Document Detail


IQGAP1 regulates ERK1/2 and AKT signalling in the heart and sustains functional remodelling upon pressure overload.
MedLine Citation:
PMID:  21493702     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: The Raf-MEK1/2-ERK1/2 (ERK1/2-extracellular signal-regulated kinases 1/2) signalling cascade is crucial in triggering cardiac responses to different stress stimuli. Scaffold proteins are key elements in coordinating signalling molecules for their appropriate spatiotemporal activation. Here, we investigated the role of IQ motif-containing GTPase-activating protein 1 (IQGAP1), a scaffold for the ERK1/2 cascade, in heart function and remodelling in response to pressure overload.
METHODS AND RESULTS: IQGAP1-null mice have unaltered basal heart function. When subjected to pressure overload, IQGAP1-null mice initially develop a compensatory hypertrophy indistinguishable from that of wild-type (WT) mice. However, upon a prolonged stimulus, the hypertrophic response develops towards a thinning of left ventricular walls, chamber dilation, and a decrease in contractility, in an accelerated fashion compared with WT mice. This unfavourable cardiac remodelling is characterized by blunted reactivation of the foetal gene programme, impaired cardiomyocyte hypertrophy, and increased cardiomyocyte apoptosis. Analysis of signalling pathways revealed two temporally distinct waves of both ERK1/2 and AKT phosphorylation peaking, respectively, at 10 min and 4 days after aortic banding in WT hearts. IQGAP1-null mice show strongly impaired phosphorylation of MEK1/2-ERK1/2 and AKT following 4 days of pressure overload, but normal activation of these kinases after 10 min. Pull-down experiments indicated that IQGAP1 is able to bind the three components of the ERK cascade, namely c-Raf, MEK1/2, and ERK1/2, as well as AKT in the heart.
CONCLUSION: These data demonstrate, for the first time, a key role for the scaffold protein IQGAP1 in integrating hypertrophy and survival signals in the heart and regulating long-term left ventricle remodelling upon pressure overload.
Authors:
Mauro Sbroggiò; Daniela Carnevale; Alessandro Bertero; Giuseppe Cifelli; Emanuele De Blasio; Giada Mascio; Emilio Hirsch; Wadie F Bahou; Emilia Turco; Lorenzo Silengo; Mara Brancaccio; Giuseppe Lembo; Guido Tarone
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-04-14
Journal Detail:
Title:  Cardiovascular research     Volume:  91     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-20     Completed Date:  2011-11-23     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  456-64     Citation Subset:  IM    
Affiliation:
Dipartimento di Genetica, Biologia e Biochimica, Molecular Biotechnology Center, Università di Torino, via Nizza 52, Turin, Italy.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aorta / physiopathology,  surgery
Apoptosis
Blood Pressure*
Cells, Cultured
Disease Models, Animal
Hypertension / complications*,  enzymology,  genetics,  physiopathology
Hypertrophy, Left Ventricular / enzymology*,  genetics,  physiopathology,  ultrasonography
Ligation
MAP Kinase Kinase 1 / metabolism
MAP Kinase Kinase 2 / metabolism
Male
Mice
Mice, 129 Strain
Mice, Knockout
Mitogen-Activated Protein Kinase 1 / metabolism*
Mitogen-Activated Protein Kinase 3 / metabolism*
Myocardium / enzymology*,  pathology
Proto-Oncogene Proteins c-akt / metabolism*
Proto-Oncogene Proteins c-raf / metabolism
Signal Transduction*
Time Factors
Ventricular Remodeling*
ras GTPase-Activating Proteins / deficiency,  genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
R01 HL091939-04/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/IQ motif containing GTPase activating protein 1; 0/ras GTPase-Activating Proteins; EC 2.7.1.-/Map2k1 protein, mouse; EC 2.7.1.-/Map2k2 protein, mouse; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/Proto-Oncogene Proteins c-raf; EC 2.7.11.24/Mapk1 protein, mouse; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 2.7.12.2/MAP Kinase Kinase 1; EC 2.7.12.2/MAP Kinase Kinase 2
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