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Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure.
Abstract
BACKGROUND: Heart failure is characterized by abnormalities in beta-adrenergic receptor
(betaAR) signaling, including increased level of myocardial betaAR kinase 1 (betaARK1).
Our previous studies have shown that inhibition of betaARK1 with the use of the Gbetagamma
sequestering peptide of betaARK1 (betaARKct) can prevent cardiac dysfunction in models
of heart failure. Because inhibition of betaARK activity is pivotal for amelioration
of cardiac dysfunction, we investigated whether the level of betaARK1 inhibition correlates
with the degree of heart failure. METHODS AND RESULTS: Transgenic (TG) mice with varying
degrees of cardiac-specific expression of betaARKct peptide underwent transverse aortic
constriction (TAC) for 12 weeks. Cardiac function was assessed by serial echocardiography
in conscious mice, and the level of myocardial betaARKct protein was quantified at
termination of the study. TG mice showed a positive linear relationship between the
level of betaARKct protein expression and fractional shortening at 12 weeks after
TAC. TG mice with low betaARKct expression developed severe heart failure, whereas
mice with high betaARKct expression showed significantly less cardiac deterioration
than wild-type (WT) mice. Importantly, mice with a high level of betaARKct expression
had preserved isoproterenol-stimulated adenylyl cyclase activity and normal betaAR
densities in the cardiac membranes. In contrast, mice with low expression of the transgene
had marked abnormalities in betaAR function, similar to the WT mice. CONCLUSIONS:
These data show that the level of betaARK1 inhibition determines the degree to which
cardiac function can be preserved in response to pressure overload and has important
therapeutic implications when betaARK1 inhibition is considered as a molecular target.
Type
Journal articleSubject
Adenylyl CyclasesAnimals
Cardiac Output, Low
Constriction
Cyclic AMP-Dependent Protein Kinases
Heart
Mice
Mice, Transgenic
Myocardium
Peptides
Pressure
Recombinant Proteins
Signal Transduction
Ultrasonography
beta-Adrenergic Receptor Kinases
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https://hdl.handle.net/10161/5908Published Version (Please cite this version)
10.1161/01.CIR.0000142291.70954.DFPublication Info
Tachibana, Hideo; Naga Prasad, Sathyamangla V; Lefkowitz, Robert J; Koch, Walter J;
& Rockman, Howard A (2005). Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac
dysfunction after chronic pressure overload-induced heart failure. Circulation, 111(5). pp. 591-597. 10.1161/01.CIR.0000142291.70954.DF. Retrieved from https://hdl.handle.net/10161/5908.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his
early career as a cardiologist and his transition to biochemistry, which led to his
Nobel Prize win.
Robert J. Lefkowitz, M.D. is Chancellor’s Distinguished Professor of Medicine and
Professor of Biochemistry and Chemistry at the Duke University Medical Center. He
has bee
Howard Allan Rockman
Edward S. Orgain Distinguished Professor of Cardiology, in the School of Medicine
Rockman Lab: Molecular Mechanisms of Hypertrophy and Heart Failure Overall Research
Direction: The major focus of this laboratory is to understand the molecular mechanisms
of hypertrophy and heart failure. My laboratory uses a strategy that combines state
of the art molecular techniques to generate transgenic and gene targeted mouse models,
combined with sophisticated physiologic measures of in vivo cardiac function. In this
manner, candidate molecules are either selectively overexp
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