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Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary β2-adrenergic receptor gene delivery
John P. Maurice, … , Donald D. Glower, Walter J. Koch
John P. Maurice, … , Donald D. Glower, Walter J. Koch
Published July 1, 1999
Citation Information: J Clin Invest. 1999;104(1):21-29. https://doi.org/10.1172/JCI6026.
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Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary β2-adrenergic receptor gene delivery

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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 β-adrenergic receptor (β-AR) system, which is impaired in HF, can enhance cardiac function. We have delivered adenoviral transgenes, including the human β2-AR (Adeno-β2AR), to the myocardium of rabbits using an intracoronary approach. Catheter-mediated Adeno-β2AR delivery produced diffuse multichamber myocardial expression, peaking 1 week after gene transfer. A total of 5 × 1011 viral particles of Adeno-β2AR reproducibly produced 5- to 10-fold β-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 β-agonist isoproterenol. Our results demonstrate that global myocardial in vivo gene delivery is possible and that genetic manipulation of β-AR density can result in enhanced cardiac performance. Thus, replacement of lost receptors seen in HF may represent novel inotropic therapy.

Authors

John P. Maurice, Jonathan A. Hata, Ashish S. Shah, David C. White, Patricia H. McDonald, Paul C. Dolber, Katrina H. Wilson, Robert J. Lefkowitz, Donald D. Glower, Walter J. Koch

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Figure 6

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In vivo assessment of LV contractile function (LV +dP/dtmax) in rabbits ...
In vivo assessment of LV contractile function (LV +dP/dtmax) in rabbits 21 days after treatment with Adeno-β2AR. Cardiac catheterization was performed in conscious sedated rabbits after intracoronary delivery (1.5 mL in PBS) of either 5 × 1011 tvp Adeno-β2AR (n = 9) or EV (n = 5) using a high-fidelity micromanometer. Shown are the baseline values (mean ± SEM) and responses to progressive doses of isoproterenol. *P < 0.05 vs. EV (Student’s t test). Total β-AR density after Adeno-β2AR treatment was 115 ± 12 fmol/mg membrane protein vs. 79 ± 7 in hearts that received the same dose of EV (P < 0.05, Student’s t test).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 9 patents
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