Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery.
Abstract
Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic
strategy for treatment of cardiovascular diseases such as heart failure (HF). Before
gene therapy approaches to alter cardiac function can be realized, efficient and reproducible
in vivo gene techniques must be established to efficiently transfer transgenes globally
to the myocardium. We have been testing the hypothesis that genetic manipulation of
the myocardial beta-adrenergic receptor (beta-AR) system, which is impaired in HF,
can enhance cardiac function. We have delivered adenoviral transgenes, including the
human beta2-AR (Adeno-beta2AR), to the myocardium of rabbits using an intracoronary
approach. Catheter-mediated Adeno-beta2AR delivery produced diffuse multichamber myocardial
expression, peaking 1 week after gene transfer. A total of 5 x 10(11) viral particles
of Adeno-beta2AR reproducibly produced 5- to 10-fold beta-AR overexpression in the
heart, which, at 7 and 21 days after delivery, resulted in increased in vivo hemodynamic
function compared with control rabbits that received an empty adenovirus. Several
physiological parameters, including dP/dtmax as a measure of contractility, were significantly
enhanced basally and showed increased responsiveness to the beta-agonist isoproterenol.
Our results demonstrate that global myocardial in vivo gene delivery is possible and
that genetic manipulation of beta-AR density can result in enhanced cardiac performance.
Thus, replacement of lost receptors seen in HF may represent novel inotropic therapy.
Type
Journal articleSubject
AdenoviridaeAdrenergic beta-Agonists
Animals
Cardiac Catheterization
Cells, Cultured
Coronary Vessels
Gene Expression Regulation
Genetic Therapy
Genetic Vectors
Heart Failure
Heart Function Tests
Humans
Injections, Intra-Arterial
Isoproterenol
Male
Myocardium
Rabbits
Receptors, Adrenergic, beta-2
Signal Transduction
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https://hdl.handle.net/10161/5923Published Version (Please cite this version)
10.1172/JCI6026Publication Info
Maurice, JP; Hata, JA; Shah, AS; White, DC; McDonald, PH; Dolber, PC; ... Koch, WJ (1999). Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic
receptor gene delivery. J Clin Invest, 104(1). pp. 21-29. 10.1172/JCI6026. Retrieved from https://hdl.handle.net/10161/5923.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Donald D. Glower Jr.
Professor of Surgery
Current clinical research projects examine the effects of patient characteristics
and surgical technique in outcome after minimally invasive cardiac surgery, valve
repair and replacement, and coronary artery bypass grafting. Prior work has examined
the role of surgical therapy versus medical therapy in aortic dissection, load-independent
means to quantify left and right ventricular function, and management of complex coronary
disease.
Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his
early career as a cardiologist and his transition to biochemistry, which led to his
Nobel Prize win.
Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of
Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator
of the
David Cloid White
Associate Professor of Surgery
This author no longer has a Scholars@Duke profile, so the information shown here reflects
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