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Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade.

dc.contributor.author Iaccarino, G
dc.contributor.author Tomhave, ED
dc.contributor.author Lefkowitz, RJ
dc.contributor.author Koch, WJ
dc.coverage.spatial United States
dc.date.accessioned 2012-10-22T16:22:16Z
dc.date.issued 1998-10-27
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/9788834
dc.identifier.issn 0009-7322
dc.identifier.uri https://hdl.handle.net/10161/5902
dc.description.abstract BACKGROUND: Impaired myocardial beta-adrenergic receptor (betaAR) signaling, including desensitization and functional uncoupling, is a characteristic of congestive heart failure. A contributing mechanism for this impairment may involve enhanced myocardial beta-adrenergic receptor kinase (betaARK1) activity because levels of this betaAR-desensitizing G protein-coupled receptor kinase (GRK) are increased in heart failure. An hypothesis has emerged that increased sympathetic nervous system activity associated with heart failure might be the initial stimulus for betaAR signaling alterations, including desensitization. We have chronically treated mice with drugs that either activate or antagonize betaARs to study the dynamic relationship between betaAR activation and myocardial levels of betaARK1. METHODS AND RESULTS: Long-term in vivo stimulation of betaARs results in the impairment of cardiac +betaAR signaling and increases the level of expression (mRNA and protein) and activity of +betaARK1 but not that of GRK5, a second GRK abundantly expressed in the myocardium. Long-term beta-blocker treatment, including the use of carvedilol, improves myocardial betaAR signaling and reduces betaARK1 levels in a specific and dose-dependent manner. Identical results were obtained in vitro in cultured cells, demonstrating that the regulation of GRK expression is directly linked to betaAR signaling. CONCLUSIONS: This report demonstrates, for the first time, that betaAR stimulation can significantly increase the expression of betaARK1 , whereas beta-blockade decreases expression. This reciprocal regulation of betaARK1 documents a novel mechanism of ligand-induced betaAR regulation and provides important insights into the potential mechanisms responsible for the effectiveness of beta-blockers, such as carvedilol, in the treatment of heart failure.
dc.language eng
dc.publisher Ovid Technologies (Wolters Kluwer Health)
dc.relation.ispartof Circulation
dc.subject Animals
dc.subject Body Weight
dc.subject CHO Cells
dc.subject Cricetinae
dc.subject GTP-Binding Proteins
dc.subject Heart Failure
dc.subject Mice
dc.subject Mice, Inbred C57BL
dc.subject Myocardium
dc.subject Organ Size
dc.subject Receptor Protein-Tyrosine Kinases
dc.subject Receptors, Adrenergic, beta
dc.subject Reverse Transcriptase Polymerase Chain Reaction
dc.subject Signal Transduction
dc.title Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade.
dc.type Journal article
duke.contributor.id Lefkowitz, RJ|0096962
duke.description.volume 98
dc.relation.journal Circulation
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/9788834
pubs.begin-page 1783
pubs.end-page 1789
pubs.issue 17
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biochemistry
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 Pathology
pubs.organisational-group School of Medicine
pubs.organisational-group Trinity College of Arts & Sciences
pubs.publication-status Published
pubs.volume 98


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