alexa β-Adrenergic Receptor Signaling Regulates rAAV Transduction through Calcineurin in Heart Muscle Cells | OMICS International | Abstract
ISSN: 2157-7412

Journal of Genetic Syndromes & Gene Therapy
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Research Article

β-Adrenergic Receptor Signaling Regulates rAAV Transduction through Calcineurin in Heart Muscle Cells

Andrew Natonson1, Jarrod Dean1, Masaaki Ii1, Atsushi Iwakura1, Jeremy Plante1, Ulrike Mende2, Jarrod S. Johnson3, R. Jude Samulski3, John E. J. Rasko4,5 and Ryuichi Aikawa1,4*

1Cardiovascular Research, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA

2Cardiovascular Research Center, Rhode Island Hospital & Brown Medical School, Providence, RI 02903, USA

3Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7352, USA

4Gene and Stem Cell Therapy, Centenary Institute, University of Sydney, Newtown, NSW2042, Australia

5Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, NSW 2050

*Corresponding Author:
Ryuichi Aikawa MD
PhD, Kuwana City Hospital
1-32-1 Chuo-cho, Kuwana city
Mie 511-0068, Japan
Tel: +81-594-22-0650
Fax: +81-594-22-5608
E-mail: [email protected]

Received date: December 11, 2010; Accepted date:January 12, 2011; Published date: January 16, 2011

Citation: Natonson A, Dean J, Li M, Iwakura A, Plante J, et al. (2010) ß-Adrenergic Receptor Signaling Regulates rAAV Transduction through Calcineurin in Heart Muscle Cells. J Genet Syndr Gene Ther 1:102. doi:10.4172/2157-7412.1000102

Copyright: © 2010 Natonson A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Recombinant adeno-associated virus (rAAV)-based gene therapy represents a promising approach for the treatment of heart muscle diseases, but the molecular mechanisms that direct rAAV transduction remain unclear. Here we demonstrate that ?-adrenergic receptor stimulation with isoproterenol (ISO) markedly increased cardiomyocyte transduction of rAAV in vitro and in vivo. Conversely, chronic ?-adrenergic receptor downregulation significantly suppressed rAAV transduction. Pretreatment with calcium signaling cascade inhibitors including calcineurin inhibitory peptide (CNIP) strongly suppressed the positive effects of ISO on rAAV transduction. Additionally we document that ISO treatment led to a significant increase in double-stranded (ds) DNA synthesis of the rAAV genome and an increase in promoter activity. Moreover, stimulation with ISO did not affect rAAV transduction in calcineurin nullizygous mice. Collectively, we conclude that a calcium-dependent pathway regulates rAAV vector transduction at a number of stages that may include vector mobilization, conversion, and transcription activity. Modulating this pathway through ?-adrenergic signaling enhances rAAV-mediated gene delivery to cardiomyocytes, and may be valuable when considering therapeutic approaches for heart muscle diseases.


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