In vivo inhibition of elevated myocardial beta-adrenergic receptor kinase activity in hybrid transgenic mice restores normal beta-adrenergic signaling and function.
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.
Type
Journal articleSubject
Adenylyl CyclasesAnimals
Cardiac Catheterization
Cardiotonic Agents
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases
Enzyme Induction
Feasibility Studies
Gene Expression Regulation
Heart Failure
Isoproterenol
Mice
Mice, Transgenic
Myocardial Contraction
Peptide Fragments
Phosphorylation
Protein Processing, Post-Translational
Receptors, Adrenergic, beta
Recombinant Proteins
Second Messenger Systems
Sodium Fluoride
Transgenes
Ventricular Function, Left
beta-Adrenergic Receptor Kinases
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Show full item recordScholars@Duke
Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his
early career as a cardiologist and his transition to biochemistry, which led to his
Nobel Prize win.
Robert J. Lefkowitz, M.D. is Chancellor’s Distinguished Professor of Medicine and
Professor of Biochemistry and Chemistry at the Duke University Medical Center. He
has bee
Howard Allan Rockman
Edward S. Orgain Distinguished Professor of Cardiology, in the School of Medicine
Rockman Lab: Molecular Mechanisms of Hypertrophy and Heart Failure Overall Research
Direction: The major focus of this laboratory is to understand the molecular mechanisms
of hypertrophy and heart failure. My laboratory uses a strategy that combines state
of the art molecular techniques to generate transgenic and gene targeted mouse models,
combined with sophisticated physiologic measures of in vivo cardiac function. In this
manner, candidate molecules are either selectively overexp
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