Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary β2-adrenergic receptor gene delivery

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

    Research output: Contribution to journalArticle

    184 Scopus citations

    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 x 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/dt(max) 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.

    Original languageEnglish (US)
    Pages (from-to)21-29
    Number of pages9
    JournalJournal of Clinical Investigation
    Volume104
    Issue number1
    DOIs
    StatePublished - Jul 1999

    ASJC Scopus subject areas

    • Medicine(all)

    Fingerprint Dive into the research topics of 'Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary β<sub>2</sub>-adrenergic receptor gene delivery'. Together they form a unique fingerprint.

  • Cite this

    Maurice, J. P., Hata, J. A., Shah, A. S., White, D. C., McDonald, P. H., Dolber, P. C., Wilson, K. H., Lefkowitz, R. J., Glower, D. D., & Koch, W. J. (1999). Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary β2-adrenergic receptor gene delivery. Journal of Clinical Investigation, 104(1), 21-29. https://doi.org/10.1172/JCI6026