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

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Shah, AS

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White, DC

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Emani, S

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Kypson, AP

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Lilly, RE

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Wilson, K

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Glower, DD

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Lefkowitz, RJ

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Koch, WJ

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United States

dc.date.accessioned

2012-10-22T20:21:46Z

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2001-03-06

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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.identifier

https://www.ncbi.nlm.nih.gov/pubmed/11238278

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1524-4539

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https://hdl.handle.net/10161/5905

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eng

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Ovid Technologies (Wolters Kluwer Health)

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Circulation

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Circulation

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Adenoviridae

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Animals

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Cyclic AMP-Dependent Protein Kinases

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Gene Expression

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Gene Transfer Techniques

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Heart Ventricles

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Male

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Myocardial Infarction

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Rabbits

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Transgenes

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beta-Adrenergic Receptor Kinases

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

dc.type

Journal article

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Lefkowitz, RJ|0000-0003-1472-7545

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9

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103

pubs.author-url

https://www.ncbi.nlm.nih.gov/pubmed/11238278

pubs.begin-page

1311

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1316

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9

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Basic Science Departments

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Biochemistry

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Chemistry

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Clinical Science Departments

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Duke

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Duke Cancer Institute

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Institutes and Centers

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Medicine

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Medicine, Cardiology

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Pathology

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School of Medicine

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Surgery

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Surgery, Cardiovascular and Thoracic Surgery

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Trinity College of Arts & Sciences

pubs.publication-status

Published

pubs.volume

103

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