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In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.

dc.contributor.author Shah, AS
dc.contributor.author White, DC
dc.contributor.author Emani, S
dc.contributor.author Kypson, AP
dc.contributor.author Lilly, RE
dc.contributor.author Wilson, K
dc.contributor.author Glower, DD
dc.contributor.author Lefkowitz, RJ
dc.contributor.author Koch, WJ
dc.coverage.spatial United States
dc.date.accessioned 2012-10-22T20:21:46Z
dc.date.issued 2001-03-06
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/11238278
dc.identifier.uri https://hdl.handle.net/10161/5905
dc.description.abstract BACKGROUND: Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo beta-adrenergic receptor kinase (betaARK1) inhibition in a model of chronic left ventricular (LV) dysfunction after myocardial infarction (MI). METHODS AND RESULTS: Rabbits underwent ligation of the left circumflex (LCx) marginal artery and implantation of sonomicrometric crystals. Baseline cardiac physiology was studied 3 weeks after MI; 5x10(11) viral particles of adenovirus was percutaneously delivered through the LCx. Animals received transgenes encoding a peptide inhibitor of betaARK1 (Adeno-betaARKct) or an empty virus (EV) as control. One week after gene delivery, global LV and regional systolic function were measured again to assess gene treatment. Adeno-betaARKct delivery to the failing heart through the LCx resulted in chamber-specific expression of the betaARKct. Baseline in vivo LV systolic performance was improved in Adeno-betaARKct-treated animals compared with their individual pre-gene delivery values and compared with EV-treated rabbits. Total beta-AR density and betaARK1 levels were unchanged between treatment groups; however, beta-AR-stimulated adenylyl cyclase activity in the LV was significantly higher in Adeno-betaARKct-treated rabbits compared with EV-treated animals. CONCLUSIONS: In vivo delivery of Adeno-betaARKct is feasible in the infarcted/failing heart by coronary catheterization; expression of betaARKct results in marked reversal of ventricular dysfunction. Thus, inhibition of betaARK1 provides a novel treatment strategy for improving the cardiac performance of the post-MI heart.
dc.language eng
dc.publisher Ovid Technologies (Wolters Kluwer Health)
dc.relation.ispartof Circulation
dc.subject Adenoviridae
dc.subject Animals
dc.subject Cyclic AMP-Dependent Protein Kinases
dc.subject Gene Expression
dc.subject Gene Transfer Techniques
dc.subject Heart Ventricles
dc.subject Male
dc.subject Myocardial Infarction
dc.subject Rabbits
dc.subject Transgenes
dc.subject beta-Adrenergic Receptor Kinases
dc.title In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.
dc.type Journal article
duke.contributor.id White, DC|0135808
duke.contributor.id Glower, DD|0117604
duke.contributor.id Lefkowitz, RJ|0096962
duke.description.issue 9
duke.description.volume 103
dc.relation.journal Circulation
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/11238278
pubs.begin-page 1311
pubs.end-page 1316
pubs.issue 9
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biochemistry
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 Pathology
pubs.organisational-group School of Medicine
pubs.organisational-group Surgery
pubs.organisational-group Surgery, Cardiovascular and Thoracic Surgery
pubs.organisational-group Trinity College of Arts & Sciences
pubs.publication-status Published
pubs.volume 103
dc.identifier.eissn 1524-4539


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