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Restoration of beta-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer.

Publication ,  Journal Article
Akhter, SA; Skaer, CA; Kypson, AP; McDonald, PH; Peppel, KC; Glower, DD; Lefkowitz, RJ; Koch, WJ
Published in: Proc Natl Acad Sci U S A
October 28, 1997

Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing cellular proteins that may improve cardiac performance. Our laboratory has been focusing on the feasibility of restoring beta-adrenergic signaling deficiencies that are a characteristic of chronic CHF. We have now studied isolated ventricular myocytes from rabbits that have been chronically paced to produce hemodynamic failure. We document molecular beta-adrenergic signaling defects including down-regulation of myocardial beta-adrenergic receptors (beta-ARs), functional beta-AR uncoupling, and an up-regulation of the beta-AR kinase (betaARK1). Adenoviral-mediated gene transfer of the human beta2-AR or an inhibitor of betaARK1 to these failing myocytes led to the restoration of beta-AR signaling. These results demonstrate that defects present in this critical myocardial signaling pathway can be corrected in vitro using genetic modification and raise the possibility of novel inotropic therapies for CHF including the inhibition of betaARK1 activity in the heart.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

October 28, 1997

Volume

94

Issue

22

Start / End Page

12100 / 12105

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Transgenes
  • Tachycardia
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Rabbits
  • Male
  • Isoproterenol
  • Heart Ventricles
  • Heart Failure
 

Citation

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Akhter, S. A., Skaer, C. A., Kypson, A. P., McDonald, P. H., Peppel, K. C., Glower, D. D., … Koch, W. J. (1997). Restoration of beta-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer. Proc Natl Acad Sci U S A, 94(22), 12100–12105. https://doi.org/10.1073/pnas.94.22.12100
Akhter, S. A., C. A. Skaer, A. P. Kypson, P. H. McDonald, K. C. Peppel, D. D. Glower, R. J. Lefkowitz, and W. J. Koch. “Restoration of beta-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer.Proc Natl Acad Sci U S A 94, no. 22 (October 28, 1997): 12100–105. https://doi.org/10.1073/pnas.94.22.12100.
Akhter SA, Skaer CA, Kypson AP, McDonald PH, Peppel KC, Glower DD, et al. Restoration of beta-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12100–5.
Akhter, S. A., et al. “Restoration of beta-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer.Proc Natl Acad Sci U S A, vol. 94, no. 22, Oct. 1997, pp. 12100–05. Pubmed, doi:10.1073/pnas.94.22.12100.
Akhter SA, Skaer CA, Kypson AP, McDonald PH, Peppel KC, Glower DD, Lefkowitz RJ, Koch WJ. Restoration of beta-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12100–12105.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

October 28, 1997

Volume

94

Issue

22

Start / End Page

12100 / 12105

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Transgenes
  • Tachycardia
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Rabbits
  • Male
  • Isoproterenol
  • Heart Ventricles
  • Heart Failure