From the Departments of Medicine (G.I., R.J.L.), Surgery (E.D.T, W.J.K.),
and Biochemistry (R.J.L.) and Howard Hughes Medical Institute, Duke University
Medical Center (R.J.L.), Durham, NC.
Correspondence to Walter J. Koch, PhD, Department of Surgery, Duke University Medical Center, Room 472, MSRB, Research Drive, Durham, NC 27710. E-mail koch0002{at}mc.duke.edu
Background—Impaired myocardial
ß-adrenergic receptor (ßAR) signaling, including desensitization
and functional uncoupling, is a characteristic of congestive heart
failure. A contributing mechanism for this impairment may involve
enhanced myocardial ß-adrenergic receptor kinase (ßARK1) activity
because levels of this ßAR-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 ßAR signaling
alterations, including desensitization. We have chronically treated
mice with drugs that either activate or antagonize ßARs to
study the dynamic relationship between ßAR activation and myocardial
levels of ßARK1.
Methods and Results—Long-term in vivo stimulation of ßARs
results in the impairment of cardiac ßAR signaling and
increases the level of expression (mRNA and protein) and activity of
ßARK1 but not that of GRK5, a second GRK abundantly expressed in the
myocardium. Long-term ß-blocker treatment, including the
use of carvedilol, improves myocardial ßAR signaling and reduces
ßARK1 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 ßAR
signaling.
Conclusions—This report demonstrates, for the first time, that
ßAR stimulation can significantly increase the expression of ßARK1,
whereas ß-blockade decreases expression. This reciprocal regulation
of ßARK1 documents a novel mechanism of ligand-induced ßAR
regulation and provides important insights into the potential
mechanisms responsible for the effectiveness of ß-blockers, such as
carvedilol, in the treatment of heart failure.
© 1998 American Heart Association, Inc.
Basic Science Reports
Reciprocal In Vivo Regulation of Myocardial G Protein–Coupled Receptor Kinase Expression by ß-Adrenergic Receptor Stimulation and Blockade
Key Words: heart failure • receptors, adrenergic, beta • myocardium • catecholamines
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