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Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure.

dc.contributor.author Harding, VB
dc.contributor.author Jones, LR
dc.contributor.author Lefkowitz, RJ
dc.contributor.author Koch, WJ
dc.contributor.author Rockman, HA
dc.coverage.spatial United States
dc.date.accessioned 2013-09-05T16:07:41Z
dc.date.issued 2001-05-08
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/11331748
dc.identifier 091102398
dc.identifier.issn 0027-8424
dc.identifier.uri https://hdl.handle.net/10161/7806
dc.description.abstract Chronic human heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased levels of betaAR kinase 1 (betaARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition of betaARK1 is sufficient to rescue a model of severe heart failure, we mated transgenic mice overexpressing a peptide inhibitor of betaARK1 (betaARKct) with transgenic mice overexpressing the sarcoplasmic reticulum Ca(2+)-binding protein, calsequestrin (CSQ). CSQ mice have a severe cardiomyopathy and markedly shortened survival (9 +/- 1 weeks). In contrast, CSQ/betaARKct mice exhibited a significant increase in mean survival age (15 +/- 1 weeks; P < 0.0001) and showed less cardiac dilation, and cardiac function was significantly improved (CSQ vs. CSQ/betaARKct, left ventricular end diastolic dimension 5.60 +/- 0.17 mm vs. 4.19 +/- 0.09 mm, P < 0.005; % fractional shortening, 15 +/- 2 vs. 36 +/- 2, P < 0.005). The enhancement of the survival rate in CSQ/betaARKct mice was substantially potentiated by chronic treatment with the betaAR antagonist metoprolol (CSQ/betaARKct nontreated vs. CSQ/betaARKct metoprolol treated, 15 +/- 1 weeks vs. 25 +/- 2 weeks, P < 0.0001). Thus, overexpression of the betaARKct resulted in a marked prolongation in survival and improved cardiac function in a mouse model of severe cardiomyopathy that can be potentiated with beta-blocker therapy. These data demonstrate a significant synergy between an established heart-failure treatment and the strategy of betaARK1 inhibition.
dc.language eng
dc.publisher Proceedings of the National Academy of Sciences
dc.relation.ispartof Proc Natl Acad Sci U S A
dc.relation.isversionof 10.1073/pnas.091102398
dc.subject Adrenergic beta-Antagonists
dc.subject Animals
dc.subject Cardiomyopathy, Dilated
dc.subject Cyclic AMP-Dependent Protein Kinases
dc.subject Disease Models, Animal
dc.subject Mice
dc.subject Mice, Transgenic
dc.subject Myocardium
dc.subject beta-Adrenergic Receptor Kinases
dc.title Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure.
dc.type Journal article
duke.contributor.id Lefkowitz, RJ|0096962
duke.contributor.id Rockman, HA|0223027
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/11331748
pubs.begin-page 5809
pubs.end-page 5814
pubs.issue 10
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 98


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