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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 2

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β-AR overexpression in rabbit hearts after intracoronary delivery of Ade...
β-AR overexpression in rabbit hearts after intracoronary delivery of Adeno-β2AR. (a) Total β-AR density in different chambers of rabbit myocardium 6 days after 1 × 1012 tvp of Adeno-β2AR was delivered via intracoronary perfusion. β-AR density after Adeno-β2AR treatment is compared with rabbit hearts that received the same dose of the EV. (b) Representative immunohistochemical detection of expressed human β2-ARs in rabbit LV 6 days after intracoronary delivery of Adeno-β2AR. (c) Dose-dependent myocardial β2-AR overexpression after delivery of increasing doses of Adeno-β2AR. Total β-AR density is shown in the RV and LV compared with myocardial β-AR density after delivery of EV, which did not change from endogenous β-AR levels. (d) Time course of β-AR overexpression in rabbit hearts after delivery of 5 × 1011 tvp Adeno-β2AR. All binding values represent the mean ± SEM.

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

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Referenced in 9 patents
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