Restoration of β -Adrenergic Signaling in Failing Cardiac Ventricular Myocytes via Adenoviral-Mediated Gene Transfer

• Published in: Proceedings of the National Academy of Sciences - PNAS 1997-10, Vol.94 (22), p.12100-12105
• Main Authors: Akhter, S A, Skaer, C A, Kypson, A P, McDonald, P H, Peppel, K C, Glower, D D, Lefkowitz, R J, Koch, W J
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; adenovirus; Animals; Antibodies; beta-Adrenergic Receptor Kinases; Biological Sciences; Congestive heart failure; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - biosynthesis; Cyclic AMP-Dependent Protein Kinases - genetics; Disease Models, Animal; Gene Expression; Gene Transfer Techniques; Genetic Vectors; Heart; Heart Failure - physiopathology; Heart Ventricles - cytology; Heart Ventricles - physiopathology; Hemodynamics; Infections; Inurement; Isoproterenol - pharmacology; Male; Myocardium; P branes; Rabbits; Receptors; Receptors, Adrenergic, beta - biosynthesis; Receptors, Adrenergic, beta - genetics; Signal Transduction - genetics; Tachycardia; Transgenes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.22.12100

Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing cellular proteins that may improve cardiac performance. Our laboratory has been focusing on the feasibility of restoring β -adrenergic signaling deficiencies that are a characteristic of chronic CHF. We have now studied isolated ventricular myocytes from rabbits that have been chronically paced to produce hemodynamic failure. We document molecular β -adrenergic signaling defects including down-regulation of myocardial β -adrenergic receptors (β -ARs), functional β -AR uncoupling, and an upregulation of the β -AR kinase (β ARK1). Adenoviral-mediated gene transfer of the human β2-AR or an inhibitor of β ARK1 to these failing myocytes led to the restoration of β -AR signaling. These results demonstrate that defects present in this critical myocardial signaling pathway can be corrected in vitro using genetic modification and raise the possibility of novel inotropic therapies for CHF including the inhibition of β ARK1 activity in the heart.