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

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

Publication , Journal Article

Shah, AS; White, DC; Emani, S; Kypson, AP; Lilly, RE; Wilson, K; Glower, DD; Lefkowitz, RJ; Koch, WJ

Published in: Circulation

March 6, 2001

Published version (DOI) Open Access Copy (Duke) Link to item

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.

Duke Scholars

Author Robert J. Lefkowitz Medicine, Cardiology

Author Donald D. Glower Jr. Surgery, Cardiovascular and Thoracic Surgery

Author Walter J. Koch Surgery, Cardiovascular and Thoracic Surgery

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Published In

Circulation

DOI

10.1161/01.cir.103.9.1311

EISSN

1524-4539

Publication Date

March 6, 2001

Volume

103

Issue

Start / End Page

1311 / 1316

Location

United States

Related Subject Headings

beta-Adrenergic Receptor Kinases
Transgenes
Rabbits
Myocardial Infarction
Male
Heart Ventricles
Gene Transfer Techniques
Gene Expression
Cyclic AMP-Dependent Protein Kinases
Cardiovascular System & Hematology

Citation

APA

Chicago

ICMJE

MLA

NLM

Shah, A. S., White, D. C., Emani, S., Kypson, A. P., Lilly, R. E., Wilson, K., … Koch, W. J. (2001). In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation, 103(9), 1311–1316. https://doi.org/10.1161/01.cir.103.9.1311

Shah, A. S., D. C. White, S. Emani, A. P. Kypson, R. E. Lilly, K. Wilson, D. D. Glower, R. J. Lefkowitz, and W. J. Koch. “In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.” Circulation 103, no. 9 (March 6, 2001): 1311–16. https://doi.org/10.1161/01.cir.103.9.1311.

Shah AS, White DC, Emani S, Kypson AP, Lilly RE, Wilson K, et al. In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation. 2001 Mar 6;103(9):1311–6.

Shah, A. S., et al. “In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.” Circulation, vol. 103, no. 9, Mar. 2001, pp. 1311–16. Pubmed, doi:10.1161/01.cir.103.9.1311.

Shah AS, White DC, Emani S, Kypson AP, Lilly RE, Wilson K, Glower DD, Lefkowitz RJ, Koch WJ. In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation. 2001 Mar 6;103(9):1311–1316.