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dc.contributor.author Akhter, SA
dc.contributor.author Eckhart, AD
dc.contributor.author Rockman, HA
dc.contributor.author Shotwell, K
dc.contributor.author Lefkowitz, RJ
dc.contributor.author Koch, WJ
dc.coverage.spatial United States
dc.date.accessioned 2012-10-22T20:36:19Z
dc.date.issued 1999-08-10
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/10441103
dc.identifier.citation Circulation, 1999, 100 (6), pp. 648 - 653
dc.identifier.uri http://hdl.handle.net/10161/5907
dc.description.abstract BACKGROUND: The clinical syndrome of heart failure (HF) is characterized by an impaired cardiac beta-adrenergic receptor (betaAR) system, which is critical in the regulation of myocardial function. Expression of the betaAR kinase (betaARK1), which phosphorylates and uncouples betaARs, is elevated in human HF; this likely contributes to the abnormal betaAR responsiveness that occurs with beta-agonist administration. We previously showed that transgenic mice with increased myocardial betaARK1 expression had impaired cardiac function in vivo and that inhibiting endogenous betaARK1 activity in the heart led to enhanced myocardial function. METHODS AND RESULTS: We created hybrid transgenic mice with cardiac-specific concomitant overexpression of both betaARK1 and an inhibitor of betaARK1 activity to study the feasibility and functional consequences of the inhibition of elevated betaARK1 activity similar to that present in human HF. Transgenic mice with myocardial overexpression of betaARK1 (3 to 5-fold) have a blunted in vivo contractile response to isoproterenol when compared with non-transgenic control mice. In the hybrid transgenic mice, although myocardial betaARK1 levels remained elevated due to transgene expression, in vitro betaARK1 activity returned to control levels and the percentage of betaARs in the high-affinity state increased to normal wild-type levels. Furthermore, the in vivo left ventricular contractile response to betaAR stimulation was restored to normal in the hybrid double-transgenic mice. CONCLUSIONS: Novel hybrid transgenic mice can be created with concomitant cardiac-specific overexpression of 2 independent transgenes with opposing actions. Elevated myocardial betaARK1 in transgenic mouse hearts (to levels seen in human HF) can be inhibited in vivo by a peptide that can prevent agonist-stimulated desensitization of cardiac betaARs. This may represent a novel strategy to improve myocardial function in the setting of compromised heart function.
dc.format.extent 648 - 653
dc.language ENG
dc.relation.ispartof Circulation
dc.subject Adenylyl Cyclases
dc.subject Animals
dc.subject Cardiac Catheterization
dc.subject Cardiotonic Agents
dc.subject Cyclic AMP
dc.subject Cyclic AMP-Dependent Protein Kinases
dc.subject Enzyme Induction
dc.subject Feasibility Studies
dc.subject Gene Expression Regulation
dc.subject Heart Failure
dc.subject Isoproterenol
dc.subject Mice
dc.subject Mice, Transgenic
dc.subject Myocardial Contraction
dc.subject Peptide Fragments
dc.subject Phosphorylation
dc.subject Protein Processing, Post-Translational
dc.subject Receptors, Adrenergic, beta
dc.subject Recombinant Proteins
dc.subject Second Messenger Systems
dc.subject Sodium Fluoride
dc.subject Transgenes
dc.subject Ventricular Function, Left
dc.subject beta-Adrenergic Receptor Kinases
dc.title In vivo inhibition of elevated myocardial beta-adrenergic receptor kinase activity in hybrid transgenic mice restores normal beta-adrenergic signaling and function.
dc.type Journal Article
duke.description.endpage 653 en_US
duke.description.issue 6 en_US
duke.description.startpage 648 en_US
duke.description.volume 100 en_US
dc.relation.journal Circulation en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/10441103
pubs.issue 6
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Biochemistry
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Cell Biology
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Molecular Genetics and Microbiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Cardiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.organisational-group /Duke/Trinity College of Arts & Sciences
pubs.organisational-group /Duke/Trinity College of Arts & Sciences/Chemistry
pubs.publication-status Published
pubs.volume 100
dc.identifier.eissn 1524-4539

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