Document Detail


Wnt signaling is critical for maladaptive cardiac hypertrophy and accelerates myocardial remodeling.
MedLine Citation:
PMID:  20177000     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The evolutionary conserved Wnt signaling pathway regulates cardiogenesis. However, members of the Wnt pathway are also expressed in the adult heart. Although Wnt-signaling is quiescent under normal conditions, we noticed activation on pathological stress of the heart, such as chronic afterload increase. To examine the role of Wnt signaling on the postnatal heart, we modified the expression and function of the Wnt regulator dishevelled 1 (Dvl-1) both in transgenic mice with cardiac-specific overexpression of Dvl-1 (Dvl-1-Tg) and in cultured cardiac myocytes. Dvl-1-Tg mice (3 months) had severe cardiac hypertrophy (heart weight:body weight ratio: 5.2+/-0.3 mg/g wild-type [WT] versus 6.4+/-0.7 mg/g Dvl-1-Tg; P<0.01), an increase in cardiomyocyte size (86% increase in Dvl-1-Tg compared with WT; P<0.01) and marked raise of atrial natriuretic factor expression (12-fold increase versus WT; P<0.01). Hypertrophy was associated with left ventricular dilatation in Dvl-1-Tg and a reduction of ejection fraction (4.4+/-0.1 mm versus 5.5+/-0.2 mm, 80+/-2% and 43+/-4% in WT versus Dvl-1-Tg, respectively; P<0.01). Transgenic animals died prematurely before 6 months of age. Both canonical as well as noncanonical Wnt signaling branches were activated in the Dvl-1-Tg animals. Small interfering RNA-mediated depletion of Dvl-1 was used to further characterize the role of Dvl-1 in cardiac myocytes. Whereas baseline parameters were unaltered, beta-adrenergic hypertrophic response was abrogated in Dvl-1 knockdown cardiac myocytes, indicating a mandatory role in beta-adrenergic stimulation. Therefore, activation of Wnt signaling is sufficient and critical for the induction of myocardial hypertrophy and cardiomyopathy.
Authors:
Pratima Malekar; Marco Hagenmueller; Adamma Anyanwu; Sebastian Buss; Marcus R Streit; Celine S Weiss; David Wolf; Johannes Riffel; Alexander Bauer; Hugo A Katus; Stefan E Hardt
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-02-22
Journal Detail:
Title:  Hypertension     Volume:  55     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-03-18     Completed Date:  2010-04-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  939-45     Citation Subset:  IM    
Affiliation:
Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / genetics,  metabolism*
Analysis of Variance
Animals
Apoptosis / genetics
Blotting, Western
Cardiomegaly / genetics,  metabolism*,  pathology
Cells, Cultured
Echocardiography
Heart / physiopathology
Heart Failure / genetics,  metabolism*,  pathology
Mice
Mice, Transgenic
Myocardial Contraction / genetics
Myocardium / metabolism,  pathology
Myocytes, Cardiac / metabolism,  pathology
Phosphoproteins / genetics,  metabolism*
Signal Transduction / physiology
Ventricular Remodeling / physiology*
Wnt Proteins / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Phosphoproteins; 0/Wnt Proteins; 0/dishevelled proteins
Comments/Corrections
Comment In:
Hypertension. 2010 Apr;55(4):852-4   [PMID:  20176999 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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