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Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.
Abstract
The medical treatment of chronic heart failure has undergone a dramatic transition
in the past decade. Short-term approaches for altering hemodynamics have given way
to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade.
This was once viewed as counterintuitive, because acute administration causes myocardial
depression. Cardiac myocytes from failing hearts show changes in betaAR signaling
and excitation-contraction coupling that can impair cardiac contractility, but the
role of these abnormalities in the progression of heart failure is controversial.
We therefore tested the impact of different manipulations that increase contractility
on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy.
High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure
in this model. In contrast, phospholamban ablation prevented systolic dysfunction
and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice.
Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented
systolic dysfunction and exercise intolerance but also decreased cardiac remodeling
and hypertrophic gene expression. These three manipulations of cardiac contractility
had distinct effects on disease progression, suggesting that selective modulation
of particular aspects of betaAR signaling or excitation-contraction coupling can provide
therapeutic benefit.
Type
Journal articleSubject
ActinsAnimals
Atrial Natriuretic Factor
Biomarkers
Calcium
Calcium Signaling
Calcium-Binding Proteins
Cardiomyopathy, Hypertrophic
Cyclic AMP-Dependent Protein Kinases
Disease Models, Animal
Disease Progression
Female
Gene Expression
Heart Failure
Male
Mice
Mice, Transgenic
Motor Activity
Myocardium
Myosin Heavy Chains
Receptors, Adrenergic, beta-2
beta-Adrenergic Receptor Kinases
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https://hdl.handle.net/10161/5924Published Version (Please cite this version)
10.1172/JCI12083Publication Info
Freeman, K; Lerman, I; Kranias, EG; Bohlmeyer, T; Bristow, MR; Lefkowitz, RJ; ...
Leinwand, LA (2001). Alterations in cardiac adrenergic signaling and calcium cycling differentially affect
the progression of cardiomyopathy. J Clin Invest, 107(8). pp. 967-974. 10.1172/JCI12083. Retrieved from https://hdl.handle.net/10161/5924.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
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

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