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    Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure.

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    Date
    2005-02-08
    Authors
    Koch, Walter J
    Lefkowitz, Robert J
    Naga Prasad, SV
    Rockman, Howard A
    Tachibana, H
    Repository Usage Stats
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    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 article
    Subject
    Adenylyl Cyclases
    Animals
    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
    Permalink
    http://hdl.handle.net/10161/5908
    Published Version (Please cite this version)
    10.1161/01.CIR.0000142291.70954.DF
    Publication Info
    Koch, Walter J; Lefkowitz, Robert J; Naga Prasad, SV; Rockman, Howard A; & Tachibana, H (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 http://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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    Scholars@Duke

    Lefkowitz

    Robert J. Lefkowitz

    James B. Duke Professor of Medicine
    The focus of work in this laboratory is on the elucidation of the molecular properties and regulatory mechanisms controlling the function of G protein-coupled receptors. As model systems we utilize the so called adrenergic receptors for adrenaline and related molecules. The goal is to learn the general principles of signal transduction from the outside to the inside of the cell which are involved in systems as diverse as sensory perception, neuro- transmitter and hormonal signaling. Stud
    Rockman

    Howard Allan Rockman

    Edward S. Orgain 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
    Alphabetical list of authors with Scholars@Duke profiles.
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