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

Academic Article
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Overview

authors

  • Akhter, S. A.
  • Skaer, C. A.
  • Kypson, A. P.
  • McDonald, Patricia
  • Peppel, K. C.
  • Glower, D. D.
  • Lefkowitz, R. J.
  • Koch, W. J.

publication date

  • October 1997

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • 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.

subject areas

  • Adenoviridae
  • Animals
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Disease Models, Animal
  • Gene Expression
  • Gene Transfer Techniques
  • Genetic Vectors
  • Heart Failure
  • Heart Ventricles
  • Isoproterenol
  • Male
  • Rabbits
  • Receptors, Adrenergic, beta
  • Signal Transduction
  • Tachycardia
  • Transgenes
  • beta-Adrenergic Receptor Kinases
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Identity

PubMed Central ID

  • PMC23716

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.94.22.12100

PubMed ID

  • 9342369
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Additional Document Info

start page

  • 12100

end page

  • 12105

volume

  • 94

issue

  • 22

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