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Content Provider | World Health Organization (WHO)-Global Index Medicus |
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Author | Peppel, K. C. Skaer, C. A. Akhter, S. A. Lefkowitz, R. J. Koch, W. J. Kypson, A. P. Mcdonald, P. H. Glower, D. D. |
Description | Author Affiliation: Akhter SA ( Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.); |
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. |
ISSN | 00278424 |
e-ISSN | 10916490 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Issue Number | 22 |
Volume Number | 94 |
Language | English |
Publisher | National Academy of Sciences |
Publisher Date | 1997-12-01 |
Publisher Place | United States |
Access Restriction | Open |
Subject Keyword | Cyclic AMP-Dependent Protein Kinases Genetics Gene Transfer Techniques Heart Failure Physiopathology Heart Ventricles Receptors, Adrenergic, Beta Signal Transduction Adenoviridae Animals Cyclic AMP Metabolism Biosynthesis Disease Models, Animal Gene Expression Genetic Vectors Cytology Isoproterenol Pharmacology Rabbits Tachycardia Transgenes Beta-Adrenergic Receptor Kinases Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
Content Type | Text |
Resource Type | Article |
Subject | Multidisciplinary |
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