Myocardial adeno-associated virus serotype 6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure.
BACKGROUND
The upregulation of G protein-coupled receptor kinase 2 in failing myocardium appears to contribute to dysfunctional beta-adrenergic receptor (betaAR) signaling and cardiac function. The peptide betaARKct, which can inhibit the activation of G protein-coupled receptor kinase 2 and improve betaAR signaling, has been shown in transgenic models and short-term gene transfer experiments to rescue heart failure (HF). This study was designed to evaluate long-term betaARKct expression in HF with the use of stable myocardial gene delivery with adeno-associated virus serotype 6 (AAV6).


RESULTS
In HF rats, we delivered betaARKct or green fluorescent protein as a control via AAV6-mediated direct intramyocardial injection. We also treated groups with concurrent administration of the beta-blocker metoprolol. We found robust and long-term transgene expression in the left ventricle at least 12 weeks after delivery. betaARKct significantly improved cardiac contractility and reversed left ventricular remodeling, which was accompanied by a normalization of the neurohormonal (catecholamines and aldosterone) status of the chronic HF animals, including normalization of cardiac betaAR signaling. Addition of metoprolol neither enhanced nor decreased betaARKct-mediated beneficial effects, although metoprolol alone, despite not improving contractility, prevented further deterioration of the left ventricle.


CONCLUSIONS
Long-term cardiac AAV6-betaARKct gene therapy in HF results in sustained improvement of global cardiac function and reversal of remodeling at least in part as a result of a normalization of the neurohormonal signaling axis. In addition, betaARKct alone improves outcomes more than a beta-blocker alone, whereas both treatments are compatible. These findings show that betaARKct gene therapy can be of long-term therapeutic value in HF.
Rengo
Giuseppe
G
Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Lymperopoulos
Anastasios
A
Zincarelli
Carmela
C
Donniacuo
Maria
M
Soltys
Stephen
S
Rabinowitz
Joseph E
JE
Koch
Walter J
WJ
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D002908:Chronic Disease; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000628:therapy*; D008790:Metoprolol / Q000494:pharmacology; D010455:Peptides / Q000235:genetics*; D051381:Rats; D055647:Rats, Transgenic; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics*; D019076:Transgenes / Q000502:physiology; D014463:Ultrasonography; D020257:Ventricular Remodeling
D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D010455:Peptides; D011943:Receptors, Adrenergic, beta; D011994:Recombinant Proteins; C445259:beta-adrenergic receptor kinase inhibitory peptide; D049452:Green Fluorescent Proteins; D000450:Aldosterone; D008790:Metoprolol