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

dc.contributor.author Tachibana, Hideo
dc.contributor.author Naga Prasad, Sathyamangla V
dc.contributor.author Lefkowitz, Robert J
dc.contributor.author Koch, Walter J
dc.contributor.author Rockman, Howard A
dc.coverage.spatial United States
dc.date.accessioned 2012-10-22T20:57:19Z
dc.date.issued 2005-02-08
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/15668342
dc.identifier 01.CIR.0000142291.70954.DF
dc.identifier.uri https://hdl.handle.net/10161/5908
dc.description.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.
dc.language eng
dc.publisher Ovid Technologies (Wolters Kluwer Health)
dc.relation.ispartof Circulation
dc.relation.isversionof 10.1161/01.CIR.0000142291.70954.DF
dc.subject Adenylyl Cyclases
dc.subject Animals
dc.subject Cardiac Output, Low
dc.subject Constriction
dc.subject Cyclic AMP-Dependent Protein Kinases
dc.subject Heart
dc.subject Mice
dc.subject Mice, Transgenic
dc.subject Myocardium
dc.subject Peptides
dc.subject Pressure
dc.subject Recombinant Proteins
dc.subject Signal Transduction
dc.subject Ultrasonography
dc.subject beta-Adrenergic Receptor Kinases
dc.title Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure.
dc.type Journal article
duke.contributor.id Lefkowitz, Robert J|0096962
duke.contributor.id Rockman, Howard A|0223027
duke.description.issue 5
duke.description.volume 111
dc.relation.journal Circulation
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/15668342
pubs.begin-page 591
pubs.end-page 597
pubs.issue 5
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biochemistry
pubs.organisational-group Cell Biology
pubs.organisational-group Chemistry
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Cardiology
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group Pathology
pubs.organisational-group School of Medicine
pubs.organisational-group Trinity College of Arts & Sciences
pubs.publication-status Published
pubs.volume 111
dc.identifier.eissn 1524-4539


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