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

dc.contributor.author Rockman, HA
dc.contributor.author Chien, KR
dc.contributor.author Choi, DJ
dc.contributor.author Iaccarino, G
dc.contributor.author Hunter, JJ
dc.contributor.author Ross, J
dc.contributor.author Lefkowitz, RJ
dc.contributor.author Koch, WJ
dc.coverage.spatial United States
dc.date.accessioned 2013-09-05T18:26:11Z
dc.date.issued 1998-06-09
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/9618528
dc.identifier.issn 0027-8424
dc.identifier.uri https://hdl.handle.net/10161/7822
dc.description.abstract 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.
dc.language eng
dc.publisher Proceedings of the National Academy of Sciences
dc.relation.ispartof Proc Natl Acad Sci U S A
dc.subject Animals
dc.subject Cyclic AMP-Dependent Protein Kinases
dc.subject Enzyme Inhibitors
dc.subject G-Protein-Coupled Receptor Kinase 2
dc.subject Gene Targeting
dc.subject Gene Transfer Techniques
dc.subject Heart Failure
dc.subject Humans
dc.subject Mice
dc.subject Mice, Transgenic
dc.subject beta-Adrenergic Receptor Kinases
dc.title Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.
dc.type Journal article
duke.contributor.id Rockman, HA|0223027
duke.contributor.id Lefkowitz, RJ|0096962
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/9618528
pubs.begin-page 7000
pubs.end-page 7005
pubs.issue 12
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biochemistry
pubs.organisational-group Cell Biology
pubs.organisational-group Chemistry
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Cardiology
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group Pathology
pubs.organisational-group School of Medicine
pubs.organisational-group Trinity College of Arts & Sciences
pubs.publication-status Published
pubs.volume 95


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