Myocardial adeno-associated virus serotype 6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure.

Abstract

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).

METHODS AND 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.

• Authors: Giuseppe Rengo, Anastasios Lymperopoulos, Carmela Zincarelli, Maria Donniacuo, Stephen Soltys, Joseph E Rabinowitz, Walter J Koch
• Journal: Circulation (Circulation) Vol. 119 Issue 1 Pg. 89-98 (Jan 06 2009) ISSN: 1524-4539 [Electronic] United States
• PMID: 19103992 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Antagonists
• Catecholamines
• Peptides
• Receptors, Adrenergic, beta
• Recombinant Proteins
• beta-adrenergic receptor kinase inhibitory peptide
• Green Fluorescent Proteins
• Aldosterone
• Metoprolol

Topics

• Adrenergic beta-Antagonists (pharmacology)
• Aldosterone (metabolism)
• Animals
• Catecholamines (metabolism)
• Chronic Disease
• Dependovirus (genetics)
• Disease Models, Animal
• Genetic Therapy (methods)
• Green Fluorescent Proteins (genetics)
• Heart Failure (diagnostic imaging, physiopathology, therapy)
• Metoprolol (pharmacology)
• Peptides (genetics)
• Rats
• Rats, Transgenic
• Receptors, Adrenergic, beta (metabolism)
• Recombinant Proteins (genetics)
• Transgenes (physiology)
• Ultrasonography
• Ventricular Remodeling