Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.

Rockman, HA

Chien, KR

Choi, DJ

Iaccarino, G

Hunter, JJ

Ross, J

Lefkowitz, RJ

Koch, WJ

United States

2013-09-05T18:26:11Z

1998-06-09

Heart failure is accompanied by severely impaired beta-adrenergic receptor (betaAR) function, which includes loss of betaAR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of betaAR function is agonist-stimulated receptor phosphorylation by the betaAR kinase (betaARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in betaAR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of betaARK1 or the beta2AR were mated into a genetic model of murine heart failure (MLP-/-). In vivo cardiac function was assessed by echocardiography and cardiac catheterization. Both MLP-/- and MLP-/-/beta2AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP-/-/betaARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP-/-/betaARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the MLP-/- mice but less than controls. Importantly, heightened betaAR desensitization in the MLP-/- mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the betaARK1 inhibitor. We report here the striking finding that overexpression of this inhibitor prevents the development of cardiomyopathy in this murine model of heart failure. These findings implicate abnormal betaAR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit betaARK1 as a novel mode of therapy.

http://www.ncbi.nlm.nih.gov/pubmed/9618528

0027-8424

https://hdl.handle.net/10161/7822

eng

Proceedings of the National Academy of Sciences

Proc Natl Acad Sci U S A

Animals

Cyclic AMP-Dependent Protein Kinases

Enzyme Inhibitors

G-Protein-Coupled Receptor Kinase 2

Gene Targeting

Gene Transfer Techniques

Heart Failure

Humans

Mice

Mice, Transgenic

beta-Adrenergic Receptor Kinases

Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.

Journal article

Rockman, HA|0000-0003-2921-1584

Lefkowitz, RJ|0000-0003-1472-7545

http://www.ncbi.nlm.nih.gov/pubmed/9618528

7000

7005

12

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

95