© 1996 American Heart Association, Inc.
Articles |
Adverse Effects of Chronic Endogenous Sympathetic Drive Induced by Cardiac Gs
Overexpression
From the Department of Medicine, Harvard Medical School, Brigham & Women's Hospital, Boston, Mass; the New England Regional Primate Research Center, Southborough, Mass; the Department of Pathology, University of Alabama, Birmingham; the Department of Molecular and Cellular Biology, The Edison Institute, Ohio University, Athens; and COR Therapeutics Inc, San Francisco, Calif.
Correspondence to Stephen F. Vatner, MD, New England Regional Primate Research Center, One Pine Hill Drive, Post Office Box 9102, Southborough, MA 01772.
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Abstract |
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Abstract To study the physiological effect of the overexpression of myocardial Gs
(protein levels increased by
approximately threefold in transgenic mice), we examined the
responsiveness to sympathomimetic amines by
echocardiography (9 MHz) in five transgenic mice
and five control mice (both 10.3±0.2 months old). Myocardial
contractility in transgenic mice, as assessed by left
ventricular (LV) fractional shortening (LVFS) and LV
ejection fraction (LVEF), was not different from that of control mice
at baseline (LVFS, 40±3% versus 36±2%; LVEF, 78±3% versus
74±3%). LVFS and LVEF values in transgenic mice during isoproterenol
(ISO, 0.02 µg/kg per minute) infusion were higher than the values in
control mice (LVFS, 68±4% versus 48±3%; LVEF, 96±1%
versus
86±3%; P<.05). Norepinephrine (NE, 0.2
µg/kg per minute) infusion also increased LVFS and LVEF in transgenic
mice more than in control mice (LVFS, 59±4% versus 47±3%; LVEF,
93±2% versus 85±3%; P<.05). Heart rates of
transgenic
mice were higher than those of control mice during ISO and NE infusion.
In three transgenic mice with heart rates held constant, LV dP/dt rose
by 33±2% with ISO (0.02 µg/kg per minute) and by only 13±2%
in
three wild-type control mice (P<.01). NE (0.1 µg/kg
per minute) also induced a greater effect on LV dP/dt in the three
transgenic mice with heart rates held constant compared with three
wild-type control mice (65±8% versus 28±4%, P<.05).
Pathological and histological analyses of older
transgenic mouse hearts (16.0±0.8 months old) revealed
hypertrophy, degeneration, atrophy of cells, and
replacement fibrosis reflected by significant increases in collagen
volume in the subendocardium (5.2±1.4% versus 1.2±0.3%,
P<.05) and in the cross-sectional area of myocytes
(298±29 versus 187±12 µm2, P<.05)
compared with control mouse hearts. These results suggest that
Gs overexpression enhances the efficacy of
the ß-adrenergic receptor–Gs–adenylyl cyclase
signaling pathway. This in turn leads to augmented inotropic and
chronotropic responses to endogenous sympathetic
stimulation. This action over the life of the animal results in
myocardial damage characterized by cellular degeneration, necrosis, and
replacement fibrosis, with the remaining cells undergoing compensatory
hypertrophy. As a model, this transgenic mouse offers new
insights into the mechanisms of cardiomyopathy and
heart failure and provides a new tool for their study.
Key Words: transgenic mice • sympathetic drive • GTP stimulatory protein • echocardiography • heart failure
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Introduction |
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Activation of the sympathetic nervous system is an important compensatory mechanism to a variety of stresses, eg, hypotension, exercise, and the "fight-or-flight" syndrome. The sympathetic nerves are poised to regulate cardiovascular function via autonomic control and, when signaled, to enhance cardiac performance by releasing catecholamines, which in turn activate myocardial beta adrenergic receptors (ß-ARs). Whether this activation is beneficial or deleterious over the long term, particularly in the pathogenesis of human heart failure, remains enigmatic. Although it seems clear that the acute role of ß-AR activation over a time frame of seconds to hours evolved as an evolutionary advantage, for predators and prey alike, a major clinical puzzle revolves around whether a persistent enhancement of sympathetic drive to the heart, as can occur after major insults such as myocardial infarction or cardiac failure, might paradoxically lead to gradual deterioration of healthy cardiocytes and thereby to global organ dysfunction.
Sympathetically mediated increases in myocardial
contractility depend upon the density of the ß-ARs,
the effector, adenylyl cyclase, and signal transduction regulatory
proteins, eg, the GTP stimulatory protein Gs. The goal of
the present investigation was to determine the
physiological and pathological consequences of
overexpression of myocardial
Gs.1 In examining the
postreceptor ß-adrenergic signal transduction pathway in the
heart, we reasoned that manipulation of its various components might
yield insight not only into the role of component stoichiometry
in signal transduction but also into the intimate role that the
sympathetic nerves play in regulating cardiac physiology. A transgenic
mouse was developed wherein Gs is
selectively overexpressed approximately threefold in the heart.
Although steady state adenylyl cyclase activities were not altered,
both the percent of agonist high-affinity or "coupled" ß-ARs
and the rate of catalyst activation are increased.1
However, it is not possible to predict the
physiological outcome of increased
Gs expression in response to
ß-adrenergic stimulation, since it is widely held that
Gs is in considerable excess relative to the
catalytic unit of adenylyl cyclase.2 Once it was
determined in the present investigation that the excess
Gs did indeed result in enhanced
responsiveness to sympathomimetic amines, a second goal was to
determine whether chronically facilitated sympathetic stimulation was
deleterious or beneficial. To address this hypothesis, older mouse
hearts were analyzed histologically.
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Materials and Methods |
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Physiological Study
Five transgenic mice (10.3±0.2 months old) and five wild-type littermates (10.3±0.2 months old) of either sex from the same genetic background as the transgenic mice were bred as described previously.1 The transgene consists of a rat
-myosin heavy chain promoter linked to a
Gs cDNA coding for the short isoform of
Gs from exon 1 to exon 12, which is ligated
to a portion of the Gs gene containing
intron 12, exon 13, and the polyadenylation signal. At least 1 day
before the day of the study, PE-10 tubing was inserted into the right
jugular vein under a dissecting microscope, and the catheter was
tunneled subcutaneously to the back. After determination of body
weight, mice were anesthetized with ketamine (0.065
mg/g), acepromazine (0.002 mg/g), and xylazine (0.013 mg/g) injected
intraperitoneally and were allowed to breathe
spontaneously according to the method of Hoit et al.3 The
chest was shaved, and mice were positioned prone on a warmed saline bag
as support. The saline bag was attached to a warming pad (Deltaphase
isothermal pad) to keep temperature constant at 37°C.
Electrocardiographic leads were attached to each limb using needle
electrodes (Grass Instruments). Echocardiography
was performed by using an Interspec Apogee X-200 ultrasonograph
(Interspec-ATL). A dynamically focused 9-MHz annular array transducer
was applied from below, using the saline bag as a standoff. The heart
was first imaged using the two-dimensional mode in the parasternal
long-axis and short-axis views. The short-axis views,
including papillary muscles, were used to position the M-mode cursor
perpendicular to the ventricular septum and LV posterior
wall. Studies were recorded on 1/2-in S-VHS videotape (Sony Corp). Freeze frames were printed on a Sony color printer (UP-5200, Sony Corp). The ECG was printed on the ultrasonograph for heart rate measurement. The images were scanned into a Macintosh IICi computer and digitized at 300 pixels per inch. Gray scale equalization was made using the Photoshop program (Adobe Photoshop, Adobe Systems Corp), and the images were imported into the NIH-Image program (National Institutes of Health) for measurement. M-mode measurements of LVID were made from more than three beats and averaged, using the leading edge–to–leading edge convention adopted by the American Society of Echocardiography.4 End-diastolic measurements were taken at the time of the apparent maximal LV diastolic dimension. End-systolic measurements were made at the time of the most anterior systolic excursion of the posterior wall. LV percent fractional shortening (LVFS) was calculated as follows: LVFS=[(LVIDd-LVIDs)/LVIDd]x100, where d indicates diastolic and s indicates systolic. LVEF was calculated by the cubed method as follows: LVEF=[(LVIDd)3-(LVIDs)3]/LVIDd3.
M-mode echocardiographic measurements of the LV were performed at baseline and during intravenous infusion of isoproterenol (0.01, 0.02, and 0.04 µg/kg per minute for 5 minutes each) using a microliter syringe (Hamilton Co) and an infusion pump (Harvard Apparatus, Inc). A lower dose of isoproterenol (0.005 µg/kg per minute) was infused in the transgenic mice because of the enhanced response. The total amount of the infusion volume was <100 µL in each mouse. On a separate occasion, each mouse received an infusion of saline as a control to ensure that the volume of infusion alone did not contribute to enhance ventricular performance. On a separate day, a similar protocol was performed during intravenous norepinephrine (0.1, 0.2, and 0.4 µg/kg per minute) in control mice, and a lower dose (0.05 µg/kg per minute) was infused in transgenic mice. These studies were conducted in four transgenic and four control mice for both isoproterenol and norepinephrine. Three animals were common to both isoproterenol and norepinephrine studies.
In addition, three transgenic mice (10.8±1.8 months old) and three wild-type control mice (10.7±1.7 months old) were studied with an acutely implanted 1.8F micromanometer (Millar Instruments) and with the heart rate held constant. After the anesthetic regimen as noted above, a 25-gauge needle was inserted into the LV through the chest wall. The needle was used for electrical pacing (stimulator, model SD9, Grass Instruments), and a 1.8F Millar micromanometer was connected for measurement of LV pressure. The LV pressure signal was differentiated (frequency response of 700 Hz) for calculation of LV dP/dt. Measurements of LV pressure, LV dP/dt, and heart rate were recorded on a multichannel tape recorder and played back on a multichannel oscillograph.
Pathological Study
Separate groups of nine transgenic mice
(16.0±0.8 months old)
and eight wild-type mice (16.4±0.8 months old) from the same
genetic background as the transgenic mice were used for this part of
the study. The hearts of four animals from each group were fixed by
immersion in 10% phosphate-buffered formalin; the remaining, by
perfusion fixation with 2% phosphate-buffered
glutaraldehyde. All animals were anesthetized
with intraperitoneal sodium pentobarbital, the
chest was opened, and the heart was either removed and dissected fresh
followed by immersion fixation or perfused at 90 mm Hg with a brief
saline wash followed by glutaraldehyde via a 21-gauge
trocar inserted directly into the LV apex. The heart was dissected to
remove the atria and right ventricular free wall, and each
portion was weighed. Fixed tissues were dehydrated, embedded in
paraffin, sectioned at 6 µm thickness, and stained with hematoxylin
and eosin and Gomori's aldehyde fuchsin trichrome. Heart sections were
also stained with picric acid sirius red.
Glutaraldehyde-fixed tissues were dehydrated and
embedded in Spurr epoxy resin and in glycol methacrylate, sectioned at
1 µm thickness, and stained with toluidine blue and methylene
blue–basic fuchsin, respectively, for light microscopic
examination. Methacrylate sections were also stained with
silver-gold (Accustain silver stain, Sigma Diagnostics) for
basement membrane to outline cardiac myocytes for cross-sectional
area measurement.
Myocyte cross-sectional area was measured from video prints of silver-stained 1 µm thick methacrylate sections of subendocardial and subepicardial regions of the LV. Suitable cross sections were defined as having nearly circular capillary profiles and circular to oval myocyte cross sections. No correction for oblique sectioning was made. Video prints (x1100 final magnification) were used to trace the outline of 40 to 130 myocytes in each region, using a sonic digitizer (Graf/Bar, Science Accessories). Myocyte cross-sectional area was determined using computer programs developed in our laboratory. The mean area was calculated for each region in each animal, and the group mean was calculated for each region and group.
Myocardial connective tissue was quantitatively analyzed on a single cross section of LV and septum obtained mid-distance from base to apex, embedded in paraffin, and stained with picric acid sirius red. Images were obtained from a video monitor and CCD72 video camera attached to an Olympus AHT microscope, using a x1 objective and a green (550 nm) filter at a final video screen magnification of x30, and were analyzed with Image-1 image analysis software (Universal Imaging Corp). The entire inner (subendocardial) and outer (subepicardial) halves of the LV were traced and analyzed separately for volume percent collagen. Areas measured in each region ranged from 2.5 to 10 mm2.
Data Analysis and Statistics
All data were reported as
mean±SE. Comparisons between
transgenic and control mice were made by using Student's t
test for group data. The dose-response curves were analyzed
by one-way ANOVA for repeated measurements. If the ANOVA
demonstrated significant overall differences, individual comparisons
between baseline and the responses to each dose were made by contrast
analysis. A value of P<.05 was taken as the minimal
level of significance.
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Results |
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Physiological Study
Preliminary experiments indicated that the transgenic mice responded with a positive effect on LV function at a lower dose than the control mice, which did not respond at all to the lowest doses, and that the transgenic mice reached the top of the dose-response curve, ie, nearly 100% ejection fraction, at a lower dose than the control mice. Accordingly, the lowest dose was only examined in the transgenic mice, and the highest dose was only examined in the control mice.
Response to Isoproterenol
Representative responses
to isoproterenol in a
control mouse and a transgenic mouse are illustrated in Fig 1A
and summarized in Table 1. Both the
baseline heart rate and the chronotropic responses to increasing doses
of isoproterenol were greater in transgenic mice than in control mice.
LV end-diastolic dimensions decreased
dose-dependently in both groups. Although baseline levels of
fractional shortening and ejection fraction were not different,
isoproterenol infusion produced significantly greater increases in both
fractional shortening and ejection fraction in transgenic mice given
isoproterenol (Fig 1B and 1C). In three
wild-type control mice with
heart rates held constant (8.0±0.0 Hz), isoproterenol (0.02 µg/kg
per minute) increased LV dP/dt by 13±2% from a baseline of
6923±281
mm Hg/s, which was significantly less (P<.01) than in
three transgenic mice with heart rates held constant (9.0±0.6 Hz), in
which isoproterenol increased LV dP/dt by 33±2% from a baseline
similar to that observed with wild-type control mice (Fig 2).
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Response to Norepinephrine
Responses to
norepinephrine in control and transgenic
mice are summarized in Table 2. Although the baseline
heart rate remained significantly greater in transgenic mice, there was
no significant chronotropic effect of norepinephrine in
either group, which was most likely due to secondary reflex cardiac
slowing induced by the rise in blood pressure. In contrast to
isoproterenol, norepinephrine infusion had no effect on LV
end-diastolic dimensions in either group. However,
similar to isoproterenol, norepinephrine produced
significantly greater (P<.05) increases both in LVFS and in
LVEF in transgenic mice. In three wild-type control mice with heart
rates held constant (6.0±0.0 Hz), norepinephrine (0.1
µg/kg per minute) increased LV dP/dt by 28±4% from a baseline of
7292±461 mm Hg/s, which was significantly less (P<.05)
than in three transgenic mice with heart rates held constant (8.3±1.2
Hz), whereas norepinephrine increased LV dP/dt by 65±8%
from a baseline similar to that observed in wild-type control
mice.
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Pathological Study
Six of the nine transgenic mice had
moderate to severe multifocal
areas of mature replacement type fibrosis and interstitial
fibrosis throughout the LV and septum but most severe in the
subendocardium (Fig 3). There was a marked increase in
the cross-sectional area of cardiac myocytes, especially in the
subendocardial half of the LV myocardium (Fig 3). In the
subendocardial regions, particularly in areas adjacent to focal
fibrosis, there was extreme variability in myocyte cross-sectional
area; some myocytes were smaller than normal, suggesting atrophy, and
others had very large cross-sectional areas, with some exceeding
500 µm2. Quantitative evaluation of myocardial fibrosis
revealed a significant increase in volume percent collagen for the
entire group of transgenic mice compared with control mice; this
increase was most prominent in the subendocardium (Fig 3).
Apparently,
the myocyte hypertrophy was offset by the cellular
degeneration and necrosis, since heart weight, even normalized to body
weight, was not significantly elevated in the transgenic mice
(5.07±0.34 mg/g) compared with control mice (4.66±0.30 mg/g)
(Table 3). Electron microscopy revealed individual cells with
myofibrillar disorganization and loss, small mitochondria, increased
lipofuscin, and bizarre nuclei, indicative of myocyte degeneration and
atrophy in the transgenic mice. Qualitative
histological data indicated the presence of
hypertrophied myocytes in 7-month-old transgenic mice (n=3) and
hypertrophied myocytes plus fibrosis in 10-month-old (n=2) and
12-month-old (n=5) transgenic mice compared with age-matched
control mice.
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Discussion |
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The stimulatory guanine nucleotide binding protein, Gs
, plays an important role
in ß-adrenergic signal transduction. It is not known whether
increases in the levels of Gs would
facilitate adrenergic signal transduction, particularly since
Gs is thought to be in excess of the
effector, adenylyl cyclase.2 The logical extension of that
concept suggests that increasing the expression and amount of
myocardial Gs might have little effect on
maximal adenylyl cyclase activity and potentially on responses to
sympathomimetic amines in vivo. Indeed, this is one potential
interpretation from the initial study by Gaudin et al1 on
the transgenic murine model in which Gs was
overexpressed. Protein levels of Gs as
measured in the hearts of these transgenic mice by Western blotting
rose 2.8-fold, and Gs activity as assessed
by S49 lymphoma cell mutant cyc– reconstitution assay
rose by only 88%. Effector activity at steady state (ie, adenylyl
cyclase, either basal or stimulated) failed to increase, which is
consistent with the concept that Gs
is present in excess. Only the findings that the fraction of
ß-ARs in the high-affinity state was increased and that the
activation of adenylyl cyclase occurred more rapidly in sarcolemma from
mice with overexpressed Gs presaged possible
augmented ß-adrenergic function.
One of the most important findings in the present investigation is
that responsiveness to sympathomimetic amines is clearly augmented in
mice with Gs overexpression. With
intravenous infusion of either isoproterenol or
norepinephrine, ventricular systolic
performance, as reflected by LVEF and LVFS as well as by LV
dP/dt, was enhanced in the transgenic mice. Because these
sympathomimetic amines exert opposing effects on preload and afterload,
the changes in indices of ventricular performance
cannot be ascribed to loading conditions but rather to a true change in
the inotropic state.
An additional concern is that heart rates were higher in the mice with
overexpressed Gs. To address this
concern, we examined the effects of isoproterenol and
norepinephrine in three transgenic mice and three
wild-type control mice with heart rates held constant. With heart
rates constant, a greater effect of the sympathomimetic amines was
observed in the transgenic mice compared with the control mice (Fig
2
).
In further support of the concept that the inotropic action of
sympathomimetic amines can be dissociated from their chronotropic
actions, note that norepinephrine (0.1 µg/kg per minute)
increased LV function significantly (both LVEF and LVFS) but did not
increase heart rate in the transgenic mice (Table 2).
These observations raise an interesting conundrum when relating the in
vivo physiological consequences of cardiac
Gs overexpression to the biochemical
alterations in vitro. We have documented in younger animals that at
steady state, adenylyl cyclase is not altered whether activated
with agonist plus GTP, Gpp(NH)p, NaF, or forskolin, a finding that is
consistent with a scenario in which the sarcolemmal content of
the catalyst itself has not changed.1 Nevertheless, in
vivo, the hearts of these mice hyperrespond to
catecholamines compared with the hearts of their
wild-type littermates. Moreover, previous observations indicate
that the activation of more distal effector pathways such as the L-type
Ca2+ channel, known to be regulated by cAMP-dependent
protein kinase A, was markedly enhanced in transgenic
cardiocytes.5 How can these apparently
contradictory observations be reconciled? Several hypotheses are
suggested. First, it is possible that these enhanced
physiological responses are transduced via
Gs but not through adenylyl cyclase
activation. There has been preliminary evidence that
Gs can directly modulate the activity of
other effector pathways.6 7 8
Nevertheless, the enhanced
inotropic and chronotropic responses seen in the present study are
characteristic, if not classic, responses to enhanced cAMP generation.
A more attractive hypothesis would argue that steady state cAMP in
vitro measurements do not accurately reflect the activity of the
ß-adrenergic signaling pathway in the heart. This organ responds
on a second-to-second basis to changing levels of
norepinephrine released and removed at the synaptic
terminal as the organism moves, changes posture, eats, or becomes
excited. In responding to these continuously changing demands, the
heart operates on the steep portion of the receptor occupancy curve
with this parameter continuously changing, thereby not
permitting steady state measurements in vitro to accurately mirror in
vivo signaling activity. Biochemical measurements of the myocardial
ß-AR–Gs–adenylyl cyclase pathway made in vitro are
thereby limited in that they may not accurately reflect the activity of
this pathway in the dynamic range in which it operates in vivo. It is
exactly in this framework that the increased
Gs levels in the
transgenic cardiocytes are likely exerting their effect by
allowing small changes in ß-AR occupancy to signal the catalyst to
activate more rapidly. Static measurements of second messenger
activity, whether cAMP or Ca2+, cannot capture the dynamic
nature of these activities, particularly in the intact
innervated heart, which responds to changing neural
activity on a time frame measured in seconds. Although the present
experiments were carried out with exogenously administered
sympathomimetic amines, one can readily extrapolate to the in vivo
situation, in which sympathetic tone fluctuates on a
moment-to-moment basis. If it is assumed that similar augmented
inotropic and chronotropic effects would be observed with
physiological increases in adrenergic drive, this
transgenic model becomes useful for the study of the cardiac effects of
chronic adrenergic hyperactivity.
The next most interesting finding of the present investigation
involved the histological studies in older transgenic
mice. It is possible to predict that the cumulative effects of
increased endogenous sympathetic stimulation secondary to
the overexpression of Gs might result in
catecholamine-induced myocardial injury. For example, a
prior study in rats that received infusions of isoproterenol for
several weeks demonstrated myocardial hypertrophy with
cellular necrosis and replacement fibrosis.9 Similarly,
another prior study in mice with chronic isoproterenol administration
demonstrated enhanced hypertrophic responses.10 Indeed, in
the present study, there was clear evidence of myocardial cellular
degeneration and extensive increases in fibrosis, as reflected by the
increased collagen, most prominent in the subendocardium. Significantly
increased myocyte size confirmed the existence of
hypertrophy in both the subepicardium and subendocardium,
but again, hypertrophy was more prominent in the
subendocardium, where wall stresses are higher and the impact of
reduced coronary reserve is greater.11
Importantly, the hypertrophic process was not evident on gross
morphology. Apparently, the cellular degeneration and myocyte loss,
evident on light microscopy and corroborated by electron microscopy,
offset the expected increase in total heart weight that should have
been observed with myocyte hypertrophy. The
hypertrophy presumably resulted as a compensatory response
to the increases in cardiac work imposed by the chronically enhanced
endogenous adrenergic function. With cellular degeneration
and myocyte loss, cardiac function might be expected to decline and
provide a further stimulus to hypertrophy in the remaining
cardiocytes, potentially through local application of the
Frank-Starling mechanism. In addition, a direct role of
Gs in myocardial growth cannot be ruled
out.
The results of the present investigation have implications for the understanding of the pathogenesis of heart failure. There are currently two opposing views as to the role of adrenergic mechanisms in the pathogenesis and therapy of heart failure. One point of view holds that catecholamine desensitization is a signature of heart failure,12 resulting in a critical defect in the normal compensatory mechanism of increased sympathetic drive, and that by replacing the sympathetic tone (eg, through increasing the expression of ß-AR13 14 or treatment with adrenergic agonists), heart failure can be ameliorated.
The studies by Koch et al13 and Milano et al14 examined the effects of overexpressing ß2-ARs and found enhanced baseline LV function, with little further effect due to ß-AR stimulation, and went on to suggest that this model may be potentially beneficial as a treatment for heart failure. Koch et al15 also found similar results with overexpressing a ß-AR kinase inhibitor. However, the later development of myocyte hypertrophy, cellular necrosis, and fibrosis in the present investigation supports the diametrically opposite point of view. The present study is the first to examine the effects of long-term adrenergic stimulation in transgenic animals with overexpression of a component of the ß-adrenergic signaling pathway. This is the major difference among the studies and may explain the differences between the present study and those of Koch and colleagues13 15 and Milano et al.14 Bertin et al16 overexpressed ß1-ARs in the atrium and found an increased incidence of arrhythmias.
In further support of the concept that chronic ß-adrenergic
stimulation is not beneficial in heart failure, a variety of
therapeutic approaches have been devised to augment the adrenergic
support that dissipates with heart failure (eg, approaches involving
dobutamine,17 18 prenalterol,19
xamoterol,20 and milrinone21 ). Unfortunately,
all of these therapeutic strategies have failed to materially alter the
course of heart failure. In contrast, the opposite approach (ie, ß-AR
blockade) may be potentially more useful.22 23 In
further
support of the latter opposing point of view is the concept that
inhibition of ß-adrenergic function is salutary in heart failure,
particularly in view of recent beneficial effects of another
ß-blocker, carvedilol, in heart failure.24 25 Our
results support the latter concept; ie, whereas the normal
physiological compensatory mechanisms to the
fight-or-flight syndrome (including increased sympathetic
drive) are important for the acute adjustments required for exercise,
excitement, and hypotension, these mechanisms are deleterious on a
chronic basis, as evidenced by the histological studies
in the older transgenic mice in the present study. The mechanism
underlying this deleterious effect remains unclear, but the
Gs transgenic mouse may offer clues as to
how enhanced sympathetic nerve drive might trigger cell death via
mechanisms such as apoptosis. A further extension of this
concept is that catecholamine desensitization mechanisms,
which are pathognomonic of heart failure, are actually salutary chronic
compensatory mechanisms and that overcoming these compensatory
mechanisms by enhancing sympathetic activation is deleterious over the
long term.
Interestingly, had the physiological and
histological studies not been conducted, the
interpretation of the model of increased Gs
would have been entirely different. Since steady state adenylyl cyclase
activity was not enhanced and since there was no evidence of
hypertrophy on gross examination of the heart (ie, the
heart weight–to–body weight ratio was not increased), one
might conclude that the increased expression of
Gs did not have profound
physiological or pathological consequences. In vivo
cAMP levels, which may fluctuate on a minute-to-minute basis or
actually be heterogeneously distributed throughout the
heart, may not be faithfully recapitulated by in vitro steady state
assays.26
In conclusion, this transgenic mouse model demonstrates first that
physiological effects may be a more sensitive
indicator of ß-adrenergic signaling than in vitro assays because
of the rapid kinetics of the response, which are hampered by the time
required to achieve steady state conditions, particularly under
conditions of low levels of receptor occupancy. Second, the unique
advantage of examining the effects of overexpression of a component of
the ß-adrenergic signaling pathway over the life of the animal
permitted demonstration of the deleterious effects of chronic
sympathetic stimulation, which may not have been apparent if only
younger animals had been studied. Thus, the transgenic mouse with
overexpressed Gs sheds insight not only into
mechanisms regulating the efficiency of ß-AR signal transduction but
also into the pathogenesis of heart failure and may provide a tool for
investigating the biological mechanisms underlying this process and for
evaluating new therapies aimed at arresting its progression.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by National Heart, Lung, and Blood Institute grants HL-38070, HL-33107, HL-33065, HL-37404, and HL-45332. Dr Iwase was a recipient of a fellowship grant from the Uehara Memorial Foundation. We thank Drs Brian D. Hoit and Richard A. Walsh for teaching us the techniques of murine echocardiography. We also thank Thomas Patrick for his assistance in the development of measurements of echocardiographic data.
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Footnotes |
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This manuscript was sent to Howard Morgan, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received September 11, 1995; accepted January 5, 1996.
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References |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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J. F. James, T. E. Hewett, and J. Robbins Cardiac Physiology in Transgenic Mice Circ. Res., March 9, 1998; 82(4): 407 - 415. [Abstract] [Full Text] [PDF]
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M. Uechi, K. Asai, M. Osaka, A. Smith, N. Sato, T. E. Wagner, Y. Ishikawa, H. Hayakawa, D. E. Vatner, R. P. Shannon, et al. Depressed Heart Rate Variability and Arterial Baroreflex in Conscious Transgenic Mice With Overexpression of Cardiac Gs{alpha} Circ. Res., March 9, 1998; 82(4): 416 - 423. [Abstract] [Full Text] [PDF]
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D. A. Kass, J. M. Hare, and D. Georgakopoulos Murine Cardiac Function : A Cautionary Tail Circ. Res., March 9, 1998; 82(4): 519 - 522. [Full Text] [PDF]
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T. Kameyama, Z. Chen, S. P. Bell, J. Fabian, and M. M. Lewinter Mechanoenergetic studies in isolated mouse hearts Am J Physiol Heart Circ Physiol, January 1, 1998; 274(1): H366 - H374. [Abstract] [Full Text] [PDF]
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David. A. Conner, M. A. Mathier, R. M. Mortensen, M. Christe, S. F. Vatner, C. E. Seidman, and J. G. Seidman ß-Arrestin1 Knockout Mice Appear Normal but Demonstrate Altered Cardiac Responses to ß-Adrenergic Stimulation Circ. Res., December 19, 1997; 81(6): 1021 - 1026. [Abstract] [Full Text]
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B. D. Hoit, N. Ball, and R. A. Walsh Invasive hemodynamics and force-frequency relationships in open- versus closed-chest mice Am J Physiol Heart Circ Physiol, November 1, 1997; 273(5): H2528 - H2533. [Abstract] [Full Text] [PDF]
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T. Kubota, C. F. McTiernan, C. S. Frye, S. E. Slawson, B. H. Lemster, A. P. Koretsky, A. J. Demetris, and A. M. Feldman Dilated Cardiomyopathy in Transgenic Mice With Cardiac-Specific Overexpression of Tumor Necrosis Factor-{alpha} Circ. Res., October 19, 1997; 81(4): 627 - 635. [Abstract] [Full Text]
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N. Sato, S. F. Vatner, Y.-T. Shen, R. K. Kudej, B. Ghaleh-Marzban, M. Uechi, K. Asai, I. Mirsky, T. A. Patrick, R. P. Shannon, et al. Effects of Cardiac Denervation on Development of Heart Failure and Catecholamine Desensitization Circulation, April 15, 1997; 95(8): 2130 - 2140. [Abstract] [Full Text]
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W. J. Koch, C. A. Milano, and R. J. Lefkowitz Transgenic Manipulation of Myocardial G Protein–Coupled Receptors and Receptor Kinases Circ. Res., April 1, 1996; 78(4): 511 - 516. [Full Text]
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P. Liao, D. Georgakopoulos, A. Kovacs, M. Zheng, D. Lerner, H. Pu, J. Saffitz, K. Chien, R.-P. Xiao, D. A. Kass, et al. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy PNAS, October 9, 2001; 98(21): 12283 - 12288. [Abstract] [Full Text] [PDF]
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J. C. Braz, O. F. Bueno, L. J. De Windt, and J. D. Molkentin PKC{alpha} regulates the hypertrophic growth of cardiomyocytes through extracellular signal-regulated kinase1/2 (ERK1/2) J. Cell Biol., March 4, 2002; 156(5): 905 - 919. [Abstract] [Full Text] [PDF]
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C. L. Antos, N. Frey, S. O. Marx, S. Reiken, M. Gaburjakova, J. A. Richardson, A. R. Marks, and E. N. Olson Dilated Cardiomyopathy and Sudden Death Resulting From Constitutive Activation of Protein Kinase A Circ. Res., November 23, 2001; 89(11): 997 - 1004. [Abstract] [Full Text] [PDF]
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