© 2000 American Heart Association, Inc.
MiniReviews |
ß-Adrenergic Receptor Signaling: An Acute Compensatory Adjustment—Inappropriate for the Chronic Stress of Heart Failure?
Insights from Gs
Overexpression and Other Genetically Engineered Animal Models
From the Sigfried and Janet Weis Center for Research (S.F.V., D.E.V.), The Pennsylvania State University College of Medicine, Danville, Pa, and COR Therapeutics, Inc (C.J.H.), South San Francisco, Calif.
Correspondence to Stephen F. Vatner, Charles B. Degenstein Professor, Director of the Henry Hood Research Program, Sigfried and Janet Weis Center for Research, The Pennsylvania State University College of Medicine, 100 N Academy Ave, Danville, PA 17822-2601.
Key Words: receptors, adrenergic • sympathetic nervous system • Gs
overexpression • animal models • heart failure
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Introduction |
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 Top Introduction References |
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Under normal physiological conditions, the heart must be able to increase its output 5-fold to supply the required blood flow to the coronary circulation and skeletal muscles during severe stress. This is normally met by
5-fold increases in myocardial contractility,
3-fold increases in heart rate, and additional increases in stroke
volume.1 This increased load requires a commensurate
increase in myocardial blood flow, because oxygen extraction across the
heart is nearly complete, even under normal conditions. Accordingly,
the design of the cardiovascular system evolved to
conserve myocardial metabolic demand, and consequently
coronary blood flow, at rest, but with considerable reserve
that can be called on rapidly in times of stress. There is a host of
compensatory adjustments, including changes in metabolic
substrates and kinetics, as well as oxygen-carrying capacity, that may
be recruited in response to stress. However, none is more important
than the autonomic nervous system in general, and the sympathetic arm
in particular, in terms of providing large, rapid changes in cardiac
function. When this compensatory mechanism is unavailable, eg, after
treatment with propranolol, the 3-fold increases in heart
rate and 5-fold increases in myocardial contractility
in response to exercise cannot be achieved.1
In this connection, it is recognized that heart failure is a state
characterized by enhanced sympathetic tone, but when the failing
myocardium is challenged by ß-adrenergic stimulation in
vivo or in vitro, the most frequent result is ß-adrenergic
downregulation or desensitization.2 3 4 5 An impairment of
cardiac function leads to autocrine, paracrine, and neurohormonal
adjustments, including a strong sympathetic component (Figure 1
); under acute conditions, these reflex
adjustments are beneficial, as noted above. However, when the
sympathetic nervous system is chronically and tonically stimulated, as
occurs in the pathogenesis of heart failure, desensitization mechanisms
are called into play, such that the effects of sympathetic stimulation
are muted.2 3 4 5 These mechanisms include decreased
ß-adrenergic receptor density, decreased adenylyl cyclase activity,
and uncoupling the ß-adrenergic receptor from Gs, in conjunction with
an increase in ß-adrenergic receptor kinase (ßARK) activity, as
well as an increase in the content of the inhibitory
GTP-binding protein, Gi.2 3 4 5 If one of the consequences of
chronic stress is the generation or development of desensitization,
then one might argue that the desensitization response is appropriate.
However, there is no consensus regarding this point, and indeed, this
aspect of cardiovascular pathophysiology and therapy
has been controversial for the past half century. Diametrically
opposing camps have emerged, one supporting a role for ß-adrenergic
supplementation in heart failure6 7 8 and the other
suggesting that further inhibition of ß-adrenergic signaling and
enhancing desensitization is palliative.9 10 11 12 In fact, a
ß-adrenergic receptor agonist, dobutamine, is still
frequently administered acutely to patients with cardiac failure,
because it may provide short-term benefit. However, a recent study
suggested that patients receiving intravenous
dobutamine have an increased risk of death.13
This is the crucial point that must be kept in mind: the differences
between the initial salutary action of sympathomimetic amines and the
effects of chronically and tonically stimulating this pathway.
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There have been several approaches to resolving this controversy related to whether chronic sympathetic stimulation or inhibition is better in heart failure therapy. Most recently, a variety of genetic approaches have been used, in which key components of the ß-adrenergic receptor signaling pathway have either been overexpressed or diminished in mice.6 7 14 15 16 17 One goal of this review is to summarize the results from these experiments and, importantly, to point out again, as noted above, the critical differences between the consequences of acute and chronic ß-adrenergic receptor stimulation.
One unifying feature for all of these models is that in young animals,
enhancement of ß-adrenergic receptor signaling, whether through
overexpression of ß1- or
ß2-adrenergic receptors,6 18
adenylyl cyclase,8 or Gs,14 15 16 leads to
enhanced cardiac function. Two major approaches have been used to
chronically enhance ß-adrenergic signaling in genetically engineered
animals, as follows: (1) augmenting the stimulating component
(overexpression of ß1- or
ß2-adrenergic receptors),6 18
overexpression of adenylyl cyclase,8 and overexpression of
Gs14 15 16 or (2) inhibiting ß-adrenergic receptor
kinase.7 Some of these approaches have proven
useful in "rescuing" pathological phenotypes that develop
cardiomyopathy and heart failure. For example, when
Gq-overexpressing mice, which develop cardiac
hypertrophy and dysfunction, are mated with mice
overexpressing ß2-adrenergic receptors at a
relatively low level (30-fold), the crossbred mice fared better in
terms of cardiac function and development of hypertrophy
than did the mice solely overexpressing Gq.19 Positive
results have been even more impressive with mice that express the
ß-adrenergic kinase inhibitor. When those mice were mated
with MLP-1 mice, which develop dilated
cardiomyopathy as a result of ablation of a
muscle-restricted gene that encodes the muscle LIM protein, the
development of cardiomyopathy was
attenuated.20 In further support of this point of view,
myocytes isolated from rabbits with heart failure demonstrated
restoration of the ß-adrenergic receptor signaling after adenoviral
gene transfer of either the ß2-adrenergic
receptor gene or the ß-adrenergic receptor kinase
gene.21 Interestingly, the muscle-specific LIM
protein–deficient mouse noted above was improved even more by mating
them with a phospholamban knockout.22 Most of these
"rescued" models were studied for 6 months. It would be important
to reevaluate them 1 to 2 years later. Thus, there is evidence that
restoring ß-adrenergic signaling may be positive in the pathogenesis
of heart failure. However, before it can be concluded that the improved
cardiac function observed in these transgenic models can translate to a
beneficial therapy for heart failure, potentially utilizing a gene
therapy approach, it is important to consider the following points.
First of all, one of the limitations to many
cardiovascular studies is the "snapshot"
experiment, in which 1 or at least a few rapid measurements are made
before the experiment is terminated. In addition, most experiments in
animals are carried out in young adults, despite the fact that heart
failure is usually a disease of older patients. In larger mammals, it
is not generally possible to conduct serial experiments over their
lifetime, because that time span may exceed the productive period
of the investigator. However, this is possible in murine models,
particularly transgenic mice, with lifetimes of 2 years.
Nonetheless, the overwhelming majority of studies have reported the
results from genetically altered mice at 1 or 2 times in their
lifetime, most often recording the last measurement in young
adulthood.
One exception to that rule is the murine model of cardiac-specific
overexpression of Gs. These animals exhibit enhanced ß-adrenergic
receptor signaling and normal myocardial architecture as young
adults.15 16 23 24 However, as they age, they develop a
picture resembling cardiomyopathy in
humans.15 16 They exhibit a dilated heart with reduced
ejection fraction, ventricular arrhythmias, sudden
death, myocardial hypertrophy, interstitial
myocardial fibrosis, and apoptosis in
humans15 16 25 (Figure 2).
These characteristics of cardiomyopathy were not
due to aging, per se, given that age-matched wild-type littermates were
entirely normal. However, although aging, per se, is not the cause of
the cardiomyopathy, it is conceivable that there
are age-related alterations in gene expression or activity of signaling
pathways that predispose the overexpressed Gs mouse, but not
normal-aged mice, to develop cardiomyopathy.
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One wonders whether a similar picture of cardiomyopathy might be observed in other models of enhanced ß-adrenergic receptor signaling with age. Only recently have some of these data become available, which also support the concept that chronically and tonically enhanced ß-adrenergic receptor signaling is deleterious. One facet of chronically enhanced sympathetic stimulation is chronic tachycardia with reduced heart rate variability, as occurs in heart failure.26 Similarly, chronically enhanced heart rate leads to heart failure, even in the absence of enhanced ß-adrenergic signaling.5
It also must be appreciated that enhanced ß-adrenergic signaling is
more complex than simply an augmentation in
contractility following an increase in cAMP generation
in response to receptor occupancy by agonist. There appear to be
cAMP-independent actions, as well, that can augment cardiac
contractility. For example, there is evidence that
ß-adrenergic stimulation through the Gs protein can affect myocyte
function, independent from cAMP generation, potentially by a direct
action on the L-type calcium channel.23 In myocytes from
the mice with overexpressed cardiac Gs, a significant increase in
myocyte contractility and Ca2+
channel activity still occurs with ß-adrenergic stimulation even
after the cAMP pathway is blocked with Rp-cAMP, a diastereoisomer of
adenosine 3',5'-phosphorothioate and inhibitor of protein kinase
A.23 It remains to be determined whether the
adverse effects of chronic ß-adrenergic signaling in the
overexpressed Gs mouse is solely cAMP-dependent or involves a
cAMP-independent, albeit Gs-mediated, activity. The latter pathway
could synergistically contribute to the adverse effects of enhanced
cAMP signaling. This question could be addressed by chronically
interrupting the ß-adrenergic signaling pathway at the level of
adenylyl cyclase or protein kinase A activation in the Gs mouse
model.
The nature of the downstream pathway responsible for the deleterious
phenotype in the setting of chronically enhanced ß-adrenergic
signaling is also likely to be complex, potentially involving
alterations in stress-activated kinase pathways as well as
aberrant energy production and utilization,27
potentially leading to alterations at the transcriptional level as
well. It is important to keep in mind that the
physiological responses induced by the altered
genotype may well invoke other genetic and/or biochemical
changes in the heart, which might play a role in determining the end
result of cardiomyopathy. This latter point is not
generally appreciated, ie, that the phenotype of many
transgenic models is more complex than being simply the consequences of
the changed genotype, because other compensatory mechanisms may
be invoked. Moreover, dissection of other compensatory mechanisms, eg,
identification of altered gene expression, remains an intriguing avenue
of research that is now possible with the development of transgenic
models of cardiac dysfunction. To reiterate, the mouse overexpressing
Gs recapitulates the pattern of chronic cardiac sympathetic
overdrive that occurs in the pathogenesis of human heart failure, but
in the absence of the setting of primary myocardial overload or
dysfunction. Thus, it offers the potential to delineate more precisely
the pathways and genes activated or inhibited by chronic
sympathetic stimulation of the heart.
How is it possible to reconcile the apparently diametrically opposing
conclusions from our studies on the transgenic mouse with overexpressed
Gs and the transgenic mice with overexpressed ß-adrenergic
receptors? In both models there is enhanced ß-adrenergic signaling
and cardiac function in young adult animals. However, the Gs mice
were also studied after they had aged. It is our thesis, and one of the
major themes of this review, that the effects of chronically enhanced
ß-adrenergic signaling over the lifetime of the animal are
deleterious, particularly in the face of ineffective desensitization
mechanisms. Until the other models of enhanced ß-adrenergic signaling
are studied for comparable periods of time, and the extent of
desensitization is analyzed, this hypothesis cannot be tested
fully.
As proof of principle, it would be useful to block the enhanced
ß-adrenergic signaling, and to determine whether the
cardiomyopathy that develops in the older Gs
mice is averted. We recently accomplished this in the overexpressed
cardiac Gs model by treating the animals chronically with a
ß-adrenergic receptor antagonist
propranolol.28 In that study, we began
administering propranolol in the drinking water to
transgenic Gs mice at 9 to 10 months of age, at a time when evidence
of the cardiomyopathy was just emerging, and
terminated the experiments 6 to 7 months later, at a time when the
cardiomyopathy was fully manifest in these animals
in the absence of treatment. Chronic ß-adrenergic receptor blockade
completely prevented the decrease in ejection fraction and cardiac
dilation, as well as the premature mortality characteristic of the
older Gs mice (Figure 2
). The histopathological features of
the cardiomyopathy, eg, myocyte
hypertrophy and fibrosis, were also completely arrested
(Figure 2). Although fibrosis that was present at 9 to 10
months of age persisted, it did not progress further in the animals
treated with propranolol.28 Most
interestingly, the myocyte apoptosis, already present at 9
to 10 months of age, was no longer evident in the 16- to 17-month
animals after 6 to 7 months of propranolol treatment
(Figure 2). Thus, chronic ß-adrenergic receptor blockade fully
prevented the expression of the cardiomyopathic
phenotype in the overexpressed Gs mice.
It is particularly relevant that our data emerged amid reports from a number of clinical trials demonstrating the beneficial effects of chronic ß-adrenergic receptor blockade in patients with heart failure.9 10 11 12 These clinical studies, which have been summarized recently,29 clearly demonstrate the positive beneficial effects of ß-adrenergic receptor blockade therapy in heart failure, improving left ventricular function and survival. Some of these drugs relieve ß-adrenergic desensitization in heart failure, whereas others do not.30 31
Even more recently, supporting evidence for the adverse effects of
chronic ß-adrenergic signaling has become apparent from transgenic
murine models of overexpressed ß2-adrenergic
receptors32 as well as
ß1-adrenergic receptors (Figure 3). Again, the extent of
overexpression (clearly high levels of overexpression are deleterious),
the duration of the enhanced ß-adrenergic receptor signaling, and the
extent to which desensitization mechanisms attenuate the adverse
effects of chronic ß-adrenergic signaling all play a role. In this
connection, it is important to keep in mind that the overexpressed
Gs mice do not fully desensitize, ie, enhanced isoproterenol
stimulation of adenylyl cyclase is still observed in the older animals.
In contrast, in animals with overexpressed
ß2-adrenergic receptors,
isoproterenol-stimulated adenylyl cyclase is downregulated, which most
likely tempers the downstream action of the enhanced ß-adrenergic
receptor signaling (K.-L. He, unpublished observations, 1999).
In addition, there may be a differential effect of
ß1- versus
ß2-adrenergic overexpression, given that
ß1-adrenergic stimulation is a more potent
stimulus for hypertrophy.33
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) have 5-fold increases in
ß1-receptor density, and WT (
) are wild-type controls.
(Reproduced with permission from Engelhardt S, Hein L, Wiesmann F,
Lohse MJ. Progressive hypertrophy and heart failure in
ß1-adrenergic receptor transgenic mice. Proc Natl
Acad Sci U S A. 1999;96:7059–7064. Copyright 1999 National
Academy of Sciences, U.S.A.).
Although complete elucidation of the role of ß-adrenergic receptor
signaling in heart failure is important, it is just 1 component in this
complex process. If the concept proposed in this review is correct, ie,
enhanced ß-adrenergic signaling is counterproductive in heart
failure, it simply represents 1 step forward in our
understanding of the complex process termed heart failure.
Nevertheless, resolution of this controversy, which has been at the
forefront of cardiovascular pathophysiology and heart
failure therapy over the past half century, remains important for both
the basic cardiovascular scientist and the clinician.
Before the controversy regarding the role of ß-adrenergic receptor
signaling in heart failure is fully resolved, there will be many other
dialectical positions proposed, including short-term adrenergic
stimulation, followed by chronic blockade or intermittent gene therapy,
or myocyte-specific activation. However, at this time, the majority of
evidence supports the position that chronic and tonic ß-adrenergic
receptor signaling is deleterious in the pathogenesis of heart failure,
whereas interruption of this pathway appears salutary. This holds for
enhanced ß-adrenergic signaling accomplished by overexpressing
ß1-adrenergic receptors (5- to 15-fold) or
Gs (5-fold). Apparently, ß2–adrenergic
receptors have to be overexpressed quantitatively more, ie, >100-fold,
to result in cardiomyopathy. Why there is this
dose-related difference between ß1- and
ß2-adrenergic receptor overexpression needs to
be resolved. The key to this problem may reside in differences in
distal signaling pathways. Additional important factors include the
chronicity of stimulation and the extent to which desensitization
mechanisms are effective.
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Acknowledgments |
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This work was supported in part by US Public Health Service Grants HL33107, AG14121, HL33065, HL59139, HL59139-02S1, HL62716, and HL59874.
Received July 12, 1999; accepted November 24, 1999.
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M. D. Faulx, P. Ernsberger, D. Vatner, R. D. Hoffman, W. Lewis, R. Strachan, and B. D. Hoit Strain-dependent {beta}-adrenergic receptor function influences myocardial responses to isoproterenol stimulation in mice Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H30 - H36. [Abstract] [Full Text] [PDF]
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S. A. Grandy, E. M. Denovan-Wright, G. R. Ferrier, and S. E. Howlett Overexpression of human {beta}2-adrenergic receptors increases gain of excitation-contraction coupling in mouse ventricular myocytes Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1029 - H1038. [Abstract] [Full Text] [PDF]
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S. Okumura, G. Takagi, J.-i. Kawabe, G. Yang, M.-C. Lee, C. Hong, J. Liu, D. E. Vatner, J. Sadoshima, S. F. Vatner, et al. Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload PNAS, August 19, 2003; 100(17): 9986 - 9990. [Abstract] [Full Text] [PDF]
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F.-L. Tan, C. S. Moravec, J. Li, C. Apperson-Hansen, P. M. McCarthy, J. B. Young, and M. Bond The gene expression fingerprint of human heart failure PNAS, August 20, 2002; 99(17): 11387 - 11392. [Abstract] [Full Text] [PDF]
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L. A Nikolaidis, T. Hentosz, A. Doverspike, R. Huerbin, C. Stolarski, Y.-T. Shen, and R. P Shannon Catecholamine stimulation is associated with impaired myocardial O2 utilization in heart failure Cardiovasc Res, February 1, 2002; 53(2): 392 - 404. [Abstract] [Full Text] [PDF]
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 R. Dash, V. J. Kadambi, A. G. Schmidt, N. M. Tepe, D. Biniakiewicz, M. J. Gerst, A. M. Canning, W. T. Abraham, B. D. Hoit, S. B. Liggett, et al. Interactions Between Phospholamban and {{beta}}-Adrenergic Drive May Lead to Cardiomyopathy and Early Mortality Circulation, February 13, 2001; 103(6): 889 - 896. [Abstract] [Full Text] [PDF]
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T. Ukai, C.-P. Cheng, H. Tachibana, A. Igawa, Z.-S. Zhang, H.-J. Cheng, and W. C. Little Allopurinol Enhances the Contractile Response to Dobutamine and Exercise in Dogs With Pacing-Induced Heart Failure Circulation, February 6, 2001; 103(5): 750 - 755. [Abstract] [Full Text] [PDF]
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X.-J. Du, X.-M. Gao, B. Wang, G. L Jennings, E. A Woodcock, and A. M Dart Age-dependent cardiomyopathy and heart failure phenotype in mice overexpressing {beta}2-adrenergic receptors in the heart Cardiovasc Res, December 1, 2000; 48(3): 448 - 454. [Abstract] [Full Text] [PDF]
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X.-F. Deng, D. G. Rokosh, and P. C. Simpson Autonomous and Growth Factor-Induced Hypertrophy in Cultured Neonatal Mouse Cardiac Myocytes : Comparison With Rat Circ. Res., October 27, 2000; 87(9): 781 - 788. [Abstract] [Full Text] [PDF]
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A. Sabri, E. Pak, S. A. Alcott, B. A. Wilson, and S. F. Steinberg Coupling Function of Endogenous {alpha}1- and {beta}-Adrenergic Receptors in Mouse Cardiomyocytes Circ. Res., May 26, 2000; 86(10): 1047 - 1053. [Abstract] [Full Text] [PDF]
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