(Circulation. 2000;101:1707.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Early and Delayed Consequences of ß2-Adrenergic Receptor Overexpression in Mouse Hearts
Critical Role for Expression Level
From the Departments of Medicine (S.B.L., A.M.C., T.D.J., G.W.D.) and Pharmacology (S.B.L., N.M.T., J.N.L., S.M., A.Y., G.W.D.), University of Cincinnati Medical Center, Cincinnati, Ohio.
Correspondence to G.W. Dorn II, University of Cincinnati Medical Center, 231 Bethesda Ave, ML 0590, Cincinnati, OH 45267-0590. E-mail dorngw{at}ucmail.uc.edu
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Abstract |
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Background—Transgenic cardiac ß2-adrenergic receptor (AR) overexpression has resulted in enhanced signaling and cardiac function in mice, whereas relatively low levels of transgenically expressed G
s or
ß1AR have resulted in phenotypes of
ventricular failure. Potential relationships between the
levels of ßAR overexpression and biochemical, molecular, and
physiological consequences have not been
reported. Methods and Results—We generated transgenic mice expressing ß2AR at 3690, 7120, 9670, and 23 300 fmol/mg in the heart, representing 60, 100, 150, and 350 times background ßAR expression. All lines showed enhanced basal adenylyl cyclase activation but a decrease in forskolin- and NaF-stimulated adenylyl cyclase activities. Mice of the highest-expressing line developed a rapidly progressive fibrotic dilated cardiomyopathy and died of heart failure at 25±1 weeks of age. The 60-fold line exhibited enhanced basal cardiac function without increased mortality when followed for 1 year, whereas 100-fold overexpressors developed a fibrotic cardiomyopathy and heart failure, with death occurring at 41±1 weeks of age. Adenylyl cyclase activation did not correlate with early or delayed decompensation. Propranolol administration reduced baseline +dP/dtmax to nontransgenic levels in all ß2AR transgenics except the 350-fold overexpressors, indicating that spontaneous activation of ß2AR was present at this level of expression.
Conclusions—These data demonstrate that the heart tolerates
enhanced contractile function via 60-fold ß2AR
overexpression without detriment for a period of 
1 year and that
higher levels of expression result in either aggressive or delayed
cardiomyopathy. The consequences for enhanced ßAR
function in the heart appear to be highly dependent on which signaling
elements are increased and to what extent.
Key Words: receptors, adrenergic, beta • cardiomyopathy • heart failure
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Introduction |
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Catecholaminergic activation of cardiac ß-adrenergic receptors (ßARs) regulates the acute hemodynamic response to stress or injury by increasing myocardial contractility and heart rate. A deleterious effect of chronic ßAR stimulation is suggested by clinical heart failure studies in which sympathomimetic agents are associated with a poor outcome,1 2 3 by a benefit of ßAR blockade in heart failure,4 5 6 and by reports of catecholamine-induced cardiomyopathies.7 8 9 10 Increasing cardiac adrenergic signaling by overexpressing ßARs or inhibiting the ßAR kinase, however, appears to have therapeutic potential in heart failure, as demonstrated by favorable effects in genetically modified mice. Transgenic overexpression of ß2ARs in mouse cardiomyocytes increased basal and isoproterenol-stimulated adenylyl cyclase activity and enhanced resting cardiac systolic function.11 12 ß2AR overexpression normalized the characteristic resting systolic dysfunction in the G
q transgenic mouse model of
hypertrophy13 but failed to improve a murine
genetic dilated cardiomyopathy.14
Interestingly, augmenting ßAR signaling through overexpressing a
peptide inhibitor of the ßAR kinase enhanced
ßAR-stimulated cardiac function15 and significantly
improved function in murine dilated
cardiomyopathy14 but not contractile
depression in the Gq hypertrophy
model.13 From these results, it appears that at least in
mice, chronic enhancement of ßAR signaling can augment contractile
function in the normal heart and provide functional benefit. However,
the favorable effects reported in
ß2AR-overexpressing mice contrast with dilated
cardiomyopathy and myocardial fibrosis after
overexpression of ß1AR or
Gs, the signaling protein that couples ßAR
to adenylyl cyclase.16 17 What is lacking in our understanding of pathological effects of enhanced ßAR signaling is a long-term assessment of signaling, structure, and in vivo function of multiple mouse lines expressing a range of a given signaling protein. To address this, transgenic mice were generated with ß2AR overexpression ranging from 60 to 350 times background. The results reported here confirm a long-term positive inotropic effect of ß2AR overexpression at 60-fold endogenous ßAR levels but also demonstrate that a long-term consequence of ß2AR overexpression at higher levels is progressive myocardial fibrosis, ultimately leading to heart failure.
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Methods |
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Transgenic Mice
The wild-type human ß2AR cDNA was ligated into the Sal-1 site (exon 3) of the full-length 5.5-kb
-myosin heavy chain promoter essentially as previously
described.12 The linearized constructs were injected into
male pronuclei of fertilized FVB/N mouse oocytes and implanted into
pseudopregnant female oviducts. Thirteen founders were identified by
genomic Southern analysis.
Analysis of Cardiac Function
In vivo ventricular function was measured with
invasive and noninvasive techniques essentially as previously
described12 18 19 in lightly anesthetized
(ketamine/thiobutabarbital), spontaneously breathing,
closed-chest mice. Noninvasive cardiac function was assessed by 2D
guided M-mode echocardiography of
tribromoethanol-anesthetized mice. In some cases,
studies were performed before and after
intraperitoneal administration of 100 ng/g
isoproterenol.
Assessment of Cardiac Hypertrophy
Hypertrophy was assessed gravimetrically by an
analytical balance and by RNA dot-blot Northern analysis of
hypertrophy-associated genes as previously
described.18 19
ßAR Signaling Studies
Radioligand binding with
125I-cyanopindolol to ventricular
membranes was performed as previously described.12 13 For
adenylyl cyclase activities, ventricular membranes (
10
µg) were coincubated with (mmol/L) phosphoenolpyruvate 2.8, GTP 0.06,
ATP 0.12, cAMP 0.1, and ascorbic acid 0.1; and 4 U/mL myokinase, 10
U/mL pyruvate kinase, and 3x106 dpm
[-32P]ATP for 10 minutes at 37°C with
various concentrations of isoproterenol, 10 mmol/L NaF, or
100 µmol/L forskolin. Reactions were stopped by dilution with
1.0 mL of a 4°C solution containing excess ATP and cAMP and 25 000
dpm/mL [3H]cAMP (used for column recovery).
[32P]cAMP was separated by
chromatography over alumina columns. GRK2 and
Gi2/3 were measured in whole-heart
homogenates by immunoblotting using
standard techniques and antibodies from Santa Cruz Biotechnology as we
have previously described in detail.20 21
Measurement of Calcium Currents
Whole-cell patch clamp studies were performed on
ventricular cardiomyocytes as described
previously.22 23 In the studies of basic
Ca2+ channel kinetics, cells were dialyzed with
5 mmol/L EGTA. For isoproterenol experiments, EGTA was replaced
with 10 mmol/L BAPTA to prevent
Ca2+-dependent inactivation.24
Statistical Analysis
Unless stated otherwise, data are presented as
mean±SEM. Transgenic mice from a single line and nontransgenic
littermates were compared by 2-tailed Student’s t test.
Multiple comparisons between different lines or at different ages
within 1 line were performed with 1-way ANOVA followed by a Bonferroni
procedure. In vivo dose-response data were analyzed by a
mixed-factor ANOVA, with repeated measures on the second factor. A
value of P<0.05 was considered significant.
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Results |
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To better understand the effects of cardiac ß2AR overexpression, we created a series of ß2AR-overexpressing mouse lines in the FVB/N background with a range in transgene copy number. Of 13 founder mice, 1 failed to breed; 3 failed to transmit the transgene to progeny, suggesting that they were chimeric; independent lines were established for 5 founders; 4 other founders died before breeding; and 1 established line was lost before the present studies. The 4 founders that died had massive cardiac enlargement with dilated atria (Figure 1
), pulmonary congestion,
and pleural effusions.
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Pharmacological Properties
The 4 successfully propagated -myosin heavy chain
(MHC)–ß2AR transgenic lines exhibited a
range of ß2AR expression
(125I-cyanopindolol binding; Table 1) 60-, 100-, 150-, and
350-fold greater than nontransgenic and were so designated
(ß2-60, etc). Results from adenylyl cyclase
studies are shown in Figure 2 and Table 1.
When normalized to NaF stimulation (Figure 2B),
basal activities were increased 3-fold in the 2 lowest-expressing
lines and 2-fold in the 2 higher-expressing lines. The extent of
maximal isoproterenol stimulation was also increased with each line
compared with nontransgenic. However, the maximal increase was not
commensurate with the increase in basal, so the fold stimulation over
basal was in fact decreased. Absolute levels of activity (pmol ·
min-1 · mg-1) are
shown in Figure 2A and Table 1. As can be seen, only the
ß2-60 line had higher basal activities when the
data are expressed in this way. Both NaF- and forskolin-stimulated
adenylyl cyclase activities were depressed to similar extents in all
transgenic lines (Figure 2, C and D), suggesting that a
compensatory event distal to the receptor occurs with chronic
overexpression of ß2AR at these levels. We
therefore assessed by immunoblotting possible changes
in expression of ßAR kinase (GRK2) or Gi,
both of which are known to alter ßAR signaling when increased in the
heart. Neither ßAR kinase nor Gi2/3 levels
were increased in any of the ß2AR
overexpressors (data not shown). Immunoreactivity of adenylyl cyclase
type V/VI was not sufficient for accurate determination, so it is not
possible to exclude a change in adenylyl cyclase expression with
ß2AR overexpression.
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Early Effects
Initial phenotypic characterizations and interline comparisons of
mice 10 to 15 weeks old demonstrated pathology in
ß2-350 mice. Gross morphological
analysis revealed a 25% increase in heart weight of the
ß2-350 line compared with
the other ß2AR lines or with nontransgenic
littermates (Table 1
). Whereas echocardiographic
left ventricular fractional shortening was enhanced in the
3 lower-expressing ß2AR lines (Table 1),
ß2-350 exhibited impaired left
ventricular function with ventricular
enlargement (Table 1). Increased cardiac ßMHC and atrial
natriuretic factor gene expression, characteristic features
of cardiac hypertrophy, were also detected only in
ß2-350 mice (see Table 1 and below).
Furthermore, whereas the 3 lower-expressing
ß2AR lines showed no
histological evidence of fibrosis or
cardiomyocyte hypertrophy (not shown),
ß2-350 hearts showed replacement fibrosis (see
below). Thus, young adult mice expressing ß2AR
at 350 times normal levels developed cardiomegaly, increased expression
of hypertrophy-associated genes, and depressed
systolic function, whereas multiple transgenic lines with lower
ß2AR expression levels had normal cardiac size
and gene expression with enhanced systolic function.
Late Effects
Because cardiomegaly, fetal gene expression, and fibrosis in
young adult mice were observed only in the highest-expressing
ß2AR transgenic line, we considered that a
longitudinal analysis of ß2AR
overexpressors might detect additional phenotypic features related to
duration of transgene expression. Cohorts of 20 to 30 mice from each of
3 lines (ß2-60, -100, and -350) were therefore
prospectively followed for 1 year. No increase in all-cause mortality
was found in ß2-60 mice compared with
nontransgenic littermates during this period (Figure 3). Early mortality was, however,
observed in ß2-350 mice, which died at 25±1
weeks (Figure 3), suggesting an association between high levels
of ß2AR expression and early death. The cause
of death appeared to be left heart failure, as shown by
pulmonary congestion (increased lung weights) and massive
cardiac enlargement (Table 2).
ß2-100 mice also developed cardiac enlargement,
heart failure, and premature death, but death occurred at 41±1 weeks
(Figure 3, Table 2). Thus, these longitudinal mortality
data demonstrate delayed deleterious effects of
ß2AR overexpression that are proportional in
severity and rapidity of progression to the level of cardiac
ß2AR.
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Because these studies indicated that mortality in
ß2-350 mice was a function of the age of the
animal, histological, morphometric, and molecular
analyses were performed at 7, 11, and 17 weeks of age. These
studies showed that the decline in left ventricular
function was associated with cardiomyocyte dropout and
fibrotic replacement. Fibrosis was not evident at 7 weeks, was apparent
at 11 weeks, and was marked by 17 weeks of age (Figure 4A). The pattern of fetal cardiac gene
expression remained constant over time (Figure 4B).
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In Vivo Hemodynamics
To more rigorously assess the effects of
ß2AR density and duration of expression on
cardiac functional status, we performed in vivo
hemodynamic studies on 12- and 20- to 24-week
ß2-350 mice compared with 12-week
ß2-60 mice. Whereas baseline heart rates were
significantly increased in ß2-60, heart rates
were not increased in either 12- or 20-week-old
ß2-350 mice (Table 3). Basal +dP/dt was doubled in
ß2-60 mice and increased in 12-week-old but not
20-week-old ß2-350 mice (Table 3).
Thus, enhanced basal cardiac systolic function was observed in
mice expressing lower levels of ß2AR and in
younger mice expressing high levels of ß2AR.
With development of cardiomegaly in the latter mice, resting
systolic function decreased.
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Because cardiac phenotypes resulting from
ß2AR overexpression may be a consequence of
either enhanced agonist-stimulated ßAR function or an increase in
spontaneous receptor activation,11 we assessed
hemodynamic responsiveness to isoproterenol. As shown
in Table 3 and Figure 5A, inotropic and chronotropic responses to isoproterenol were generally
blunted in the ß2AR-overexpressing mice. In
ß2-60 mice, this was because basal heart rate
and +dP/dt were already near maximal. Likewise,
echocardiographic left ventricular
fractional shortening was increased by isoproterenol in nontransgenic
mice (44±3% basal, 61±3% isoproterenol, P<0.001) but
not in ß2-60 mice (54±3% basal,
56±4% isoproterenol, P=NS). However, in
ß2-350 mice, there was no dP/dt response to
isoproterenol, whether basal values were increased (12 week) or normal
(20 week) (Table 3, Figure 5A). The response to
nonselective ßAR blockade with intravenous
propranolol was used to distinguish between
agonist-dependent and -independent effects of overexpressed
ß2AR (Figure 5B).
Propranolol prevented isoproterenol-mediated increases in
+dP/dt in nontransgenic mice, demonstrating the adequacy of the dose
used. Basal +dP/dt, which was elevated in the
ß2-60 mice, was normalized by
propranolol. At 12 weeks of age, when
ß2-350 mice had significantly elevated basal
dP/dt, propranolol failed to normalize
contractility. Thus, a critical difference between the
ß2AR overexpressors may be
endogenous agonist participation in enhanced cardiac
function at lower levels of ß2AR but
predominantly agonist-independent ß2AR effects
at higher levels of receptor expression.
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Ca2+ Channel Activity
To confirm that the observed perturbations in cardiac function,
myocyte signaling, and adenylyl cyclase activity did not simply reflect
increased fibrotic content of ß2-350 hearts,
patch-clamp studies of inward calcium currents
(ICa) were performed on
ventricular cardiomyocytes from 12- and
24-week-old ß2-350 mice. Cardiomyocyte
capacitance, a measure of cell size, was significantly increased
compared with nontransgenic siblings at 12 weeks (159.1±4.2 pF, n=129
versus 143.7±4.8 pF, n=67) and 24 weeks (274.7±14 pF, n=41 versus
145.4±5.8 pF, n=59; P<0.05), consistent with the
molecular and morphometric indices of cardiac hypertrophy
noted above. Whereas the voltage dependence of
ICa in ß2-350 cells
was not altered, ICa density (shown in
Figure 6A) was significantly reduced
compared with that in nontransgenic cells (5.0±0.3 pA/pF, n=24 versus
8.9±0.4 pA/pF, n=38 at 12 weeks; 5.2±0.5 pA/pF, n=12 versus 10.3±0.6
pA/pF, n=26 at 24 weeks, P<0.05). Myocytes from 24-week
ß2-350 mice showed significantly reduced
isoproterenol responsiveness (50% of control) without any change in
EC50 (Figure 6B). These results
demonstrate progressive cardiomyocyte
ßAR-Ca2+ dysfunction in aging
ß2-350 mice.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The objective of these studies was to establish a "transgene dose-response" for ß2AR expression in the heart. In pursuit of this objective, we created a series of cardiac-specific ß2AR transgenic mice and found that the range of ß2AR expression was associated with a spectrum of phenotypes: (1) enhanced contractile function in young mice with ß2AR levels 60 times normal; (2) rapidly progressive fibrosis, cardiac hypertrophy, and heart failure with ß2AR levels 350 times normal; and (3) early enhanced function with delayed development of fibrotic cardiomyopathy at intermediate expression levels. Enhanced baseline function accruing from ß2AR overexpression at levels 60 times normal occurred in the absence of any detectable pathological consequences over a 1-year period. Although the ß2-60 overexpressing mice are similar to ß2AR transgenic mice initially reported by Lefkowitz and coworkers11 and by us,12 it is of course not possible to exclude the possibility that pathological characteristics may eventually develop in ß2-60 mice as they continue to age. The particularly important findings of the present studies, however, pertain to the ß2-100 and -350 lines, which exhibited progressive ventricular dysfunction, directly related in severity and rapidity of progression to the level of ß2AR expression. With all lines, we observed a decrease in NaF- and forskolin-stimulated activities, but the ßAR signaling appears to be even further dampened in the higher-expressing lines. Physiologically, this is manifested as lower systolic function with a lack of responsiveness to agonist, which is common in both. This further loss of ventricular function may be due to a decrease in L-type Ca2+ channel density, as observed in the ß2-350 mice, or some other post–receptor-effector derangement.
Another important distinction between the rapidly progressive ß2-350 and ß2-60 lines is the evidence for intrinsic receptor signaling activity. Catheterization-based hemodynamic studies in ß2-350 mice showed no effect of ß2AR blockade with propranolol, whereas in ß2-60 mice, propranolol normalized the basal enhanced contractile function. As a neutral antagonist, propranolol would be expected to block endogenous catecholamine activation of the receptor but not the spontaneous transition of a proportion of ß2AR to the active (R*) conformation. It is interesting to speculate that the unrestricted signaling activity of R* in the ß2-350 line contributes to its aggressive cardiomyopathy. Thus, expression of ß2AR at a level that enhances the in vivo response to agonists but does not cause in vivo ligand-independent signaling may improve cardiac function without deleterious effects. However, exceeding the putative threshold for ligand-independent ß2AR receptor signaling may cause rapid development of the cardiomyopathic syndrome reported here, as well as additional counterregulatory effects not observed with the other lines.
The pathological and physiological
characteristics exhibited by the older ß2-350
and ß2-100 mice reproduce some features of
catecholamine cardiomyopathy as
described in human subjects with pheochromocytomas.7 8 9 10
The pathophysiology of catecholamine-mediated
cardiomyopathy has been postulated to result from
ischemic necrosis secondary to intense vasospasm or from direct
toxic effects of oxidized catecholamines. Our studies
demonstrate that none of these putative mechanisms are necessary for
development of cardiomyopathy, because
ß2ARs were selectively overexpressed in cardiac
myocytes, and there is no reason to believe that circulating or local
catecholamine levels are increased in these mice. Rather,
these studies and those with the previously reported
ß1AR- and
Gs-overexpressing models16 17
support a direct effect of chronic unrestricted ßAR signaling on
cardiomyocytes, a notion consistent with
catecholamine cardiomyocyte toxicity
demonstrated in some tissue culture studies.25
The variability in adenylyl cyclase responsiveness in the various
ß2AR overexpressors suggests that regulatory
mechanisms may be evoked by certain levels of long-term overexpression
that seem to partially desensitize receptor signaling. Changes in the
expression of ßAR kinase,26 Gi,
and adenylyl cyclase27 in the heart have been reported to
be associated with decreased ßAR signaling. An increase in ßAR
kinase would be expected to exclusively alter receptor-mediated
stimulation, which is not the case in these
ß2AR overexpressors, in which we find
forskolin- and NaF-stimulated activities also depressed, and ßAR
kinase protein expression was not altered in any of the
ß2AR lines. An increase in
Gi could theoretically alter basal,
ßAR-mediated, and NaF-mediated signaling; however, we found no
evidence of such an increase. Finally, we also considered that a
decrease in adenylyl cyclase expression could serve to decrease
signaling at baseline and in response to agonist, forskolin, and NaF.
Indeed, given the above, a decrease in adenylyl cyclase expression
seems to be quite a reasonable candidate. However, we are unable to
quantitatively assess type V/VI adenylyl cyclase expression in the
mouse heart, so we cannot reach a conclusion in this regard.
We have shown that cardiac ß2AR
overexpression 60 times background results in enhanced in vitro and in
vivo signaling without apparent pathological consequences in mice up to
1 year old. Higher levels of expression result in delayed
(ß2-100) or rapidly progressive
(ß2-350) cardiomyopathies.
That deleterious effects can occur at some level of
ß2AR expression is not altogether surprising.
The obverse finding, that moderate levels of overexpression are
apparently not detrimental, is contrary to the notion heralded by some
that enhanced ßAR-Gs–adenylyl cyclase
signaling by any means is universally deleterious. Indeed, it is
notable that cardiomyopathy caused by
ß1AR overexpression is observed at 5 to 15
times endogenous ßAR levels,17 whereas a
60-fold increase in ß2AR appears to be well
tolerated. Thus, overly broad generalizations regarding potential
deleterious effects of ßAR signaling via increased
ß1AR, ß2AR, or
Gs or via inhibition of ßARK may be overly
simplistic, because there appear to be fundamental differences in
signaling evoked by these mechanisms.
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Acknowledgments |
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This study was supported by grants GM-54169, HL-58010, HL 22619, and P50-HL-52318 from the National Institutes of Health.
Received August 13, 1999; revision received October 18, 1999; accepted November 5, 1999.
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