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

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.

• Authors: A S Shah, D C White, S Emani, A P Kypson, R E Lilly, K Wilson, D D Glower, R J Lefkowitz, W J Koch
• Journal: Circulation (Circulation) Vol. 103 Issue 9 Pg. 1311-6 (Mar 06 2001) ISSN: 1524-4539 [Electronic] United States
• PMID: 11238278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cyclic AMP-Dependent Protein Kinases
• beta-Adrenergic Receptor Kinases

Topics

• Adenoviridae (genetics)
• Animals
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Gene Expression
• Gene Transfer Techniques
• Heart Ventricles (metabolism, physiopathology)
• Male
• Myocardial Infarction (genetics, metabolism, therapy)
• Rabbits
• Transgenes (genetics)
• beta-Adrenergic Receptor Kinases