Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.

Freeman, K

Lerman, I

Kranias, EG

Bohlmeyer, T

Bristow, MR

Lefkowitz, RJ

Iaccarino, G

Koch, WJ

Leinwand, LA

United States

2012-10-24T17:45:10Z

2001-04

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.

https://www.ncbi.nlm.nih.gov/pubmed/11306600

0021-9738

https://hdl.handle.net/10161/5924

eng

American Society for Clinical Investigation

J Clin Invest

10.1172/JCI12083

Journal of Clinical Investigation

Actins

Animals

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

Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.

Journal article

8

107

https://www.ncbi.nlm.nih.gov/pubmed/11306600

967

974

8

Basic Science Departments

Biochemistry

Chemistry

Clinical Science Departments

Duke

Duke Cancer Institute

Institutes and Centers

Medicine

Medicine, Cardiology

Pathology

School of Medicine

Trinity College of Arts & Sciences

Published

107