(Circulation. 2001;103:2195.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Beneficial Effects on Skeletal Muscle of the Angiotensin II Type 1 Receptor Blocker Irbesartan in Experimental Heart Failure
From the CNR Unit for Muscle Pathophysiology, Department of Biomedical Sciences (L.D.L., B.R., K.R., M.S.), and the Department of Cardiovascular Pathology (A.A., G.T.), University of Padua, Padua, Italy; Internal Medicine I, City Hospital, Venice, Italy (G.B.A.); and Internal Medicine, City Hospital, Adria, Italy (G.V.).
Correspondence to Giorgio Vescovo, MD, PhD, FESC, Internal Medicine, City Hospital, 45011 Adria (RO), Italy. E-mail ldl{at}civ.bio.unipd.it
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Abstract |
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Background—In congestive heart failure (CHF), skeletal muscle shows increased expression of fast myosin heavy chains (MHC) and fibers, muscle atrophy, increased fatigability, and decreased endurance. Atrophy is secondary to myocyte apoptosis, which is probably triggered by tumor necrosis factor-
(TNF). Angiotensin II receptors are thought to
play a role in controlling apoptosis. We tested the hypothesis that
angiotensin II receptor blockade could prevent skeletal muscle
apoptosis in rats with CHF.
Methods and Results—CHF
was induced by injecting 36 rats with 30 mg/kg monocrotaline. Ten
additional animals were injected with saline and acted as controls.
After 2 weeks, 18 of the 36 rats with CHF were treated with 7 mg ·
kg–1 · d–1
irbesartan through osmotic minipumps, and 10 of the 36 rats were
treated with 2 mg · kg–1 ·
d–1 nifedipine in drinking water. After 2
additional weeks, rats were killed. Tibialis anterior cross-sectional
area, MHC composition, myocyte apoptosis, Bcl-2, pro-caspase 3, and
activated caspases 3 and 9 were determined, as were plasma levels of
TNF and angiotensin II. Myocyte apoptosis and muscle atrophy were
significantly decreased with irbesartan compared with untreated CHF
rats. Irbesartan-treated rats had fewer cells labeled positively with
terminal deoxynucleotidal transferase–mediated dUTP nick-end labeling
and fewer caspases; however, they also had increased Bcl-2 levels and
muscle fiber cross-sectional areas. The MHC pattern in
irbesartan-treated animals was similar to that in controls. Nifedipine
animals behaved like the untreated CHF animals. Angiotensin II was
increased 3- to 4-fold in all CHF rats (treated and untreated). TNF
levels were decreased in irbesartan-treated rats but not in
nifedipine-treated rats.
Conclusions—Angiotensin
II receptor blockade can protect from the development of
apoptosis-dependent atrophy and from changes in MHCs. The reduction of
TNF may play a role in this
process.
Key Words: heart failure • irbesartan • muscles • apoptosis • tumor necrosis factor
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Introduction |
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Heart failure is characterized by a decreased exercise capacity with early occurrence of fatigue and dyspnea. These symptoms are partially due to a skeletal muscle myopathy, with atrophy and a shift from the "slow" fatigue resistant type I fibers to the more fatigable "fast" type II fibers.1 2 This is evident in humans and in animal models of congestive heart failure (CHF), in which we also found a correlation between the severity of the syndrome and skeletal muscle myosin heavy chain (MHC) composition.3 4 5 The origin of this myopathy is not yet clear, although its specificity has been hypothesized.3 6 Similarly, the link between exercise capacity and endurance, muscle atrophy, and changes in fiber type are still ill-defined.
We recently showed in rats with
CHF7 that the degree of
muscle atrophy correlates with the magnitude of apoptosis and the
severity of CHF and is accompanied by elevated plasma levels of tumor
necrosis factor- (TNF). In humans, muscle bulk loss, one of the
most important determinants of exercise
capacity,2 is equally
secondary to myocyte
apoptosis.8
Apoptosis is involved in myocyte loss both in CHF and in
cardiomyopathies.9 It has
been suggested that in the heart, apoptosis can be triggered by
angiotensin II (AngII) or cytokines, such as
TNF.10 11
However, it is not clear whether AngII determines apoptosis via type 1
(AT1) or type 2 (AT2)
receptors. Many authors have suggested that AT2
receptor stimulation brings about
apoptosis.12 13
In contrast, losartan, an AT1 receptor blocker,
and captopril, an ACE inhibitor, can block apoptosis both in vitro
(isolated stretched myocytes) and in vivo (spontaneously hypertensive
rats with
CHF).14 15
All these results are intriguing and, in this article, we tested the hypothesis that AT1 blockade with irbesartan can prevent apoptosis and skeletal muscle atrophy.
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Methods |
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Experimental Model
We studied 36 male Sprague-Dawley rats weighing 80 to 100 g that had CHF induced by monocrotaline. This alkaloid produces severe pulmonary hypertension followed by right ventricular (RV) failure16 without itself inducing changes in skeletal muscle MHC composition and apoptosis.7 Monocrotaline was injected intraperitoneally in the rats at a dose of 30 mg/kg. The rats were then divided into 3 groups.
After 2 weeks, 18 of the 36 rats had 7 mg · kg–1 · d–1 irbesartan delivered through Alzet osmotic minipumps. Irbesartan 250 mg was solubilized in 3.75 mL of 0.19 mol/L KOH at room temperature and sonicated for 1 minute; 0.75 mL of 50 mmol/L Tris was added and neutralized at pH 8. This is the method used for intravenous preparations.17 The second group consisted of 10 rats (of the 36) that were treated with 2 mg · kg–1 · d–1 nifedipine, which was given in drinking water. Rats were kept in single cages, and the amount of water drunk was measured daily. The final 8 rats had a saline-delivering minipump, and they formed the (untreated) CHF group.
A total of 10 additional age- and diet-matched rats were
injected with saline and served as controls. After 28 days, when overt
heart failure had developed, animals were killed and their body weight
and tibialis anterior (TA) weight were measured. Muscles were
immediately frozen in liquid nitrogen and stored at -80°C. Blood
was drawn for TNF and AngII measurements.
Experiments were approved by the Biological Ethical Committee of the University of Padua and performed according to Italian law.
Assessment of RV Hypertrophy and
Failure
To ensure that the monocrotaline-treated animals
developed RV failure, left ventricular mass/RV mass (LVM/RVM) and the
RV mass/RV volume index (RVM/RVV) were calculated with a computerized
planimeter on photographic pictures of formalin-fixed transverse
sections of the heart taken in the middle portion of the
interventricular septum.
Electrophoretic Separation of MHCs
MHCs (MHC2a [fast oxidative] and MHC2b [fast
glycolytic]) were separated using the previously described
electrophoretic
method.3
Assessment of MHC Distribution
The percent distribution of the MHCs was determined
by a densitometric scan using a Jandel Scientific
system.3 4 7
Single-Fiber Cross-Sectional Area
We used single-fiber cross-sectional areas (CSA) as
an index of myofiber
atrophy.7 8 Cross
cryosections were taken for histological examination and stained with
hematoxylin and eosin. The fiber CSA was calculated with a computerized
interactive method and expressed in µm2 by
counting at least 400 fibers per
specimen.8
Assessment of Apoptosis
In Situ Terminal Deoxynucleotidyl
Transferase–Mediated dUTP Nick-End Labeling
In situ terminal deoxynucleotidyl
transferase–mediated dUTP nick-end labeling (TUNEL) of fragmented DNA
was performed on cryosections using the In Situ Cell Death Detection
Kit POD (Boehringer Mannheim). Labeled nuclei were identified from the
negative nuclei counterstained by Hoechst 33258 and were counted after
being photographed. The total number of positive nuclei was determined
by counting (at a magnification of 250x) all the labeled nuclei
present in the whole specimen. The number of positive nuclei was then
expressed as the number of TUNEL-positive nuclei per
mm3.18
TUNEL-positive myofibers and interstitial nuclei were distinguished on
the basis of their location on sections stained with laminin, which
selectively reacts with the basal lamina. TUNEL positive nuclei within
the basal lamina were taken as
myonuclei.19 Separate
calculations were made for total TUNEL-positive nuclei and
TUNEL-positive myonuclei.
TA Western Blot for Pro-Caspase 3, Activated
Caspases 3 and 9, and Bcl-2
Western blotting was performed on 12.5 polyacrylamide
gels as previously
described.7 Anti–pro-caspase
3 CPP 32 (H-277, 34 kDa) and anti–Bcl-2 (29 kDa) antibodies (Santa
Cruz Biotechnology) were used with anti-rabbit alkaline phosphatase
(Sigma). Anti-cleaved caspase-3 (17 kDa) and anti-cleaved caspase-9 (37
kDa) (Cell Signaling Technology) were used with anti-rabbit
peroxidase-conjugated antibody and revealed by chemiluminescent
substrate (SuperSignal West Pico, Pierce). The absolute values of
pro-caspase 3, activated caspases 3 and 9, and Bcl-2 were calculated on
the blot bands with the densitometric system described above and
expressed as percent of controls.
DNA Ladder
DNA was extracted from the TA muscle as previously
described.7 The ApoAlert
LM-PCR Ladder assay kit (Clontech) was used to amplify the detection of
nucleosomal ladder. A total of 0.5 µg of genomic DNA was used.
Reaction conditions were as follows: 1 cycle at 72°C for 8 minutes,
25 cycles at 94°C for 1 minute and at 72°C for 3 minutes, and 1
cycle at 72°C for 15 minutes. Polymerase chain reaction (PCR)
products were electrophoresed on 1.8% agarose
gels.
Confocal Microscopy Immunofluorescence
Frozen sections were incubated with anti–activated
caspase-3 antibody diluted 1:50 overnight at 4°C. Slices were then
incubated with anti-rabbit Cy3-conjugated antibody for 1 hour at
room temperature and analyzed by Bio-Rad confocal
microscopy.
AngII Assay
AngII was measured on serum using an
enzyme-immunometric assay kit from SPI-BIO.
TNF
TNF was measured with a solid-phase sandwich ELISA
using a monoclonal antibody specific for rat TNF
(Euroclone).
Statistical Analysis
Values are reported as mean±SD. Student’s
t tests for unpaired data were
used, as was ANOVA when appropriate. A 5% difference was considered
statistically significant. ANOVA was also used to look at differences
in TNF, AngII, caspases, Bcl-2, and percentage of apoptotic
nuclei.
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Results |
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Occurrence of Heart Failure in the Monocrotaline-Treated Animals
At 28 days, all the rats with monocrotaline-induced CHF showed the presence of pericardial, pleural, and peritoneal effusions at post-mortem examination (Figure 1
and
Table 1). LVM/RVM was 2.6±0.8 in untreated CHF
rats, 3.5±0.8 in controls
(P<0.02), 2.4±0.7 in
irbesartan-treated rats
(P=0.0005 versus controls), and
2.0±0.5 in nifedipine-treated rats
(P=NS versus irbesartan and
P=0.0005 versus controls). The
RV cavity was markedly dilated in all the CHF rats, as reflected by the
RVM/RVV index, which was 0.24±0.18 in untreated CHF rats versus
1.10±0.7 (P=0.01) in controls
and 0.41±0.09 in the irbesartan-treated animals
(P=0.014 versus CHF and
P=0.04 versus controls). In the
nifedipine-treated animals, we observed a RVM/RVV of 0.60±0.18, which
was significantly higher than that of both controls and
irbesartan-treated rats
(P=0.02), indicating a lower
degree of dilatation.
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Degree of Muscle Atrophy
The degree of TA atrophy, as measured by TA weight/body
weight ratio, was 1.60±0.05 in untreated CHF rats, 1.78±0.05 in
controls, 1.69±0.04 in irbesartan-treated rats, and 1.60±0.12 in
nifedipine-treated rats.
TA Fiber CSA
The CSA of the TA was 1340±460
µm2 in the untreated CHF rats, 2150±350
µm2 in the controls
(P=0.01), 1750±300
µm2 in the irbesartan-treated rats
(P=0.05 versus CHF), and
900±250 µm2 in the nifedipine-treated
rats (P<0.002 versus
irbesartan group and controls;
Table 1
).
MHC Pattern
The electrophoretic pattern of the TA in the CHF
animals showed a shift toward the fast glycolytic isoform
(Table 2). In fact, MHC2a decreased from 26.4±1.5% to
18.0±3.5% (P=0.005). MHC2b
increased from 74.0±1.5% to 82.0±3.5%
(P=0.005). In the irbesartan
group, MHC2a was 25.5±5.9%
(P=0.04 versus CHF) and MHC2b
was 74.5±5.9% (P=0.04 versus
CHF), whereas in the nifedipine group, MCH2a was 18.7±1.7% and MCH2b
was 81.2±1.7% (P=NS versus
CHF).
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Count of TUNEL-Positive Nuclei
The count of the total TUNEL-positive nuclei in the TA
of the control rats was 1.1±3.9 per mm3,
whereas in the CHF rats, this percentage was higher
(41.9±44.1/mm3,
P=0.04). In the irbesartan
group, we found 12.0±12.9/mm3
TUNEL-positive nuclei (P=0.03
versus controls and P=0.05
versus CHF). In the nifedipine group, the total number of
TUNEL-positive nuclei was 56.1±43.4/mm3
(P=NS versus CHF and
P<0.05 with irbesartan;
Figure 2 and
Table 3).
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The myocyte TUNEL-positive nuclei count was 0.4±0.8/mm3 in controls, 12.6±11.9/mm3 in CHF untreated animals, 4.0±4.1/mm3 in irbesartan-treated rats, and 18.0±14.3/mm3 in nifedipine-treated rats.
Activated Caspases 3 and 9
We confirmed the occurrence of apoptosis in
animals with high numbers of TUNEL-positive nuclei by testing for the
presence of activated caspases 9 and 3 (the mitochondrial regulator and
the executioner, respectively;
Figure 3). Caspase 3 is detectable during the execution
phase of apoptosis, when the caspase cascade leads inevitably to
programmed cell death.20 The
presence of these caspases in the muscles of untreated CHF and
nifedipine-treated animals, who had the highest TUNEL positivity, and
their absence in controls further indicate the presence of apoptosis
and suggest that mitochondria could play an important role in this
process. The presence of activated caspases 3 and 9 was shown with
immunoblotting
(Figures 3A and 3B) and that of activated caspase 3 was also
shown with immunofluorescence and confocal microscopy
(Figure 3C) in the CHF and nifedipine rats. These caspases
were absent in controls. Note that the activation of caspase 3 occurred
in some areas of myofiber cytoplasm.
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DNA Ladder
In our model of CHF, in which only a small percentage
of cells are apoptotic and in which apoptosis occurs asynchronously,
the genomic DNA ladder may not be visible. For this reason, we used a
PCR assay to amplify specifically the nucleosomal ladder. We found a
positive DNA ladder only in the untreated and nifedipine-treated
animals with CHF; the ladder was negative in controls
(Figure 3D). This experiment further stresses the occurrence
of apoptosis in the muscles showing TUNEL-positive
nuclei.
Pro-Caspase 3
Pro-caspase 3 was significantly increased in the
untreated CHF rats when compared with controls (211±87% versus
100±10%, P=0.05). In
irbesartan-treated rats, although the percentage of pro-caspase 3 was
lower than in untreated CHF rats, it was still significantly higher
than in controls (191±72%,
P=0.03). In the
nifedipine-treated animals, the percentage of pro-caspase 3 was similar
to that of untreated CHF rats (213±76%;
Table 3).
Bcl-2
Bcl-2 was 97±12% in controls, which was similar to
that in irbesartan-treated animals (94±35%,
P=NS). In the untreated CHF
rats, Bcl-2 was 70±16%
(P=0.02 versus both controls
and irbesartan;
Table 3).
TNF
There was a rise in plasma TNF levels in the CHF
animals (139±6% versus 100±8% in controls,
P=0.001). In the irbesartan
group, the levels did not differ from controls but were lower than
those in untreated CHF rats (108±11%,
P=0.05). In the
nifedipine-treated animals, TNF levels were similar to those of
untreated CHF rats (140±12%;
Table 3).
AngII
Plasma levels of AngII in the untreated CHF,
irbesartan-treated, nifedipine-treated, and control animals are shown
in
Table 4. We found significant, 3- to 4-fold higher levels
of AngII in the untreated CHF, irbesartan-treated, and
nifedipine-treated rats when compared with controls
(P<0.008 for
all).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the rat, monocrotaline induces RV hypertrophy followed by RV dilatation and CHF. In these animals, we found TA atrophy secondary to myocyte apoptosis and a shift of the MHCs toward the fast glycolytic isoforms, confirming previously published data.5 7 8 The occurrence of apoptosis was confirmed by different techniques, including immunoblotting, immunohistochemistry, confocal microscopy, and DNA ladder. Activated caspases 3 and 9 were also present; this ensured that the caspase cascade, which inevitably leads to programmed cell death, was initiated.20
Irbesartan, a drug that selectively blocks the AT1 receptor, could not prevent RV hypertrophy in this study, as shown by an LVM/RVM index that did not differ between the irbesartan and untreated CHF groups. The occurrence of RV dilatation, however, was partially prevented. In irbesartan-treated animals, RVM/RVV was, in fact, significantly lower than in controls and higher than in untreated CHF rats. This confirms that a certain degree of compensated hypertrophy with a lower degree of failure was present in the monocrotaline-treated rats that were treated with irbesartan for 2 weeks. Therefore, we can assume that irbesartan produced only a partial improvement in the hemodynamic pattern. A similar finding was observed in the nifedipine-treated animals, in which RV dilatation was prevented to an even higher degree and a greater deal of compensated RV hypertrophy was found. Nifedipine was used to obtain favorable hemodynamic changes in a model of CHF due to pulmonary hypertension, without directly interfering with AngII receptors.
Despite their similar hemodynamic effects, irbesartan greatly differed from nifedipine in terms of biological effects. This is, in fact, the first demonstration in vivo that an AT1 blocker can produce beneficial effects on the skeletal muscle of rats with experimental CHF. These effects could not be obtained with the calcium blocker. In irbesartan, the MHC pattern was similar to that in controls, with a partial improvement in the degree of TA atrophy (higher TA weight/body weight and larger myocyte CSA). In the nifedipine group, however, neither MHC composition nor indices of muscle atrophy were different from untreated CHF animals.
We can reasonably speculate that this effect of irbesartan on muscle atrophy is secondary to the lower levels of apoptosis. The absolute number of TUNEL-positive cells was lower in the irbesartan group when compared with untreated CHF rats. In the nifedipine-treated rats, in which apoptosis was detected at even higher levels than in untreated CHF rats, muscle atrophy was worse. Pro-caspase 3 and activated caspases 3 and 9, which are compulsory steps in the death receptor signaling pathway, were equally decreased in irbesartan-treated animals but remained high in nifedipine-treated rats. Bcl-2, which has a protective effect, was significantly higher in irbesartan-treated than in untreated CHF rats and was similar to that in controls.
The role of TNF in CHF is not entirely understood.
We know that in CHF, the circulating amounts of TNF are increased
both in humans21 and in
animal models.7 TNF
blockade with specific antagonists (Enbrel) can improve the clinical
status of CHF patients.22
TNF levels parallel the severity of CHF and the number of
TUNEL-positive skeletal
myocytes.7 Moreover, TNF
is known to worsen CHF by depressing cardiac
contractility.23 Although
still debated, TNF has been shown to trigger
apoptosis.10 We know that in
the heart, it induces the production of sphingolipids, such as
sphingosine and ceramide, which are in turn mediators of
apoptosis.23 24
In this study, TNF was significantly increased in
untreated CHF animals when compared with controls, and it remained high
in nifedipine-treated rats. In irbesartan-treated rats, it was slightly
decreased, reaching borderline significance. The TNF figures,
therefore, resemble those of TUNEL, pro-caspase 3, and Bcl-2 in
suggesting the existence of a link between TNF and apoptosis. We can
only speculate why TNF is decreased with irbesartan. We may
hypothesize that the less compromised hemodynamics may have interfered
with TNF synthesis, which in CHF is linked to clinical
status.22 23 If
that was the case, even the nifedipine-treated rats, which had a
similar hemodynamic improvement, should have shown a TNF reduction.
Therefore, we think that the interplay between TNF, AngII receptors,
and apoptosis is much more complicated.
From the present results, we can hypothesize that the favorable effects of irbesartan on apoptosis are likely to be secondary to a direct AT1-mediated antiapoptotic effect rather than to hemodynamic improvements. In fact, nifedipine-treated rats, which show a similar degree of compensated RV hypertrophy with an even lower dilatation of the RV, do not exhibit any skeletal muscle change.
The role of AngII receptors on apoptosis is far from clear. Several observations suggest that AT2 stimulation mediates apoptosis through extracellular signal-regulated kinase (ERK) inhibition,25 ceramide accumulation, activation of mitogen-activated protein kinase phosphatase 1 (MKP1) with subsequent inhibition of mitogen-activated protein kinase, and Bcl2 dephosphorylation.12 Apoptosis can be blocked by PD-123319 and PD-123177,26 27 which are specific AT2 blockers. In contrast, some authors26 have shown that AT1 blockade with losartan can equally protect from apoptosis. AT1 stimulation can lead to an increase in Fas, together with a fall in constitutive NO synthase and Blc-2 levels. Li et al27 and Leri et al28 have also demonstrated that myocyte stretch–induced apoptosis can be blocked by losartan, which can also increase levels of Bcl-2 and decrease levels of Bax and p53. Similar observations have been made in the hearts of spontaneously hypertensive rats.14 The ACE inhibitor captopril reduced apoptosis in spontaneously hypertensive rats with CHF.15
AngII-induced apoptosis can be blocked in postinfarcted, hypertrophied ventricular myocytes by AT1 blockers, but AT2 antagonists had no impact on these cellular events.29 The conflict regarding whether AT1 or AT2 receptors mediate apoptosis can be mediated by the observation that tissues that express primarily AT2 exhibit AT2-mediated apoptosis, whereas tissues that express primarily AT1 exhibit AT1-mediated apoptosis.27 Moreover, in many tissues, skeletal muscle included, the majority of physiological responses to AngII occurs through its accumulation, which is AT1-mediated.30 These observations allow us to speculate on the mechanism by which irbesartan, a highly specific AT1 blocker, may have prevented apoptosis by acting through a receptor mechanism involving the AT1 receptor. This specific action can be brought about even in the presence of very high levels of AngII. In fact, in irbesartan-treated rats, we found a 3- to 4-fold increase in AngII, which was similar to increases in untreated CHF and nifedipine-treated rats. It may be also speculated that excessive AT2 stimulation due to AT1 blockade with irbesartan may reduce the number of apoptotic cells in the skeletal muscle of CHF rats. A recent observation in humans,31 however, shows that the AT2 gene is not expressed in the skeletal muscle of men with CHF. In the present study, AngII levels are in keeping with those in the literature, both for normal32 and AngII blocker–treated rats, which show a 4- to 5-fold increase in AngII. CHF itself and the reflex sympathetic tone are likely to be the cause of AngII elevation in nifedipine-treated animals.
That AngII receptor blockade and ACE inhibition can
have a favorable effect on skeletal muscle fiber type, MHCs, and
exercise capacity has been previously
demonstrated.4 This article
is a further insight into the pathophysiology of CHF myopathy, allowing
speculations on the pathogenesis of this syndrome. In fact, muscle
atrophy is the main "muscular" determinant of the reduced exercise
capacity in CHF. This is due to the reduced muscle force and
endurance2 and to the shift
toward the fast and more fatigable
fibers.1 Irbesartan has shown
potential for reducing skeletal muscle apoptosis and atrophy and in
protecting from the shift toward the fast MHCs, further contributing to
a possible improvement in exercise tolerance and
symptoms.33 The reason for
the MHC shift remains to be established, as does the interplay between
AT1 and AT2 receptors in
the genesis and prevention of apoptosis. Thus, further experiments need
to be performed. The role of TNF and AngII receptors, which seem to
be synergistic in the induction of apoptosis, must be further
investigated.
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Acknowledgments |
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The skill of Valerio Gobbo is greatly acknowledged.
Received September 27, 2000; revision received November 21, 2000; accepted November 28, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lipkin D, Jones D, Round J, et al. Abnormalities of skeletal muscle in patients with chronic heart failure. Int J Cardiol. 1988;18:187–195.[Medline] [Order article via Infotrieve]
2.
Mancini DM, Reichek
N, Chance B, et al. Contribution of skeletal muscle atrophy to exercise
intolerance and altered muscle metabolism in heart failure.
Circulation. 1992;85:1364–1373.
3.
Vescovo G, Serafini
F, Facchin L, et al. Specific changes in skeletal muscle myosin heavy
chain composition in cardiac failure: differences compared with disuse
atrophy as assessed on microbiopsies by high resolution
electrophoresis. Heart. 1996;76:337–343.
4.
Vescovo G,
Dalla Libera L, Serafini F, et al. Improved exercise tolerance after
losartan and enalapril in heart failure: correlation with changes in
skeletal muscle myosin heavy chain composition.
Circulation. 1998;98:1742–1749.
5.
Dalla Libera L,
Zennaro R, Sandri M, et al. Apoptosis and atrophy in rat slow skeletal
muscles in chronic heart failure. Am
J Physiol. 1999;277:C982–C986.
6.
Simonini A, Long
CS, Dudley GA, et al. Heart failure in rats causes changes in skeletal
muscle morphology and gene expression that are not explained by reduced
activity. Circ Res. 1996;79:128–136.
7. Vescovo G, Zennaro R, Sandri M, et al. Apoptosis of skeletal muscle myofibers and interstitial cells in experimental heart failure. J Mol Cell Cardiol. 1998;30:2449–2459.[Medline] [Order article via Infotrieve]
8.
Vescovo G,
Volterrani M, Zennaro R, et al. Apoptosis in the skeletal muscle of
patients with heart failure: investigation of clinical and biochemical
changes. Heart. 2000;84:431–437.
9.
Olivetti G, Abbi R,
Quaini F, et al. Apoptosis in the failing human heart.
N Engl J Med. 1997;336:1131–1141.
10. Krown KA, Page MT, Nguyen C, et al. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes: involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest. 1996;98:2854–2865.[Medline] [Order article via Infotrieve]
11. Kajstura J, Cigola E, Malhotra A, et al. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Mol Cell Cardiol. 1997;29:859–870.[Medline] [Order article via Infotrieve]
12.
Yamada T,
Horiuchi M, Dzau VJ. Angiotensin II type 2 receptor mediates programmed
cell death. Proc Natl Acad Sci
U S A. 1996;93:156–160.
13. Li W, Ye Y, Fu B, et al. Genetic deletion of AT2 receptor antagonizes angiotensin II-induced apoptosis in fibroblasts of the mouse embryo. Biochem Biophys Res Commun. 1998;250:72–76.[Medline] [Order article via Infotrieve]
14.
Fortuno MA,
Ravassa S, Etayo JC, et al. Overexpression of Bax protein and enhanced
apoptosis in the left ventricle of spontaneously hypertensive rats:
effects of AT1 blockade with losartan.
Hypertension. 1998;32:280–286.
15.
Li Z, Bing OH,
Long X, et al. Increased cardiomyocyte apoptosis during the transition
to heart failure in the spontaneously hypertensive rat.
Am J Physiol. 1997;272:H2313–H319.
16. Vescovo G, Jones SM, Harding SE, et al. Isoproterenol of isolated cardiac myocytes from rats with monocrotaline-induced right-sided hypertrophy and cardiac failure. J Mol Cell Cardiol. 1989;21:1047–1061.[Medline] [Order article via Infotrieve]
17. Culman J, Von Heyer C, Piepenburg B, et al. Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats. Eur J Pharmacol. 1999;367:255–265.[Medline] [Order article via Infotrieve]
18. Sandri M, Carraro U, Podhorska-Okolov M, et al. Apoptosis, DNA damage and ubiquitin expression in normal and mdx muscle fibers after exercise. FEBS Lett. 1995;1995:373:291–295.
19.
Allen DL,
Linderman JK, Roy RR, et al. Apoptosis: a mechanism contributing to
remodeling of skeletal muscle in response to hindlimb unweighting.
Am J Physiol. 1997;273:C579–C587.
20.
Green DR, Reed
JC. Mitochondria and apoptosis.
Science. 1998;281:1309–1312.
21.
Ferrari R,
Bachetti T, Confortini R, et al. Tumor necrosis factor soluble
receptors in patients with various degrees of congestive heart failure.
Circulation. 1995;92:1479–1486.
22.
Deswal A, Bozkurt
B, Seta Y, et al Safety and efficacy of a soluble P75 tumor necrosis
factor receptor (Enbrel Etanercept) in patients with advanced heart
failure. Circulation. 1999;99:3224–3226.
23.
Oral H, Dorn GW
II, Mann DL. Sphingosine mediates the immediate negative inotropic
effects of tumor necrosis factor alpha in the adult mammalian cardiac
myocyte. J Biol Chem. 1997;272:4836–4842.
24. Sabbadini RP, Danieli-Betto D, Betto R. The role of shingolipids in the control of skeletal muscle function: a review. Ital J Neurol Sci. 1999;20:423–430.[Medline] [Order article via Infotrieve]
25.
Lehtonen JY,
Daviet L, Nahmias C, et al. Analysis of functional domains of
angiotensin II type 2 receptor involved in apoptosis.
Mol Endocrinol. 1999;13:1051–1060.
26.
Li D, Tomson K,
Yang B, et al. Modulation of constitutive nitric oxide synthase, bcl-2
and Fas expression in cultured human coronary endothelial cells exposed
to anoxia-reoxygenation and angiotensin II: role of AT1 receptor
activation. Cardiovasc Res. 1999;41:109–115.
27. Li D, Yang B, Philips MI, et al. Proapoptotic effects of ANG II in human coronary artery endothelial cells: role of AT1 receptor and PKC activation. Am J Physiol. 1999;276:H786–H792.
28.
Leri A, Liu Y,
Claudio PP, et al. Insulin-like growth factor-1 induces Mdm2 and
down-regulates p53, attenuating the myocyte renin-angiotensin system
and stretch-mediated apoptosis. Am J
Pathol. 1999;154:567–580.
29.
Leri A, Liu Y, Li
B, et al. Up-regulation of AT1 and AT2 receptors in post-infarcted
hypertrophied myocytes and stretched-mediated apoptotic cell death.
Am J Pathol. 2000;156:1663–1672.
30.
van Kats JP, de
Lannoy LM, Danser AHJ, et al. Angiotensin II type 1
(AT1) receptor-mediated accumulation of
angiotensin II in tissues and its intracellular half-life in vivo.
Hypertension. 1997;30:42–49.
31.
Malendowicz SL,
Ennezat PV, Testa M, et al. Angiotensin II receptor subtypes in the
skeletal muscle vasculature of patients with severe congestive heart
failure. Circulation. 2000;102:2210–2213.
32.
Tamura K, Umemura
S, Nyui N, et al. Tissue-specific regulation of angiotensinogen gene
expression in spontaneously hypertensive rats.
Hypertension. 1996;27:1216–1223.
33. Coats AJS, Clark AL, Piepoli M, et al. Symptoms and quality of life in heart failure: the muscle hypothesis. Br Heart J. 1994;72:36–39.
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