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.
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
Title and authors | Publication | Year |
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Gastrointestinal Pharmacology
BG Meerveld |
2016 | |
Gastrointestinal Pharmacology
BG Meerveld |
2016 | |
Gastrointestinal Pharmacology
BG Meerveld |
2016 | |
Gastrointestinal Pharmacology
BG Meerveld |
2016 | |
Gastrointestinal Pharmacology
BG Meerveld |
2016 | |
Gastrointestinal Pharmacology
BG Meerveld |
2016 | |
Gastrointestinal Pharmacology
BG Meerveld |
2016 | |
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Prospects for Gene Therapy for Heart Failure
RJ Hajjar, F del Monte, T Matsui, A Rosenzweig |
Circulation research | 2000 |
Intracoronary Adenovirus-Mediated Delivery and Overexpression of the β 2 -Adrenergic Receptor in the Heart: Prospects for Molecular Ventricular Assistance
AS Shah, RE Lilly, AP Kypson, O Tai, JA Hata, A Pippen, SC Silvestry, RJ Lefkowitz, DD Glower, WJ Koch |
Circulation | 2000 |
Molecular Approaches to Heart Failure Therapy
G Hasenfuss, E Marbán |
2000 | |
Spontaneous Activation of β 2 - but Not β 1 -Adrenoceptors Expressed in Cardiac Myocytes from β 1 β 2 Double Knockout Mice
YY Zhou, D Yang, WZ Zhu, SJ Zhang, DJ Wang, DK Rohrer, E Devic, BK Kobilka, EG Lakatta, H Cheng, RP Xiao |
Molecular pharmacology | 2000 |
Catecholamines, Cardiac β-Adrenergic Receptors, and Heart Failure
RJ Lefkowitz, HA Rockman, WJ Koch |
Circulation | 2000 |
Molecular Inotropy: A Future Approach to the Treatment of Heart Failure?
WH Barry |
Circulation | 1999 |