARs, with PPAR being abundantly present in adipocytes and
virtually absent from cardiomyocytes. The involvement of PPAR in
mediating fatty acid responsiveness to the UCP-2 gene is further
supported by the observation that 9-cis retinoic acid, the
ligand for the retinoid X receptor (which in turn acts as the
dimerization partner for PPAR), also enhances UCP-2 expression in
cultured brown adipocytes (41)
. However, it should be
noted that to the best of our knowledge, and unlike UCP-1
(42)
, a functional PPAR response element has not yet been
identified in the UCP-2 gene.
Induction of neonatal myocyte hypertrophy with the
1-adrenergic agonist phenylephrine, which is
an established model of in vitro hypertrophy
(43)
, did not result in changes in UCP-2 gene expression.
This observation corroborates the absence of alterations in UCP-2 mRNA
levels in hypertrophied hearts of aorta-banded rats. In contrast, UCP-2
expression increased after enhancing cellular metabolism by the thyroid
hormone T3. The current findings are in line with those of Teshima et
al. (32)
, who reported a stimulatory effect of T3 and
ß-adrenergic agonists, but not of
1-adrenergic agonists, on UCP-2 expression in
neonatal cardiomyocytes. However, fatty acids are far more potent
inducers of UCP-2 expression than either ß-adrenergic agonists or T3.
Furthermore, in our hands the stimulatory effect of T3 depended on the
coadministration of fatty acids, which strongly suggests a permissive
action of fatty acids to T3-induced UCP-2 expression.
Physiological implications
Taken together, the present findings indicate that the expression
of UCP-2 in neonatal hearts, isolated neonatal cardiomyocytes, and
embryonic heart-derived H9c2 cells is responsive to changes in the
dietary environment, in contrast to its expression in the adult heart.
Currently, the mechanism responsible for this difference in behavior is
unclear. First, it is striking that PPAR ligands affect UCP-2
expression in neonatal cardiomyocytes but not in the adult rat heart
after in vivo administration (44)
. This
coincides with the effects of PPAR ligands on the expression of
proteins involved in fatty acid transport and metabolism. Their
expression is increased in neonatal cardiomyocytes after addition of
the PPAR-specific ligand Wy-14,643 (36)
, whereas mRNA
levels of fatty acid transport protein and acyl-CoA synthetase are
hardly altered after administration of a potent PPAR activator to
adult rats (45)
. Second, the changes in fatty acid levels
in the cellular model systems (0.0 mM vs. 0.5 mM) and during the
perinatal development (0.02 to 0.4 mM) (46)
are more
obvious than those induced by fasting and diabetes (0.3 to 1.5 mM). It
is conceivable that maximal stimulation of cardiac UCP-2 expression by
fatty acids is already achieved at the relatively high circulating
fatty acid levels found in adult rats.
Although UCP-2 is expressed abundantly in the heart, the biological
significance of UCP-2 in this tissue is incompletely understood. It has
been hypothesized that mitochondrial uncoupling reduces the formation
of reactive oxygen species, by-products of mitochondrial oxidation
(47
, 48)
. In this respect, uncoupling by both ADP/ATP
translocase and UCP-2 has been demonstrated to mediate this antioxidant
effect, as evidenced by their capacity to inhibit mitochondrial
formation of H2O2
(47
, 49)
. Although the uncoupling activity of UCP-1 can be
enhanced by fatty acids (50)
, a direct stimulatory effect
of fatty acids on UCP-2 uncoupling activity has not been demonstrated.
The fact that fatty acids induce UCP-2 in neonatal cardiomyocytes along
with a panel of genes encoding proteins known to be involved in cardiac
fatty acid transport and metabolism (36)
is indicative of
a relationship between UCP-2 and fatty acid handling. The finding that
the modulatory effects of fatty acids on UCP-2 gene expression appears
to be restricted to neonatal cardiomyocytes and absent in the adult
heart is very intriguing and warrants further investigation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 
. Proc. Natl. Acad. Sci. USA 94,4312-4317 and . Proc. Natl. Acad. Sci. USA 94,4318-4323 induce the expression of the uncoupling protein-3 gene in skeletal muscle. A potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth. Diabetes 48,1217-1222[Abstract]
. J. Biol. Chem. 273,23786-23792. Mol. Cell. Biol. 16,3410-3419 and mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression. Endocrinology 139,4920-4927 and PPAR activators. J. Biol. Chem. 272,28210-28217This article has been cited by other articles:
|
|
 |
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  C. Pecqueur, T. Bui, C. Gelly, J. Hauchard, C. Barbot, F. Bouillaud, D. Ricquier, B. Miroux, and C. B. Thompson Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization FASEB J, January 1, 2008; 22(1): 9 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Boudina, S. Sena, B. T. O'Neill, P. Tathireddy, M. E. Young, and E. D. Abel Reduced Mitochondrial Oxidative Capacity and Increased Mitochondrial Uncoupling Impair Myocardial Energetics in Obesity Circulation, October 25, 2005; 112(17): 2686 - 2695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Faadiel Essop and L. H. Opie Metabolic therapy for heart failure Eur. Heart J., October 2, 2004; 25(20): 1765 - 1768. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. J. Jiang, B. Lu, F. Y. Xu, J. Gartshore, W. A. Taylor, A. J. Halayko, F. J. Gonzalez, J. Takasaki, P. C. Choy, and G. M. Hatch Stimulation of cardiac cardiolipin biosynthesis by PPAR{alpha} activation J. Lipid Res., February 1, 2004; 45(2): 244 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Teshima, M. Akao, S. P. Jones, and E. Marban Uncoupling Protein-2 Overexpression Inhibits Mitochondrial Death Pathway in Cardiomyocytes Circ. Res., August 8, 2003; 93(3): 192 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Francis, J.-S. Annicotte, and J. Auwerx PPAR-{alpha} effects on the heart and other vascular tissues Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H1 - H9. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. H. A. G. M. van der Putten, E. C. H. Friesema, N. A. Abumrad, M. E. Everts, and T. J. Visser Thyroid Hormone Transport by the Rat Fatty Acid Translocase Endocrinology, April 1, 2003; 144(4): 1315 - 1323. [Abstract] [Full Text] [PDF]
|
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|
|
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A. J. Gilde, K. A.J.M. van der Lee, P. H.M. Willemsen, G. Chinetti, F. R. van der Leij, G. J. van der Vusse, B. Staels, and M. van Bilsen Peroxisome Proliferator-Activated Receptor (PPAR) {alpha} and PPAR{beta}/{delta}, but not PPAR{gamma}, Modulate the Expression of Genes Involved in Cardiac Lipid Metabolism Circ. Res., March 21, 2003; 92(5): 518 - 524. [Abstract] [Full Text] [PDF]
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H. Degens, A. J. Gilde, M. Lindhout, P. H. M. Willemsen, G. J. van der Vusse, and M. van Bilsen Functional and metabolic adaptation of the heart to prolonged thyroid hormone treatment Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H108 - H115. [Abstract] [Full Text] [PDF]
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 G. Patane, M. Anello, S. Piro, R. Vigneri, F. Purrello, and A. M. Rabuazzo Role of ATP Production and Uncoupling Protein-2 in the Insulin Secretory Defect Induced by Chronic Exposure to High Glucose or Free Fatty Acids and Effects of Peroxisome Proliferator-Activated Receptor-{gamma} Inhibition Diabetes, September 1, 2002; 51(9): 2749 - 2756. [Abstract] [Full Text] [PDF]
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E. Aasum, D. D. Belke, D. L. Severson, R. A. Riemersma, M. Cooper, M. Andreassen, and T. S. Larsen Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-alpha activator Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H949 - H957. [Abstract] [Full Text] [PDF]
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L. Cai, W. Li, G. Wang, L. Guo, Y. Jiang, and Y. J. Kang Hyperglycemia-Induced Apoptosis in Mouse Myocardium: Mitochondrial Cytochrome c-Mediated Caspase-3 Activation Pathway Diabetes, June 1, 2002; 51(6): 1938 - 1948. [Abstract] [Full Text] [PDF]
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K. A. J. M. Van der Lee, P. H. M. Willemsen, S. Samec, J. Seydoux, A. G. Dulloo, M. M. A. L. Pelsers, J. F. C. Glatz, G. J. Van der Vusse, and M. Van Bilsen Fasting-induced changes in the expression of genes controlling substrate metabolism in the rat heart J. Lipid Res., November 1, 2001; 42(11): 1752 - 1758. [Abstract] [Full Text] [PDF]
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R. Carroll and D. L. Severson Peroxisome proliferator-activated receptor-{alpha} ligands inhibit cardiac lipoprotein lipase activity Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H888 - H894. [Abstract] [Full Text] [PDF]
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M. E. YOUNG, S. PATIL, J. YING, C. DEPRE, H. S. AHUJA, G. L. SHIPLEY, S. M. STEPKOWSKI, P. J. A. DAVIES, and H. TAEGTMEYER Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor {alpha} in the adult rodent heart FASEB J, March 1, 2001; 15(3): 833 - 845. [Abstract] [Full Text] [PDF]
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 E. Chevillotte, J. Rieusset, M. Roques, M. Desage, and H. Vidal The Regulation of Uncoupling Protein-2 Gene Expression by omega -6 Polyunsaturated Fatty Acids in Human Skeletal Muscle Cells Involves Multiple Pathways, Including the Nuclear Receptor Peroxisome Proliferator-activated Receptor beta J. Biol. Chem., March 30, 2001; 276(14): 10853 - 10860. [Abstract] [Full Text] [PDF]
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