Document Detail


Transgenic Galphaq overexpression induces cardiac contractile failure in mice.
MedLine Citation:
PMID:  9223325     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The critical cell signals that trigger cardiac hypertrophy and regulate the transition to heart failure are not known. To determine the role of Galphaq-mediated signaling pathways in these events, transgenic mice were constructed that overexpressed wild-type Galphaq in the heart using the alpha-myosin heavy chain promoter. Two-fold overexpression of Galphaq showed no detectable effects, whereas 4-fold overexpression resulted in increased heart weight and myocyte size along with marked increases in atrial naturietic factor ( approximately 55-fold), beta-myosin heavy chain ( approximately 8-fold), and alpha-skeletal actin ( approximately 8-fold) expression, and decreased ( approximately 3-fold) beta-adrenergic receptor-stimulated adenylyl cyclase activity. All of these signals have been considered markers of hypertrophy or failure in other experimental systems or human heart failure. Echocardiography and in vivo cardiac hemodynamic studies indeed revealed impaired intrinsic contractility manifested as decreased fractional shortening (19 +/- 2% vs. 41 +/- 3%), dP/dt max, a negative force-frequency response, an altered Starling relationship, and blunted contractile responses to the beta-adrenergic agonist dobutamine. At higher levels of Galphaq overexpression, frank cardiac decompensation occurred in 3 of 6 animals with development of biventricular failure, pulmonary congestion, and death. The element within the pathway that appeared to be critical for these events was activation of protein kinase Cepsilon. Interestingly, mitogen-activated protein kinase, which is postulated by some to be important in the hypertrophy program, was not activated. The Galphaq overexpressor exhibits a biochemical and physiologic phenotype resembling both the compensated and decompensated phases of human cardiac hypertrophy and suggests a common mechanism for their pathogenesis.
Authors:
D D D'Angelo; Y Sakata; J N Lorenz; G P Boivin; R A Walsh; S B Liggett; G W Dorn
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; 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:  94     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  1997 Jul 
Date Detail:
Created Date:  1997-08-27     Completed Date:  1997-08-27     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  8121-6     Citation Subset:  IM    
Affiliation:
University of Cincinnati, 231 Bethesda Avenue, Cincinnati, OH 45267-0542, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Body Weight
Cardiomyopathy, Dilated / genetics*,  pathology
Female
Founder Effect
GTP-Binding Proteins / genetics*
Gene Expression
Male
Mice
Mice, Transgenic
Myocardial Contraction / genetics*
Organ Size
Grant Support
ID/Acronym/Agency:
HL41496/HL/NHLBI NIH HHS; HL45967/HL/NHLBI NIH HHS; HL49267/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
EC 3.6.1.-/GTP-Binding Proteins
Comments/Corrections

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


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