Document Detail


Cardiac overexpression of a G(q) inhibitor blocks induction of extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase activity in in vivo pressure overload.
MedLine Citation:
PMID:  11245652     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Understanding the cellular signals that initiate cardiac hypertrophy is of critical importance in identifying the pathways that mediate heart failure. The family of mitogen-activated protein kinases (MAPKs), including the extracellular signal-regulated kinases (ERKs), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPKs, may play specific roles in myocardial growth and function. METHODS AND RESULTS: To determine the mechanism of activation of MAPK pathways during the development of cardiac hypertrophy, we evaluated the induction of MAPK activity after aortic constriction in wild-type and in 2 types of cardiac gene-targeted mice: one overexpressing a carboxyl-terminal peptide of Galpha(q) that inhibits G(q)-mediated signaling (TG GqI mouse) and another overexpressing a carboxyl-terminal peptide of beta-adrenergic receptor kinase-1 that inhibits Gbetagamma signaling (TG betaARKct mouse). Wild-type mice with pressure overload showed an acute induction of JNK, followed by the induction of p38/p38beta at 3 days and ERK at 7 days. Both JNK and p38 activity remained elevated at 7 days after banding. In TG GqI mice, hypertrophy was significantly attenuated, and induction of ERK and JNK activity was abolished, whereas the induction of p38 and p38beta was robust, but delayed. By contrast, all 3 MAPK pathways were activated by aortic constriction in the TG betaARKct hearts, suggesting a role for Galpha(q), but not Gbetagamma. CONCLUSIONS: Taken together, these data show that the induction of ERK and JNK activity in in vivo pressure-overload hypertrophy is mediated through the stimulation of G(q)-coupled receptors and that non-G(q)-mediated pathways are recruited to activate p38 and p38beta.
Authors:
G Esposito; S V Prasad; A Rapacciuolo; L Mao; W J Koch; H A Rockman
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Circulation     Volume:  103     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2001 Mar 
Date Detail:
Created Date:  2001-03-14     Completed Date:  2001-05-24     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1453-8     Citation Subset:  IM    
Affiliation:
Department of Medicine and Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cardiomegaly / enzymology*,  metabolism
Disease Models, Animal
Enzyme Induction
GTP-Binding Protein alpha Subunits, Gq-G11
Heterotrimeric GTP-Binding Proteins / antagonists & inhibitors,  metabolism*
JNK Mitogen-Activated Protein Kinases
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitogen-Activated Protein Kinase 11
Mitogen-Activated Protein Kinases / biosynthesis*,  metabolism*
Myocardium / enzymology*
Peptides
Pressure
p38 Mitogen-Activated Protein Kinases
Grant Support
ID/Acronym/Agency:
HL-56687/HL/NHLBI NIH HHS; HL-61690/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Peptides; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinase 11; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 3.6.5.1/GTP-Binding Protein alpha Subunits, Gq-G11; EC 3.6.5.1/Heterotrimeric GTP-Binding Proteins

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