Document Detail

Regulation of myocardial betaARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing alpha1B-adrenergic receptors.
MedLine Citation:
PMID:  11499749     Owner:  NLM     Status:  MEDLINE    
OBJECTIVES: Using a transgenic mouse model of myocardial-targeted overexpression of the wild-type alpha1B adrenergic receptor (AR) (Tg alpha43), we studied the role of the betaAR kinase (betaARK1) in the evolution of myocardial hypertrophy and its transition to heart failure (HF). BACKGROUND: Increased myocardial expression of betaARK1 has been shown to be associated with HF and certain models of hypertrophy. METHODS: Tg alpha43 mice and their nontransgenic littermate controls were treated with the alpha1AR agonist phenylephrine (PE) for 3, 7 or 14 days to characterize the cardiac consequences. RESULTS: Nontransgenic littermate control mice treated for 14 days with PE display cardiac hypertrophy with no increase in betaARK1 expression. However, Tg alpha43 animals show a reduced tolerance to 14-day PE treatment, demonstrated by reduced survival and severe cardiac hypertrophy. Moreover, PE treatment for three and seven days in Tg alpha43 mice resulted in an exaggerated hypertrophic response accompanied by significant cardiac biochemical abnormalities that are normally associated with HF, including fetal gene expression, reduced betaAR density and enhanced betaARK1 expression. We also found reduced myocardial stores of the sympathetic neurotransmitter neuropeptide Y. CONCLUSIONS: These data suggest that PE-treated Tg alpha43 mice have chronic activation of the cardiac sympathetic nervous system, which may be responsible for the appearance of apparent maladaptive hypertrophy with an evolution towards HF and sudden death. Thus, the cardiac phenotypes found in these mice are not the direct result of enhanced alpha1B AR signaling and suggest that betaARK1 is a key molecule in the transition of myocardial hypertrophy to HF.
G Iaccarino; J R Keys; A Rapacciuolo; K F Shotwell; R J Lefkowitz; H A Rockman; 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:  Journal of the American College of Cardiology     Volume:  38     ISSN:  0735-1097     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2001 Aug 
Date Detail:
Created Date:  2001-08-13     Completed Date:  2001-10-04     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  534-40     Citation Subset:  AIM; IM    
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
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MeSH Terms
Adrenergic alpha-Agonists
Body Weight
Cardiomegaly / chemically induced,  complications,  enzymology*
Cardiomyopathy, Dilated / etiology*
Cyclic AMP-Dependent Protein Kinases / metabolism*
Mice, Transgenic
Muscle Proteins / biosynthesis,  genetics
Myocardium / enzymology*,  pathology
Neuropeptide Y / metabolism
Organ Size
RNA, Messenger / biosynthesis
Receptors, Adrenergic, alpha-1 / genetics*,  metabolism
Receptors, Adrenergic, beta / metabolism
Signal Transduction
beta-Adrenergic Receptor Kinases
Grant Support
Reg. No./Substance:
0/Adrenergic alpha-Agonists; 0/Muscle Proteins; 0/Neuropeptide Y; 0/RNA, Messenger; 0/Receptors, Adrenergic, alpha-1; 0/Receptors, Adrenergic, beta; 0/adrenergic receptor alpha(1a); 0/adrenergic receptor alpha(1b); 59-42-7/Phenylephrine; EC AMP-Dependent Protein Kinases; EC Receptor Kinases
Comment In:
J Am Coll Cardiol. 2001 Aug;38(2):541-5   [PMID:  11499750 ]

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