Document Detail

A G13-Mediated Signaling Pathway is Required for Pressure Overload-Induced Cardiac Remodeling and Heart Failure.
MedLine Citation:
PMID:  22972902     Owner:  NLM     Status:  Publisher    
BACKGROUND: Cardiac remodeling in response to pressure or volume overload plays an important role in the pathogenesis of heart failure. Various mechanisms have been suggested to translate mechanical stress into structural changes, one of them being the release of humoral factors such as angiotensin II or endothelin-1, which in turn promote cardiac hypertrophy and fibrosis. A large body of evidence suggests that the pro-hypertrophic effects of these factors are mediated by receptors coupled to the G(q/11) family of heterotrimeric G-proteins. Most G(q/11)-coupled receptors, however, can also activate G-proteins of the G(12/13) family, but the role G(12/13) in cardiac remodeling is not understood. METHODS AND RESULTS: We use in this study siRNA-mediated knockdown in vitro as well as conditional gene inactivation in vivo to study the role of the G(12/13) family in pressure overload-induced cardiac remodeling. In detail, we show that inducible, cardiomyocyte-specific inactivation of the α-subunit of G(13), Gα(13), does not affect basal heart function, but protects mice from pressure overload-induced hypertrophy and fibrosis equally efficient as inactivation of Gα(q/11). Furthermore, inactivation of Gα(13) prevents development of heart failure up to one year after overloading. On the molecular level we show that Gα(13), but not Gα(q/11), controls agonist-induced expression of hypertrophy-specific genes through activation of the small GTPase RhoA and consecutive activation of myocardin-related transcription factors (MRTF). CONCLUSIONS: Our data show that the G(12/13) family of heterotrimeric G-proteins is centrally involved in pressure overload-induced cardiac remodeling and plays a central role in the transition to heart failure.
Mikito Takefuji; Angela Wirth; Martina Lukasova; Seiko Takefuji; Thomas Boettger; Thomas Braun; Till Althoff; Stefan Offermanns; Nina Wettschureck
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-12
Journal Detail:
Title:  Circulation     Volume:  -     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-9-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
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