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Alterations in cardiac adrenergic signal ... e progression of cardiomyopathy
Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.
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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.
Freeman K, Lerman I, Kranias EG, Bohlmeyer T, Bristow MR, Lefkowitz RJ, Iaccarino G, Koch WJ, Leinwand LA
The Journal of clinical investigation
2001-04-01 00:00
107
8
967-74
Actins,Animals,Atrial Natriuretic Factor,Biological Markers,Calcium,Calcium Signaling,Calcium-Binding Proteins,Cardiomyopathy, Hypertrophic,Cyclic AMP-Dependent Protein Kinases,Disease Models, Animal,Disease Progression,Female,Gene Expression,Heart Failure, Congestive,Male,Mice,Mice, Transgenic,Motor Activity,Myocardium,Myosin Heavy Chains,Receptors, Adrenergic, beta-2,beta-Adrenergic Receptor Kinase,Actins,Biological Markers,Calcium-Binding Proteins,Myosin Heavy Chains,Receptors, Adrenergic, beta-2,phospholamban,Calcium,Atrial Natriuretic Factor,beta-Adrenergic Receptor Kinase,Cyclic AMP-Dependent Protein Kinases
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309-0347, USA
J. Clin. Invest.
NHLBI HL50560, NHLBI HL61690, NCRR P40RR12358
0021-9738
675
True
11306600
