title: G(13)-mediated signaling pathway is required for pressure overload-induced cardiac remodeling and heart failure.
abstract: 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 and endothelin-1, which in turn promote cardiac hypertrophy and fibrosis. A large body of evidence suggests that the prohypertrophic 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 of G(12/13) in cardiac remodeling is not understood.
  
  
  RESULTS
  We use siRNA-mediated knockdown in vitro and conditional gene inactivation in vivo to study  the role of the G(12/13) family in pressure overload-induced cardiac remodeling. We show in detail 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 as efficiently as inactivation of Gα(q/11). Furthermore, inactivation of Gα(13) prevents the development of heart failure up to 1 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.
  
  
  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.
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Mikito
authors.initials: M
authors.lastname: Takefuji
authors.forename: Angela
authors.initials: A
authors.lastname: Wirth
authors.forename: Martina
authors.initials: M
authors.lastname: Lukasova
authors.forename: Seiko
authors.initials: S
authors.lastname: Takefuji
authors.forename: Thomas
authors.initials: T
authors.lastname: Boettger
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Till
authors.initials: T
authors.lastname: Althoff
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004719:Endomyocardial Fibrosis / Q000378:metabolism / Q000473:pathology; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016296:Mutagenesis / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D017725:Ventricular Pressure / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C511173:Mrtfa protein, mouse; D034741:RNA, Small Interfering; D015534:Trans-Activators; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020742:rhoA GTP-Binding Protein