Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure.

Tachibana, Hideo

Naga Prasad, Sathyamangla V

Lefkowitz, Robert J

Koch, Walter J

Rockman, Howard A

United States

2012-10-22T20:57:19Z

2005-02-08

BACKGROUND: Heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased level of myocardial betaAR kinase 1 (betaARK1). Our previous studies have shown that inhibition of betaARK1 with the use of the Gbetagamma sequestering peptide of betaARK1 (betaARKct) can prevent cardiac dysfunction in models of heart failure. Because inhibition of betaARK activity is pivotal for amelioration of cardiac dysfunction, we investigated whether the level of betaARK1 inhibition correlates with the degree of heart failure. METHODS AND RESULTS: Transgenic (TG) mice with varying degrees of cardiac-specific expression of betaARKct peptide underwent transverse aortic constriction (TAC) for 12 weeks. Cardiac function was assessed by serial echocardiography in conscious mice, and the level of myocardial betaARKct protein was quantified at termination of the study. TG mice showed a positive linear relationship between the level of betaARKct protein expression and fractional shortening at 12 weeks after TAC. TG mice with low betaARKct expression developed severe heart failure, whereas mice with high betaARKct expression showed significantly less cardiac deterioration than wild-type (WT) mice. Importantly, mice with a high level of betaARKct expression had preserved isoproterenol-stimulated adenylyl cyclase activity and normal betaAR densities in the cardiac membranes. In contrast, mice with low expression of the transgene had marked abnormalities in betaAR function, similar to the WT mice. CONCLUSIONS: These data show that the level of betaARK1 inhibition determines the degree to which cardiac function can be preserved in response to pressure overload and has important therapeutic implications when betaARK1 inhibition is considered as a molecular target.

http://www.ncbi.nlm.nih.gov/pubmed/15668342

01.CIR.0000142291.70954.DF

1524-4539

https://hdl.handle.net/10161/5908

eng

Ovid Technologies (Wolters Kluwer Health)

Circulation

10.1161/01.CIR.0000142291.70954.DF

Circulation

Adenylyl Cyclases

Animals

Cardiac Output, Low

Constriction

Cyclic AMP-Dependent Protein Kinases

Heart

Mice

Mice, Transgenic

Myocardium

Peptides

Pressure

Recombinant Proteins

Signal Transduction

Ultrasonography

beta-Adrenergic Receptor Kinases

Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure.

Journal article

Lefkowitz, Robert J|0000-0003-1472-7545

Rockman, Howard A|0000-0003-2921-1584

5

111

http://www.ncbi.nlm.nih.gov/pubmed/15668342

591

597

5

Basic Science Departments

Biochemistry

Cell Biology

Chemistry

Clinical Science Departments

Duke

Duke Cancer Institute

Institutes and Centers

Medicine

Medicine, Cardiology

Molecular Genetics and Microbiology

Pathology

School of Medicine

Trinity College of Arts & Sciences

Published

111