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2-adrenergic receptors
Baker Medical Research Institute and Alfred Heart Centre, Alfred Hospital, Melbourne 8008, Victoria, Australia
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects
of cardiac specific overexpression of 
2-adrenergic
receptors (2-AR) on the development of heart failure
(HF) were studied in wild-type (WT) and transgenic (TG) mice following
myocardial infarction (MI) by coronary artery occlusion. Animals were
studied by echocardiography at weeks 7 to 8 and
by catheterization at week 9 after surgery. Post-infarct
mortality, due to HF or cardiac rupture, was not different among WT
mice, and there was no difference in infarct size (IS). Compared with
the sham-operated group (all P < 0.01), WT mice with
moderate (<36%) and large (>36%) IS developed lung congestion,
cardiac hypertrophy, left ventricular (LV) dilatation, elevated LV
end-diastolic pressure (LVEDP), and suppressed maximal rate of increase
of LV pressure (LV dP/dtmax) and fractional
shortening (FS). Whereas changes in organ weights and echo parameters
were similar to those in infarcted WT groups, TG mice had significantly higher levels of LV contractility in both moderate
(dP/dtmax 4,862 ± 133 vs. 3,694 ± 191 mmHg/s) and large IS groups (dP/dtmax
4,556 ± 252 vs. 3,145 ± 312 mmHg/s, both P < 0.01). Incidence of pleural effusion (36% vs. 85%,
P < 0.05) and LVEDP levels (6 ± 0.3 vs. 9 ± 0.8 mmHg, P < 0.05) were also lower in TG than in
WT mice with large IS. Thus 2-AR overexpression
preserved LV contractility following MI without adverse consequence.
echocardiography; heart failure; hemodynamics; transgenic mice
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE
-ADRENERGIC SYSTEM plays a key role in heart
failure (HF) (5). In response to chronically elevated
cardiac sympathetic drive, -adrenergic signaling is suppressed with
30-50% loss of 1-adrenergic receptors
(1-AR), reduced adenylyl cyclase (AC) activity, and a
lower ratio of Gs/Gi proteins (5).
Meanwhile, the expression and the activity of -AR kinase 1 (ARK1), which is involved in -AR downregulation and
desensitization, are elevated (5). However, whether these
changes in -adrenergic activity are beneficial or detrimental in the
development of HF remains controversial.
Clinical studies provide evidence that excessive -adrenergic
activity is detrimental in the heart with compromised structure and
function (5). Long-term -blockade treatment
significantly improves cardiac function and prognosis in HF patients
(5, 11, 18), and hence a downregulated -adrenergic
system could be interpreted as adaptive and self-protective. However,
treatment with -blockers simultaneously improves both contractile
function and -adrenergic signaling (4, 11-13, 16),
suggesting the possibility that restoration of the latter, with or
without upregulation of 1-AR, might contribute to the
improved function. The controversy extends to the experimental
situation. Transgenic strains that overexpress 1-AR and
Gs
have a cardiac phenotype of hypertrophy and
dysfunction (3, 8, 14, 23). In contrast, transgenic (TG)
mice that overexpress 2-AR, ARK inhibitor, or AC have
markedly enhanced cardiac contractility without significant cardiac
pathology at least up to 8 mo of age (9, 15, 19, 25, 29).
While overexpression of 2-AR at a high level accelerates
the development of HF induced genetically or by pressure overload
(6, 7, 24), expressing 2-AR at a low level
(~30-fold) or expressing a ARK inhibitor prevented cardiac
hypertrophy and dysfunction in two genetic HF models (6,
24).
TG mice (TG4) with cardiac-specific overexprssion of
2-AR have constitutively activated -adrenergic
signaling due to an ~200-fold increase in 2-AR
concentration (19). In this study, we sought to determine
whether overexpression of 2-AR was beneficial or
detrimental following experimentally induced myocardial infarction (MI).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Mice, genotyping, and 2-AR binding.
Parent TG mice (TG4) that overexpress 2-AR by
~200-fold were generated at the Howard Hughes Medical Institute, Duke
University Medical Center (Durham, NC) (19). TG mice were
crossed with F1 mice from C57BL × SJL strains. The
genomic DNA was extracted from tail biopsy, and expression of the
transgene was detected by Southern blot hybridization with the use of a
32P-labeled Hinc II fragment of the transgene
construct (19). Both male and female animals, ages
12-18 wk, were used.
2-AR density in the left ventricle (LV) was measured in
a separate group of TG and WT mice (n = 6 each).
Saturation curves were generated by incubating myocardial membrane
proteins with [125I]-(l)-iodocyanopindalol
(125I-CYP; 2,200 Ci/mmol; NEN) at 12-400 pmol/l for
1 h to determine the affinity of receptors. Nonspecific binding
was determined by the presence of l-isoproterenol at 20 µmol/l. The binding assay was performed by incubating membrane
proteins with 100 pmol/l 125I-CYP for 1 h in the
presence of ICI-118551 (Sigma) at
10
11-105 mol/l. 2-AR
density was 300-fold higher in TG than in WT hearts (1,506 ± 274 vs. 5 ± 2 fmol/mg protein).
Microsurgery. Experimental procedures were approved by the local animal experimentation ethics committee. Mice were anesthetized (mixture of 8 mg/100 g ketamine, 2 mg/100 g xylazine, 0.06 mg/100 g atropine, and 0.1 mg/100 g temgesic as a pain reliever), intubated, and ventilated. Under a surgical microscope, a left thoracotomy was performed to expose the heart. The location of the left coronary artery was identified and then occluded with a 7-0 silk suture, as described previously in detail (10). Sham-operated mice underwent similar surgery without occlusion of the coronary artery.
Echocardiography.
Transthoracic echocardiography was performed with the use of a
Hewlett-Packard Sonos 5500 ultrasound machine with a 12-MHz phased-array transducer (0.5- to 0.7-cm standoff added), as described previously (10). Mice were anesthetized with the
anesthetic mixture as used for surgery and placed on a heating pad. A
standard lead II electrocardiogram was recorded for heart rate (HR)
measurement. After a short-axis two-dimensional (2D) image of the LV
was obtained at a level close to the papillary muscles, a 2D guided
M-mode image crossing the anterior and posterior walls was recorded
(sweep speed 100 mm/s). Parameters measured digitally on the M-mode
trace were LV inner dimensions of diastole and systole
(LVIDd, LVIDs), LV external dimension of
diastole (LVEDd), and fractional shortening [FS = (LVIDd 
LVIDs)/LVIDd]
(10).
Cardiac catheterization. Cardiac function was assessed by cardiac catheterization. Mice were anesthetized (pentobarbitone 8 mg/100 g and atropine 0.06 mg/100g ip) and placed supine on a heating pad. A 1.4-F Millar microtipped transducer catheter was inserted into the LV via the right carotid artery. The aortic blood pressure, LV pressures, and the maximal rate of increase or decay of LV pressure (dP/dtmax or dP/dtmin, respectively) were recorded. HR was derived from pulse signals.
To further characterize the murine MI model of HF, in sham-operated and infarcted WT mice, a1-agonist, dobutamine, was infused intravenously at increasing doses of 7.5-480 ng/min per mouse for
1-3 min (0.028-1.8 µg/kg), and the functional response was monitored.
To assess the cardiac functional reserve, in some WT and TG mice with
MI, the peak levels of LV systolic pressure (LVSP) and dP/dtmax were measured during a brief occlusion
of the aorta by following the method previously applied to the rat
(21). While the Millar catheter remained in the LV,
mechanical ventilation was commenced, and the chest was opened by a
midline incision via the sternum. The ascending aorta was dissected,
and a fine suture enclosed the aorta. After stabilization, the aortic
blood flow was stopped by tightening the suture for 3 s, and LV
pressure and dP/dt were continuously recorded immediately
before and during the occlusion of the aorta. This procedure was
repeated three times, and the averages of the peak levels of
dP/dtmax and LVSP were used as indexes for the
maximal contractile reserve.
Morphometry and organ weights. Animals were killed by pentobarbitone overdose. The chest was opened to determine whether pleural effusion was present before isolation of the heart. The heart was immersed in saline on ice. The LV, right ventricle (RV), and atria were separated and weighed. When organic thrombus was present in the left atrium, the weight of thrombus was subtracted. The lungs and liver were weighed, and the tibial length was measured. LVs were fixed in 10% formalin in PBS for sectioning.
Infarct size determination. The LV was embedded in paraffin and serially cut from the apex to the base. A 5-µm transverse section was collected every 0.8 mm, and 5-7 sections were obtained from each LV. Sections were stained with hematoxylin and eosin, and images were digitized. The lengths of the entire endo- and epicardial circumferences and portions of infarcted segments from both sides were measured using the Optimas 6.5 program. Percentages of infarcted LV of the endo- and epicardial circumferences were calculated, and the averages were used (10, 21).
Statistics. Results are expressed as means ± SE or as percentages. For parametric data, between-group comparison was made by analysis of variance followed by unpaired Student's t-test. The chi-square test or Fisher's exact test was used to compare percentages between groups. The least-square method was used for linear correlation and regression.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Outcome of surgery. Of 125 operated mice, 20 (11 WT and 9 TG) died within 24 h due to surgical reasons. All sham-operated mice survived until the time of functional study. Of 83 mice with coronary artery occlusion that survived longer than 24 h, 35 (21 WT and 14 TG) died of cardiac rupture or acute and chronic HF with a mortality of 46% for WT and 38% for TG groups (P = not significant). Mice that died of HF had a threefold increase in lung weight versus sham-operated mice (405 ± 15 vs. 137 ± 3 mg, P < 0.001), and the incidences of atrial thrombus and pleural effusion were 87% and 100%, respectively. Infarct size (IS) was measured in the 27 mice that died and was 52.0 ± 2.5% (n = 17) in the mice that died of HF and 41.4 ± 2.4% (n = 10) in the mice that died of rupture.
Infarct size and grouping of surviving mice.
All mice that survived coronary artery occlusion had a transmural
infarct localized to the LV free wall and apex. The RV and septum were
not involved (Fig. 1). IS ranged from 8%
to 54% of LV and was not significantly different between WT and TG
groups (36 ± 2% vs. 33 ± 3%). To compare cardiac function
of WT and TG mice with different IS, we divided animals into subgroups
with moderate and large IS by the median IS of 36% (Table
1).
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Organ weights in WT mice. Since body weights and tibial length were similar in all groups of WT and TG mice, the organ weights are presented as absolute values (Table 1). At 9 wk, weights of whole heart or LV, RV, and atria were significantly increased in WT mice, with MI indicating the development of hypertrophy in noninfarcted myocardium. Lung weights increased significantly, implying chronic pulmonary congestion. The degree of these changes was dependent on IS (Table 1).
Cardiac function in WT mice.
Echocardiography was performed at 7-8 wk, and LV catheterization
was done at 9 wk after surgery. In WT and TG mice, HR levels recorded
at echo test were higher than those recorded during catheterization (Table 2), most likely because of the
different anesthetic regimes used (see METHODS).
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-adrenergic signaling in the infarcted mouse
heart.
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Differences between TG and WT mice. Pleural effusion, a sign of left HF (7), was less frequent in TG than in WT mice with large IS (36% vs. 85%, P < 0.05, Table 1). Increases in weights of heart or LV, RV, and atria were similar between WT and TG mice with MI. In infarcted mice surviving to the time of study, nine (4 TG, 5 WT) had chronic thrombus in the left atrium. All but one (32.6%) had IS >36% (38.2-50.5%, average 44 ± 2%).
There was no significant difference among sham-operated and infarcted WT and TG groups in any of the echocardiographic parameters (Table 2), except that TG mice had a higher HR. The TG mice with large IS had significantly lower LVEDP compared with the respective WT group (P < 0.05). Although infarcted TG and WT mice had similar percent reduction in LV dP/dtmax and dP/dtmin versus respective sham-operated groups, dP/dt levels were significantly higher than those in the respective WT groups (P < 0.01, Fig. 3A). HR itself is known to influence the measurement of LV dP/dt (20). The possibility that higher levels of LV dP/dt in TG mice was due to higher HR was examined in a separate group of infarcted WT mice (n = 5) under conditions of ventilation and rapid atrial pacing by following the method described by Palakodeti et al. (20). Increasing HR from 350 ± 10 to 450 to 500 beats/min led to an 18% fall in dP/dtmax (P < 0.05) from a basal level of 3,350 ± 250 mmHg/s. A similar change was also observed for dP/dtmin. This suppression of dP/dt levels with rapid atrial pacing was immediately reversed when atrial pacing was stopped. Thus the difference between WT and TG mice in LV dP/dt cannot be attributed to the difference in HR levels. The contractile response to acute aortic occlusion was tested in randomly selected infarcted WT (n = 6) and TG mice (n = 7) with similar IS (38 ± 3% vs. 35 ± 3%, P = NS). Under conditions of open chest and ventilation, baseline LVSP (P = 0.069) and dP/dtmax (P < 0.05) were higher in TG than in WT mice. LVSP and dP/dtmax increased in both groups in response to temporary aortic occlusion. While the peak LVSP was not significantly different between groups, TG mice had higher levels of dP/dtmax than WT mice did (P < 0.05, Fig. 3B).Correlation of morphometric and functional parameters. Lung weights correlated well with weights of heart (r = 0.704), LV (r = 0.523), RV (r = 0.848), and atria (r = 0.766; all P < 0.001). Furthermore, when IS exceeded a certain level (~30%), weights of the heart, LV, RV, atria, and lungs were increased (Table 1).
IS correlated positively with LVIDd, LVIDs, and LVEDP and negatively with FS, LVSP, dP/dtmax, and dP/dtmin (all P < 0.01; Fig. 5). FS modestly correlated with dP/dtmax in either WT (r = 0.421) or TG mice (r = 0.369; both P < 0.05). The extent of LV dilatation, estimated from the LVEDd correlated negatively with FS (r =0.781,
P < 0.0001). LVEDP correlated significantly with
weights of the RV ( r =0.466), atria (r = 0.408),
and lungs (r = 0.526; all P < 0.01).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study, the development of HF in WT mice with MI was
evidenced by pulmonary congestion, pleural effusion, LV dilatation, elevation in LVEDP, and reduction in both LV contractility
(dP/dt) and FS. The blunted inotropic and chronotropic
responses to dobutamine indicate downregulation of the -adrenergic
system in this model. Similarly to that in other species, including
humans (21, 22), IS in mice is a major determinant of the
extent of cardiac dysfunction, morphometric abnormalities, incidence of
pathological events, and mortality. These data elucidate the features
of the murine model of MI.
We observed that, 9 wk after MI, TG mice with large IS had lower LVEDP
and a lower incidence of pleural effusion compared with the WT group.
Although dP/dt fell significantly in TG mice to the extent
comparable to that in the infarcted WT mice, dP/dt levels
were significantly higher in infarcted TG mice than in respective WT
mice irrespective of IS. Furthermore, the peak levels of
dP/dtmax caused by a brief occlusion of the
ascending aorta were also significantly higher in TG than in WT mice
with infarct. These findings suggest that the noninfarcted myocardium
in TG mice maintained the phenotype of an enhanced inotropy. Therefore, these data demonstrate that overexpressing 2-AR in the
heart provides inotropic support to the infarcted and failing ventricle.
It might be expected that markedly enhanced 2-adrenergic
activity under conditions of MI would increase the risk of arrhythmias. In the present study, MI did not lead to excessive death in TG mice,
with mortality slightly lower than that in WT mice. There was no
evidence to indicate arrhythmic death in either WT or TG mice, although
arrhythmias were recorded occasionally during the functional
experiments. Thus overexpression of 2-AR at a high level
did not cause adverse consequences in mice following MI.
We recently observed facilitated onset of HF and higher mortality due
to critical HF in 2-AR transgenic mice following
thoracic aortic constriction (7). The different outcomes
from HF models of pressure overload and MI raise the possibility that
the effect of 2-AR overexpression is not only dependent
on the receptor number, as suggested by recent studies
(6), but also on the etiology of HF. Interestingly, it is
known that the extent of -adrenergic downregulation and
desensitization is more severe in pressure-overloaded heart than in
ischemic disease (5). The mechanism responsible for such
differences remains unclear, and potential differences in some key
molecules, such as ARK1 and Gi protein, require further investigation.
In infarcted TG and WT mice, the percent reduction in LV
dP/dt from the respective sham-operated control levels was
comparable. However, the absolute levels of
dP/dtmax and dP/dtmin
were significantly higher in infarcted TG than in WT groups. This
finding indicates that, in TG mice, the noninfarcted myocardium
maintained its hyperdynamic phenotype supported by the genetically
overexpressed 2-AR. Interestingly, although infarcted TG
mice had LV dP/dt levels similar to those of sham-operated
WT mice, the extent of LV dilatation measured by echocardiography did
not significantly improve compared with that of the infarcted WT
groups. The average levels of FS in TG groups were 20-30% higher
than those in WT groups, but such differences were statistically not
significant. It is not clear why cardiac 2-AR
overexpression differentially influences LV contractility and
echocardiographic measures. We found similar FS levels in sham-operated
WT and TG groups, although LV contractility was much higher in the
latter. Unchanged echo indexes were also previously observed in mice
with cardiac overexpression of adenylyl cyclase or 2-AR,
although the basal LV dP/dt was significantly higher compared with that of WT littermate controls (9, 27).
TG mice overexpressing 2-AR have markedly enhanced
inotropy and chronotropy (19, 29) without deleterious
changes in function and histology up to 8 mo of age, except for a mild
increase in collagen content in the LV myocardium (7). In
contrast, a TG line overexpressing 1-AR by 15-fold
exhibits early mortality, cardiac hypertrophy, and failure (8,
23). The reasons for the differences in these TG lines remain to
be elucidated and may be related to some important differences between
1-AR and 2-AR in downstream coupling and
signaling, such as coupling to Gi proteins by
2-AR but not by 1-AR and the
compartmentalization of 2-AR-activated AC/cAMP signaling
(2, 15a, 29).
2-AR overexpression (~200-fold) in mice with
disruption of muscle lim protein (MLP/) leads to
worsening of HF and higher mortality (24). In another HF
model caused by overexpression of Gq, overexpressing
2-AR at a high level worsened the outcome, whereas a low
level overexpression (~30-fold) reversed ventricular dysfunction and
suppressed cardiac hypertrophy (6). Expressing a ARK
inhibitor enhanced ventricular contractility in normal mice (1,
15) and rescued the cardiomyopathic phenotype in
MLP/ mice (24) but not in
Gq-overexpressing mice (6). Overexpressing adenylyl cyclase in Gq mice by crossbreeding improved
ventricular function (26). These studies and the findings
from the present study indicate that enhanced -adrenergic activity
is not always associated with adverse consequences.
Rapid pacing per se is able to induce the development of HF in large
animals (28). It is therefore possible that higher HR in
TG mice may confound the findings of the present study. The
2-AR TG strain is unique for the high HR level with the
ionic mechanism undefined. Patch-clamp studies have shown that there are no significant changes in slow delayed rectifier K+
current but that the density of L-type Ca2+ current is
increased because of modulation by the activated AC/cAMP system
(2, 29). Higher HR would increase energy expenditure and
shorten the diastolic filling time. It is likely that, in TG mice
with genetically induced cardiomyopathy or pressure overload, the
higher energy demand and restricted usage of Frank-Starling mechanism, due to shortened diastolic filling time, compromise the cardiac function and that this contributes to the adverse outcome
(7, 24). It is also possible that a higher energy demand
partially offsets the beneficial effect, observed in the present study,
of 2-AR overexpression in TG mice with MI.
Our results demonstrate a preserved ventricular contractility in
2-AR TG mice following chronic MI. This finding implies that an improved 2-adrenergic activity by
2-AR overexpression in the infarcted and failing heart
could provide inotropic support to the overall ventricular
contractility and is in keeping with the view for 2-AR
expression or transfection as a potential approach for HF gene therapy
(6, 17, 24). However, considering the diverse effects of
2-AR overexpression observed in other HF models (6, 7, 24), it is likely that the effect of transgenic overexpression of 2-AR on HF is dependent on the
etiology of HF.
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ACKNOWLEDGEMENTS |
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We thank Dr. Robert J. Lefkowitz for supplying the transgenic line. We thank the staff at the Biological Research Unit, Elodie Percy, Binghui Wang, Rodney Dilley, and Brian Jones, for help in animal breeding, transgene screening, and image analysis.
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FOOTNOTES |
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This work was supported by the National Health and Medical Research Council of Australia and a grant from the Merck Sharp & Dohme Research Fund (Australia). X.-M. Gao is the recipient of a scholarship from the Australia/China/Indonesia/Singapore Heart Foundation via Prof Y. M. Lim, Director, Singapore National Heart Center.
Address for reprint requests and other correspondence: X.-J. Du, Baker Medical Research Institute, St Kilda Road Central, PO Box 6492, Melbourne 8008, Victoria, Australia (E-mail: xiaojun.du{at}baker.edu.au).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 March 2000; accepted in final form 2 June 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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, WT mice; 
, TG mice. LVEDP, LV
end-diastolic pressure; LVIDs, LV inner dimension at
systole; FS, fractional shortening; LVEDd, LV external
dimension at diastole.