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Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery.

Publication ,  Journal Article
Maurice, JP; Hata, JA; Shah, AS; White, DC; McDonald, PH; Dolber, PC; Wilson, KH; Lefkowitz, RJ; Glower, DD; Koch, WJ
Published in: J Clin Invest
July 1999

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.

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Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

July 1999

Volume

104

Issue

1

Start / End Page

21 / 29

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, Adrenergic, beta-2
  • Rabbits
  • Myocardium
  • Male
  • Isoproterenol
  • Injections, Intra-Arterial
  • Immunology
  • Humans
  • Heart Function Tests
 

Citation

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Maurice, J. P., Hata, J. A., Shah, A. S., White, D. C., McDonald, P. H., Dolber, P. C., … Koch, W. J. (1999). Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery. J Clin Invest, 104(1), 21–29. https://doi.org/10.1172/JCI6026
Maurice, J. P., J. A. Hata, A. S. Shah, D. C. White, P. H. McDonald, P. C. Dolber, K. H. Wilson, R. J. Lefkowitz, D. D. Glower, and W. J. Koch. “Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery.J Clin Invest 104, no. 1 (July 1999): 21–29. https://doi.org/10.1172/JCI6026.
Maurice JP, Hata JA, Shah AS, White DC, McDonald PH, Dolber PC, et al. Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery. J Clin Invest. 1999 Jul;104(1):21–9.
Maurice, J. P., et al. “Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery.J Clin Invest, vol. 104, no. 1, July 1999, pp. 21–29. Pubmed, doi:10.1172/JCI6026.
Maurice JP, Hata JA, Shah AS, White DC, McDonald PH, Dolber PC, Wilson KH, Lefkowitz RJ, Glower DD, Koch WJ. Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery. J Clin Invest. 1999 Jul;104(1):21–29.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

July 1999

Volume

104

Issue

1

Start / End Page

21 / 29

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, Adrenergic, beta-2
  • Rabbits
  • Myocardium
  • Male
  • Isoproterenol
  • Injections, Intra-Arterial
  • Immunology
  • Humans
  • Heart Function Tests