(Circulation. 2000;101:1634.)
© 2000 American Heart Association, Inc.
Editorial |
Catecholamines, Cardiac ß-Adrenergic Receptors, and Heart Failure
From the Howard Hughes Medical Institute and the Departments of Medicine and Biochemistry (R.J.L.), Department of Medicine (H.A.R.), and Department of Surgery (W.J.K.), Duke University Medical Center, Durham, NC.
Correspondence to Robert J. Lefkowitz, HHMI, Duke University Medical Center, Box 3821, Durham, NC 27710. E-mail lefko001{at}receptor-biol.duke.edu
Key Words: Editorials • catecholamines • receptors, adrenergic, beta • heart failure
It is now generally accepted that chronically elevated stimulation of the cardiac ß-adrenergic system is toxic to the heart and that such stimulation may contribute to the pathogenesis of congestive heart failure of various causes. Administration of either ß-adrenergic agonists or phosphodiesterase inhibitors has been shown to decrease survival of patients with chronic heart failure, even though they produce immediate and long-term hemodynamic benefits.1 Moreover, in human heart failure, as well as in several animal models, elevated circulating catecholamines lead, via various compensatory mechanisms, to decreased levels and functional activity of cardiac ß1-adrenergic receptors (ß1ARs) and thus to marked desensitization of the heart to inotropic ß-adrenergic stimulation.2
These biochemical and physiological changes appear to be mediated by elevated levels of the enzyme ßAR kinase1 (ßARK-1, GRK2) in the heart that are invariably associated with dampened responsiveness to catecholamine stimulation.3 ßARK is one of a family of enzymes (G protein–coupled receptor kinases) that phosphorylate ßARs and other G protein–coupled receptors after they have been stimulated, thus leading to their desensitization.4 Currently, it is widely believed that these mechanisms protect the heart from the toxic effects of inotropic ß-adrenergic support. The recent success of ß-blockers in treating chronic heart failure is generally explained by their ability to block the noxious effects of chronic endogenous sympathetic stimulation of the failing heart. In contrast, infusion of ß-adrenergic agonists is used solely for short-term and palliative inotropic support.
Given these findings, it is not surprising that there has been little
recent interest in therapeutic strategies that aim to facilitate or
augment signaling through ß-adrenergic–coupled systems in the
failing heart. All such approaches, it is generally assumed, must lead
to negative consequences for the heart. Such assumptions have gained
support from animal studies that demonstrate that even very modest
transgenic overexpression of ß1ARs in the
hearts of mice leads to early and marked
cardiomyopathy.5 In addition, cardiac
transgenic overexpression of the 
-subunit of the heterotrimeric G
protein Gs also leads to a
cardiomyopathic phenotype.6 It is
against this background that an article in this issue by Liggett et
al7 highlights several misconceptions and unfounded
assumptions about ß-adrenergic stimulation of the heart and points
the way toward a more rational reconsideration of the potential for
manipulating ß-adrenergic signaling in the heart for therapeutic
gain.
The first widely held erroneous assumption, and the one most directly
addressed by Liggett et al, is that ß1ARs and
ß2ARs are essentially equivalent in their
signaling properties and hence in the consequences of their activation.
However, in striking contrast to the early
cardiomyopathy resulting from even low-level
(
5-fold) transgenic overexpression of ß1ARs
in the heart recently reported by Engelhardt et al,5
Liggett et al now demonstrate that up to 100-fold overexpression of
ß2ARs in the mouse heart causes significantly
increased cardiac contractile force without any
cardiomyopathic consequences during the 1-year study
period.7 (Recall that 1 year is approximately half the
normal life span of a mouse.) Only at even higher levels of
overexpression (up to 350-fold) were pathological changes observed. Are
these results surprising?
In fact, they are not. The first study of transgenic overexpression of
a ßAR in the mouse heart by Milano et al8 reported very
high levels of expression of the ß2AR (up to
200-fold), similar to the higher-expressing lines of Liggett et al.
These animals had remarkably elevated contractility
unresponsive to further ß-adrenergic stimulation. Like the
highest-expressing lines of Liggett et al, the inotropic effect in
these animals appeared to be due to the constitutive activity of the
highly expanded pool of receptors and could not be reduced by
conventional ß-blockers such as propranolol. These
animals still displayed markedly elevated cardiac
contractility at 1 year of age and developed mild
fibrosis late in life (
1 year),9 as would be expected
from the dose-response curves for receptor expression now provided by
Liggett et al.7 The Liggett group also reported a
transgenic mouse expressing ß2ARs at much lower
levels of expression (15-fold). Even at these very low levels,
marked potentiation of catecholamine-stimulated inotropy
was observed, with no pathological consequences.10
Other findings also indicate that the consequences of ß1- and ß2-adrenergic stimulation in the heart are quite different. Although both receptors classically activate adenylate cyclase via stimulation of Gs, ß2-receptors can also powerfully stimulate Gi11 (the myocardial concentrations of which are elevated in CHF). This has at least 2 types of consequences. First, it limits the extent of the contractile response to overexpressed ß2ARs, as in the animals reported by Milano et al8 (because Gi inhibits adenylate cyclase). Only when Gi proteins were inactivated by pertussis toxin treatment did these transgenically overexpressed ß2ARs fully stimulate contractility.11 Second, activation of Gi has the potential to couple these receptors to other important signaling pathways, such as the MAP kinases.12 Cardiac ß1ARs and ß2ARs have also been shown to differ in their effects on contraction, cytosolic Ca2+ concentrations, and Ca2+ currents in isolated rat ventricular cells.13
That ß1ARs and ß2ARs
should display distinctly different signaling patterns is predictable
from their molecular structures. Both are heptahelical or
7-membrane-span receptors. Greatest amino acid identity is present
in the transmembrane regions (71%), which determine the specificity
of ligand binding.14 However, the cytoplasmic regions of
the receptors, which interact with other cellular proteins to mediate
various signaling events, are considerably more
divergent.14 In fact, Liggett et al have previously called
attention to polyproline stretches present in the third cytoplasmic
loop of ß1ARs but not
ß2ARs.15 Swapping of this region
between the ß1ARs and
ß2ARs significantly altered their signaling
properties.15 Moreover, we recently identified a novel
family of the SH3 domain containing proteins that
interact with the ß1ARs (and not the
ß2ARs) via this region.16
Distinctly different proteins also interact with the
ß1ARs and ß2ARs via
protein interaction domains called PDZ domains that bind to the
divergent last 4 amino acid residues of the carboxy-terminal tails of
these receptors.17
Recent studies have increasingly implicated the process of apoptosis, or programmed cell death, in the development of cardiomyopathy and heart failure.18 In vitro experiments with isolated cardiac myocytes,19 20 as well as in vivo experiments with knockout mice lacking either ß1AR, ß2AR, or both (A.J. Patterson, B.K. Kobilka, personal communication, 1999), indicate that chronic catecholamine stimulation induces apoptosis or sudden death, respectively. However, these responses appear to be initiated by ß1ARs, whereas ß2AR stimulation either has no effect or may even be protective.19 20 Thus, although both receptors are present in cardiac myocytes and mediate inotropic effects, the toxic effect of ß-adrenergic stimulation appears to be mediated largely, if not exclusively, by the ß1AR.
Another recent line of research relevant to issues raised in the article by Liggett et al concerns the consequences of lowering the elevated levels of cardiac ßARK-1 activity generally found in human heart failure or in animal models of the disease. Lowering of ßARK-1 activity in the heart presumably would enhance signaling through not only ßARs but other G protein–coupled receptors as well. As shown in animal models of several cardiac disorders, cardiac ßARK-1 levels rise early, before marked cardiac deterioration and desensitization occur, presumably in response to the increased sympathetic stimulation that accompanies heart failure.21 Moreover, 3-fold transgenic overexpression of ßARK in the mouse heart (a level comparable to that observed in heart failure) reproduces the marked biochemical and physiological desensitization to ß-adrenergic stimulation observed in heart failure.22
What are the physiological effects of lowering
cardiac ßARK activity? One approach lowered ßARK activity by
transgenic overexpression of an inhibitory peptide derived
from the carboxy-terminus of ßARK. This peptide blocks the
interaction of endogenous ßARK with
Gß
, preventing agonist-induced translocation
of the enzyme to the plasma membrane.22 A second approach
was to knock out a single ßARK allele by homologous
recombination.23 In both models, reduction in myocardial
ßARK activity increased basal and isoproterenol-stimulated myocardial
contractility in vivo. When these 2 mouse lines were
crossed to produce animals with even lower myocardial ßARK-1
activity, contractility rose even more.23
These data suggest that ßARK-1–mediated desensitization of ßARs
and perhaps other G protein–coupled receptors acts as a brake on
myocardial contractility. Of course, other, as yet
undefined, activities of ßARK might also be involved. Animals with
reduced cardiac ßARK activity and increased myocardial
contractility have normal life spans, with no cardiac
pathological conditions detectable at any point.22
Therapeutic Implications
The observations summarized above, indicating that increased
ß2AR activity or reduction in ßARK levels can
improve myocardial performance without noxious effects on the
heart, call into question the widely held notion that any maneuver that
chronically augments ß-adrenergic signaling in the heart will have
deleterious consequences. They also immediately suggest several novel
therapeutic strategies for the treatment of heart failure, some of
which are currently being tested in animal models.
ß2-Adrenergic Receptors
Can overexpression of ß2ARs (a possible
future target of gene therapy) improve cardiac performance in
the setting of heart failure without causing negative effects? The
question is being approached in several ways. One is to cross animals
overexpressing ß2ARs in the heart with
genetically engineered lines of mice that develop heart
failure.24 25 An important caveat in this approach is
that, as described above, many of the lines of transgenic
ßAR-overexpressing mice described thus far express the receptors at
extraordinarily high levels, well beyond the therapeutic window
delineated by Liggett et al.7 In fact, when a transgenic
animal model of hypertrophic cardiomyopathy with
heart failure (overexpression of the -subunit of the heterotrimeric
G protein Gq) was made to coexpress the
ß2AR at relatively low levels, improved
myocardial performance was observed, whereas at higher levels,
deterioration was observed.25 Very high levels of
transgenic ß2AR overexpression did not improve
another genetic mouse model of heart failure (MLP
knockout).24 However, as delineated by Liggett et al, such
studies need to be performed in the future with much lower levels of
ß2AR expression.
Another approach has been to transfer the ß2AR
with adenoviral vectors. Enhanced function of cultured cardiac myocytes
isolated from failing rabbit hearts has been achieved via gene
transfer, leading to expression levels 15-fold above
normal.26 In addition, by use of a catheter-based
technique for delivery of an adenovirus containing the human
ß2AR transgene to the rabbit coronary
circulation in vivo27 or by delivering the
ß2AR virus to heterotopically transplanted rat
hearts, global myocardial expression of receptor was achieved at levels
5- to 10-fold above normal.28 Strikingly, this was
sufficient to raise basal and isoproterenol-stimulated cardiac
contractility. These studies underscore the potential
feasibility of a gene therapy approach with
ß2ARs. They also highlight an apparently broad
therapeutic window, because at least 10- to 20-fold higher levels of
transgenic overexpression than were functionally effective in these
adenoviral studies in rat and rabbit were necessary to observe any
chronic cardiotoxicity.
ßARK Inhibition
Transgenic overexpression of a ßARK inhibitor
peptide largely reverses the impaired cardiac performance in
both the MLP knockout mouse24 and the
calsequestrin-overexpression mouse models of heart
failure.29 In the latter model, not only is cardiac
function improved but survival time is approximately doubled with the
ßARK inhibitor peptide. In both cases, the markedly
blunted ß-adrenergic responsiveness of the heart is reversed and the
elevated ßARK levels are lowered toward normal. In another example,
the blunted cardiac response to isoproterenol and elevated cardiac
ßARK activity in transgenic mice overexpressing ßARK in the heart
are both reversed when these animals are mated with mice expressing the
ßARK inhibitor peptide in the heart.30 These
results directly demonstrate that the ability of the ßARK
inhibitor to increase cardiac responsiveness to
catecholamines (endogenous and exogenous) is,
in fact, associated with its ability to inhibit the enzyme in vivo.
In vitro, adenovirus-mediated transfer of the ßARK
inhibitor peptide into cardiac myocytes derived from
rabbits previously paced into ventricular failure has also
been shown to restore ß-adrenergic–responsive cAMP accumulation to
normal.26 A caveat to the interpretation of these studies,
however, is that the ßARK inhibitor peptide works by
blocking Gß interaction with the enzyme.
Because Gß undoubtedly plays a variety of
other signaling roles in the heart, the possibility remains that the
ßARK inhibitor peptide in fact has activities unrelated
to ßARK inhibition.
One case in which ßARK inhibition has not reversed deteriorating
cardiac function is the previously mentioned
Gq-overexpressing mouse with
hypertrophy and heart failure.25 However, it
should be noted that unlike the other models cited, and in fact most
cases of human heart failure, these animals do not display elevated
cardiac ßARK activity or downregulated cardiac ßARs.
Taken together, these results suggest that inhibition of cardiac ßARK
activity, either by gene transfer or more directly by the development
of suitable inhibitor drugs, may represent a novel
approach to the treatment of heart failure. The concern about such an
approach has stemmed from the notion that elevated myocardial ßARK
levels and the resulting desensitization of cardiac ßARK are purely
protective mechanisms. Abrogation of such compensatory mechanisms, it
has been reasoned, would surely only worsen the
physiological deterioration caused by excess
catecholamine stimulation. However, as demonstrated above,
when this notion is directly tested in animal models, it is found not
to be so. Inhibition of elevated ßARK activity by blockade of
Gß interactions in several animal models of
heart failure leads to reversal of desensitization and improved cardiac
performance and longevity.24 29 These findings, in
turn, suggest that elevated ßARK activity and desensitization are, at
least in some respects, maladaptive in the failing heart. Thus, the
best strategy for developing potentially useful ßARK
inhibitors may be to target the
Gß-ßARK interaction.
How can one reconcile a potential role for augmentation of ß2AR signaling or for ßARK inhibition in heart failure with the well-established findings that ß-adrenergic agonist therapy, although of short-term benefit, does not improve long-term outcomes1 and with the recent success of ß-blocker31 therapy for heart failure? The answer appears to lie in the very different consequences of each of these means of augmenting ß-adrenergic stimulation of the heart. Chronic catecholamine (agonist) stimulation of the heart demonstrably has deleterious effects, which appear to be mediated largely via ß1ARs. The concept of inotropic gene therapy with ß2ARs appears to circumvent these negative effects by engaging a distinct portfolio of signaling pathways that lack the apoptotic and perhaps some of the arrhythmogenic potential of ß1AR stimulation.
Inhibitors of ßARK increase contractility
in several animal models of heart failure without any evidence of
pathological consequences even over very long
periods.24 29 This is in striking contrast to the effects
of chronic stimulation of ß1ARs5
or Gs.6 This may be due to
facilitation of cardiac support mediated by the normal ebb and flow of
endogenous catecholamines (which is blocked by
desensitization in heart failure) and perhaps by other, as yet
unspecified, endogenous G protein–coupled receptor
agonists (ßARK activity is not limited to ßARs).4 It
is striking that ßARK inhibition shares with other pharmacological
therapies known to improve heart failure (eg, ß-blockers) the ability
to normalize or remodel signaling through the cardiac ß-adrenergic
system by reducing desensitization, lowering cardiac GRK
activity,32 enhancing catecholamine
sensitivity, and raising levels of ß1ARs. Thus,
it is plausible that the salutary effects of ß-blockers in chronic
treatment of heart failure may be due, at least in part, to their
demonstrated ability to reduce the elevated levels of myocardial
ßARK.
With recent landmark trials showing beneficial effects of ß-blockers in the treatment of chronic heart failure,33 it is natural to ask why anyone would want to augment ßAR signaling with a ßARK inhibitor. However, given the experimental data showing the remarkable salutary effects of the ßARK inhibitory peptide on reversing ßAR desensitization, it becomes apparent that ß-blocker therapy and ßARK inhibition may in fact be complementary therapeutic modalities. For example, whereas treatment with ß-blockers will antagonize the catecholamine toxicity associated with heart failure, ßARK inhibition will act to preserve normal ßAR–G protein coupling in times of need, such as during exercise and periods of stress. Thus, there are likely to be major differences between the deleterious effects of chronic ßAR stimulation and the potentially beneficial effects of intermittent ßAR stimulation.
Twenty years ago, the idea that ß-adrenergic antagonists
could be used as therapeutic agents to treat heart failure was viewed
as quite heretical, even though clinical data to support this were
already emerging.34 Almost 2 decades was necessary to
reverse the well-established, although erroneous, conventional wisdom
on this point and bring these drugs into the therapeutic armamentarium
for the treatment of heart failure. Given the rapid pace of current
experimental efforts, a much more rapid assessment of
ß2AR augmentation and ßARK inhibition as
novel therapeutic modalities in heart failure seems likely. Testing of
the latter therapeutic target would be greatly facilitated by the
development of small-molecule inhibitors of the
ßARK-Gß interaction.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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 A. Hu, X. Jiao, E. Gao, W. J. Koch, S. Sharifi-Azad, Z. Grunwald, X. L. Ma, and J.-Z. Sun Chronic beta-Adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia/Reperfusion Injury by Provoking Inducible Nitric-Oxide Synthase-Mediated Nitrative Stress J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 469 - 475. [Abstract] [Full Text] [PDF]
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 M. A.G. van der Heyden, T. J.M. Wijnhoven, and T. Opthof Molecular aspects of adrenergic modulation of the transient outward current Cardiovasc Res, August 1, 2006; 71(3): 430 - 442. [Abstract] [Full Text] [PDF]
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 G. D. Mills, H. Kubo, D. M. Harris, R. M. Berretta, V. Piacentino III, and S. R. Houser Phosphorylation of phospholamban at threonine-17 reduces cardiac adrenergic contractile responsiveness in chronic pressure overload-induced hypertrophy Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H61 - H70. [Abstract] [Full Text] [PDF]
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C. M. Filipeanu, F. Zhou, M. L. Lam, K. E. Kerut, W. C. Claycomb, and G. Wu Enhancement of the Recycling and Activation of beta-Adrenergic Receptor by Rab4 GTPase in Cardiac Myocytes J. Biol. Chem., April 21, 2006; 281(16): 11097 - 11103. [Abstract] [Full Text] [PDF]
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 M. A. Nordlie, L. E. Wold, B. Z. Simkhovich, C. Sesti, and R. A. Kloner Molecular Aspects of Ischemic Heart Disease: Ischemia/Reperfusion-Induced Genetic Changes and Potential Applications of Gene and RNA Interference Therapy Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2006; 11(1): 17 - 30. [Abstract] [PDF]
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 P. K. Pandalai, J. M. Lyons, J. Y. Duffy, K. M. McLean, C. J. Wagner, W. H. Merrill, J. M. Pearl, and S. A. Akhter Role of the {beta}-adrenergic receptor kinase in myocardial dysfunction after brain death J. Thorac. Cardiovasc. Surg., October 1, 2005; 130(4): 1183 - 1189. [Abstract] [Full Text] [PDF]
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 S. Mieno, F. Watanabe, Y. Sawa, and H. Horimoto Gene transfer of {beta}2 adrenergic receptor enhances cardioprotective effects of ischemic preconditioning in rat hearts after myocardial infarction Interactive CardioVascular and Thoracic Surgery, June 1, 2005; 4(3): 163 - 167. [Abstract] [Full Text] [PDF]
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M. A.G. van der Heyden, T. J.M. Wijnhoven, and T. Opthof Molecular aspects of adrenergic modulation of cardiac L-type Ca2+ channels Cardiovasc Res, January 1, 2005; 65(1): 28 - 39. [Abstract] [Full Text] [PDF]
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 J. M. Jones, J. A. Petrofski, K. H. Wilson, C. Steenbergen, W. J. Koch, and C. A. Milano {beta}2 Adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery Eur. J. Cardiothorac. Surg., December 1, 2004; 26(6): 1161 - 1168. [Abstract] [Full Text] [PDF]
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 L. Covolo, U. Gelatti, M. Metra, S. Nodari, A. Piccichè, N. Pezzali, C. Zani, A. Alberti, F. Donato, G. Nardi, et al. Role of {beta}1- and {beta}2-adrenoceptor polymorphisms in heart failure: a case-control study Eur. Heart J., September 1, 2004; 25(17): 1534 - 1541. [Abstract] [Full Text] [PDF]
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T.-a. Koshimizu, G. Tsujimoto, A. Hirasawa, Y. Kitagawa, and A. Tanoue Carvedilol selectively inhibits oscillatory intracellular calcium changes evoked by human {alpha}1D- and {alpha}1B-adrenergic receptors Cardiovasc Res, September 1, 2004; 63(4): 662 - 672. [Abstract] [Full Text] [PDF]
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 J. M. Liebler, Z. Borok, X. Li, B. Zhou, A. J. Sandoval, K.-J. Kim, and E. D. Crandall Alveolar Epithelial Type I Cells Express {beta}2-Adrenergic Receptors and G-protein Receptor Kinase 2 J. Histochem. Cytochem., June 1, 2004; 52(6): 759 - 767. [Abstract] [Full Text] [PDF]
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T. Bupha-Intr and J. Wattanapermpool Cardioprotective effects of exercise training on myofilament calcium activation in ovariectomized rats J Appl Physiol, May 1, 2004; 96(5): 1755 - 1760. [Abstract] [Full Text] [PDF]
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 M. L. Williams, J. A. Hata, J. Schroder, E. Rampersaud, J. Petrofski, A. Jakoi, C. A. Milano, and W. J. Koch Targeted {beta}-Adrenergic Receptor Kinase ({beta}ARK1) Inhibition by Gene Transfer in Failing Human Hearts Circulation, April 6, 2004; 109(13): 1590 - 1593. [Abstract] [Full Text] [PDF]
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Y. Hayakawa, M. Chandra, W. Miao, J. Shirani, J. H. Brown, G. W. Dorn II, R. C. Armstrong, and R. N. Kitsis Inhibition of Cardiac Myocyte Apoptosis Improves Cardiac Function and Abolishes Mortality in the Peripartum Cardiomyopathy of G{alpha}q Transgenic Mice Circulation, December 16, 2003; 108(24): 3036 - 3041. [Abstract] [Full Text] [PDF]
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 A. E. Luckey, C. J. Parsa, and A. H. Harken Reversible Cardiac Sympathectomy by High Thoracic Epidural Anesthesia Improves Regional Left Ventricular Function in Patients Undergoing Coronary Artery Bypass Grafting--Invited Critique Arch Surg, December 1, 2003; 138(12): 1291 - 1291. [Full Text] [PDF]
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Y. Xiang and B. Kobilka The PDZ-binding motif of the {beta}2-adrenoceptor is essential for physiologic signaling and trafficking in cardiac myocytes PNAS, September 16, 2003; 100(19): 10776 - 10781. [Abstract] [Full Text] [PDF]
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P. Most, A. Remppis, S. T. Pleger, E. Loffler, P. Ehlermann, J. Bernotat, C. Kleuss, J. Heierhorst, P. Ruiz, H. Witt, et al. Transgenic Overexpression of the Ca2+-binding Protein S100A1 in the Heart Leads to Increased in Vivo Myocardial Contractile Performance J. Biol. Chem., September 5, 2003; 278(36): 33809 - 33817. [Abstract] [Full Text] [PDF]
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 J. A. Hata and W. J. Koch Phosphorylation of G Protein-Coupled Receptors: GPCR Kinases in Heart Disease Mol. Interv., August 1, 2003; 3(5): 264 - 272. [Abstract] [Full Text] [PDF]
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 J. W. Hughes, A. Sherwood, J. A. Blumenthal, E. C. Suarez, and A. L. Hinderliter Hostility, Social Support, and Adrenergic Receptor Responsiveness Among African-American and White Men and Women Psychosom Med, July 1, 2003; 65(4): 582 - 587. [Abstract] [Full Text] [PDF]
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A. Godecke, A. Molojavyi, J. Heger, U. Flogel, Z. Ding, C. Jacoby, and J. Schrader Myoglobin Protects the Heart from Inducible Nitric-oxide Synthase (iNOS)-mediated Nitrosative Stress J. Biol. Chem., June 6, 2003; 278(24): 21761 - 21766. [Abstract] [Full Text] [PDF]
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 C. Xia, W. Ma, L. J. Stafford, C. Liu, L. Gong, J. F. Martin, and M. Liu GGAPs, a New Family of Bifunctional GTP-Binding and GTPase-Activating Proteins Mol. Cell. Biol., April 1, 2003; 23(7): 2476 - 2488. [Abstract] [Full Text] [PDF]
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L. Pan, E. V. Gurevich, and V. V. Gurevich The Nature of the Arrestin{middle dot}Receptor Complex Determines the Ultimate Fate of the Internalized Receptor J. Biol. Chem., March 21, 2003; 278(13): 11623 - 11632. [Abstract] [Full Text] [PDF]
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 S. R. Houser and K. B. Margulies Is Depressed Myocyte Contractility Centrally Involved in Heart Failure? Circ. Res., March 7, 2003; 92(4): 350 - 358. [Abstract] [Full Text] [PDF]
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H. T. Tevaearai, G. B. Walton, A. D. Eckhart, J. R. Keys, and W. J. Koch Donor heart contractile dysfunction following prolonged ex vivo preservation can be prevented by gene-mediated {beta}-adrenergic signaling modulation Eur. J. Cardiothorac. Surg., November 1, 2002; 22(5): 733 - 737. [Abstract] [Full Text] [PDF]
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P. C. Brum, J. Kosek, A. Patterson, D. Bernstein, and B. Kobilka Abnormal cardiac function associated with sympathetic nervous system hyperactivity in mice Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1838 - H1845. [Abstract] [Full Text] [PDF]
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 S. Mieno, H. Horimoto, F. Watanabe, Y. Nakai, E. Furuya, and S. Sasaki Potent adenylate cyclase agonist forskolin restores myoprotective effects of ischemic preconditioning in rat hearts after myocardial infarction Ann. Thorac. Surg., October 1, 2002; 74(4): 1213 - 1218. [Abstract] [Full Text] [PDF]
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J.M. Jones, K.H. Wilson, W.J. Koch, and C.A. Milano Adenoviral gene transfer to the heart during cardiopulmonary bypass: effect of myocardial protection technique on transgene expression Eur. J. Cardiothorac. Surg., May 1, 2002; 21(5): 847 - 852. [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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A. D. Eckhart and W. J. Koch Transgenic Studies of Cardiac Adrenergic Receptor Regulation J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 1 - 5. [Abstract] [Full Text] [PDF]
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G. Iaccarino, J. R. Keys, A. Rapacciuolo, K. F. Shotwell, R. J. Lefkowitz, H. A. Rockman, and W. J. Koch Regulation of myocardial {beta}ARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing {alpha}1B-adrenergic receptors J. Am. Coll. Cardiol., August 1, 2001; 38(2): 534 - 540. [Abstract] [Full Text] [PDF]
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Z.-S. Zhang, H.-J. Cheng, T. Ukai, H. Tachibana, and C.-P. Cheng Enhanced Cardiac L-Type Calcium Current Response to beta 2-Adrenergic Stimulation in Heart Failure J. Pharmacol. Exp. Ther., July 1, 2001; 298(1): 188 - 196. [Abstract] [Full Text]
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A. S. Shah, D. C. White, S. Emani, A. P. Kypson, R. E. Lilly, K. Wilson, D. D. Glower, R. J. Lefkowitz, and W. J. Koch In Vivo Ventricular Gene Delivery of a {beta}-Adrenergic Receptor Kinase Inhibitor to the Failing Heart Reverses Cardiac Dysfunction Circulation, March 6, 2001; 103(9): 1311 - 1316. [Abstract] [Full Text] [PDF]
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 R. Schulz and G. Heusch Review: AT 1-receptor blockade in experimental myocardial ischaemia/reperfusion Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S136 - S140. [PDF]
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 R. J. Lefkowitz and J. T. Willerson Prospects for Cardiovascular Research JAMA, February 7, 2001; 285(5): 581 - 587. [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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D. C. White, J. A. Hata, A. S. Shah, D. D. Glower, R. J. Lefkowitz, and W. J. Koch Preservation of myocardial beta -adrenergic receptor signaling delays the development of heart failure after myocardial infarction PNAS, May 9, 2000; 97(10): 5428 - 5433. [Abstract] [Full Text] [PDF]
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