Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure.
Abstract
Chronic human heart failure is characterized by abnormalities in beta-adrenergic receptor
(betaAR) signaling, including increased levels of betaAR kinase 1 (betaARK1), which
seems critical to the pathogenesis of the disease. To determine whether inhibition
of betaARK1 is sufficient to rescue a model of severe heart failure, we mated transgenic
mice overexpressing a peptide inhibitor of betaARK1 (betaARKct) with transgenic mice
overexpressing the sarcoplasmic reticulum Ca(2+)-binding protein, calsequestrin (CSQ).
CSQ mice have a severe cardiomyopathy and markedly shortened survival (9 +/- 1 weeks).
In contrast, CSQ/betaARKct mice exhibited a significant increase in mean survival
age (15 +/- 1 weeks; P < 0.0001) and showed less cardiac dilation, and cardiac function
was significantly improved (CSQ vs. CSQ/betaARKct, left ventricular end diastolic
dimension 5.60 +/- 0.17 mm vs. 4.19 +/- 0.09 mm, P < 0.005; % fractional shortening,
15 +/- 2 vs. 36 +/- 2, P < 0.005). The enhancement of the survival rate in CSQ/betaARKct
mice was substantially potentiated by chronic treatment with the betaAR antagonist
metoprolol (CSQ/betaARKct nontreated vs. CSQ/betaARKct metoprolol treated, 15 +/-
1 weeks vs. 25 +/- 2 weeks, P < 0.0001). Thus, overexpression of the betaARKct resulted
in a marked prolongation in survival and improved cardiac function in a mouse model
of severe cardiomyopathy that can be potentiated with beta-blocker therapy. These
data demonstrate a significant synergy between an established heart-failure treatment
and the strategy of betaARK1 inhibition.
Type
Journal articleSubject
Adrenergic beta-AntagonistsAnimals
Cardiomyopathy, Dilated
Cyclic AMP-Dependent Protein Kinases
Disease Models, Animal
Mice
Mice, Transgenic
Myocardium
beta-Adrenergic Receptor Kinases
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http://hdl.handle.net/10161/7806Published Version (Please cite this version)
10.1073/pnas.091102398Publication Info
(2001). Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci U S A, 98(10). pp. 5809-5814. 10.1073/pnas.091102398. Retrieved from http://hdl.handle.net/10161/7806.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Robert J. Lefkowitz
James B. Duke Professor of Medicine
The focus of work in this laboratory is on the elucidation of the molecular properties
and regulatory mechanisms controlling the function of G protein-coupled receptors.
As model systems we utilize the so called adrenergic receptors for adrenaline and
related molecules. The goal is to learn the general principles of signal transduction
from the outside to the inside of the cell which are involved in systems as diverse
as sensory perception, neuro- transmitter and hormonal signaling. Stud
Howard Allan Rockman
Edward S. Orgain 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
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