title: 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).
  
  
  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.affiliation: Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rengo
authors.forename: Anastasios
authors.initials: A
authors.lastname: Lymperopoulos
authors.forename: Carmela
authors.initials: C
authors.lastname: Zincarelli
authors.forename: Maria
authors.initials: M
authors.lastname: Donniacuo
authors.forename: Stephen
authors.initials: S
authors.lastname: Soltys
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rabinowitz
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: 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
chemical_list: 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