Document Detail


Preservation of myocardial beta-adrenergic receptor signaling delays the development of heart failure after myocardial infarction.
MedLine Citation:
PMID:  10779554     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
D C White; J A Hata; A S Shah; D D Glower; R J Lefkowitz; W J Koch
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
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:
Created Date:  2000-06-13     Completed Date:  2000-06-13     Revised Date:  2013-04-17    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  5428-33     Citation Subset:  IM    
Affiliation:
Department of Surgery, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
HL-16037/HL/NHLBI NIH HHS; HL-56205/HL/NHLBI NIH HHS; HL-59533/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
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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