| Preservation of myocardial beta-adrenergic receptor signaling delays the development of heart failure after myocardial infarction. | |
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MedLine Citation:
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PMID: 10779554 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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When the heart fails, there is often a constellation of biochemical alterations of the beta-adrenergic receptor (betaAR) signaling system, leading to the loss of cardiac inotropic reserve. betaAR down-regulation and functional uncoupling are mediated through enhanced activity of the betaAR kinase (betaARK1), the expression of which is increased in ischemic and failing myocardium. These changes are widely viewed as representing an adaptive mechanism, which protects the heart against chronic activation. In this study, we demonstrate, using in vivo intracoronary adenoviral-mediated gene delivery of a peptide inhibitor of betaARK1 (betaARKct), that the desensitization and down-regulation of betaARs seen in the failing heart may actually be maladaptive. In a rabbit model of heart failure induced by myocardial infarction, which recapitulates the biochemical betaAR abnormalities seen in human heart failure, delivery of the betaARKct transgene at the time of myocardial infarction prevents the rise in betaARK1 activity and expression and thereby maintains betaAR density and signaling at normal levels. Rather than leading to deleterious effects, cardiac function is improved, and the development of heart failure is delayed. These results appear to challenge the notion that dampening of betaAR signaling in the failing heart is protective, and they may lead to novel therapeutic strategies to treat heart disease via inhibition of betaARK1 and preservation of myocardial betaAR function. |
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Authors:
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D C White; J A Hata; A S Shah; D D Glower; R J Lefkowitz; W J Koch |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 97 ISSN: 0027-8424 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2000 May |
Date Detail:
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Created Date: 2000-06-13 Completed Date: 2000-06-13 Revised Date: 2013-04-17 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 5428-33 Citation Subset: IM |
Affiliation:
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Department of Surgery, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenoviridae Adenylate Cyclase / metabolism Animals Animals, Genetically Modified Blood Pressure Cell Membrane / enzymology Cyclic AMP-Dependent Protein Kinases / genetics*, metabolism Gene Transfer Techniques Genetic Therapy* Genetic Vectors Heart Failure / prevention & control* Heart Rate Hemodynamics* Humans Male Myocardial Infarction / complications, physiopathology* Myocardium / metabolism Rabbits Receptors, Adrenergic, beta / physiology* Signal Transduction Ventricular Function, Left beta-Adrenergic Receptor Kinases |
| Grant Support | |
ID/Acronym/Agency:
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HL-16037/HL/NHLBI NIH HHS; HL-56205/HL/NHLBI NIH HHS; HL-59533/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Adrenergic, beta; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 2.7.11.15/beta-Adrenergic Receptor Kinases; EC 4.6.1.1/Adenylate Cyclase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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