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 |
|