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


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.
Department of General and Thoracic Surgery and the Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
A S
AS
Shah
D C
DC
White
S
S
Emani
A P
AP
Kypson
R E
RE
Lilly
K
K
Wilson
D D
DD
Glower
R J
RJ
Lefkowitz
W J
WJ
Koch
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D011817:Rabbits; D019076:Transgenes / Q000235:genetics; D051552:beta-Adrenergic Receptor Kinases
D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases