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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2014     Display Documents



ID: 682141.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2014
RhoGEF12 controls cardiac remodeling by integrating G protein- and integrin-dependent signaling cascades
Authors:Takefuji, M.; Kruger, M.; Sivaraj, K. K.; Kaibuchi, K.; Offermanns, S.; Wettschureck, N.
Date of Publication (YYYY-MM-DD):2013-04-08
Journal Abbrev.:J Exp Med
Volume:210
Issue / Number:4
Start Page:665
End Page:673
Audience:Not Specified
Abstract / Description:Structural cardiac remodeling, including hypertrophy and fibrosis, plays a crucial role in the pathogenesis of heart failure. In vitro studies suggested a role of the small GTPase RhoA in hypertrophic cardiomyocyte growth, but neither the molecular mechanisms leading to RhoA activation nor their relevance in vivo are known. We use here a mass spectrometric approach to identify Rho guanine nucleotide exchange factors (RhoGEFs) activated during cardiac pressure overload in vivo and show that RhoGEF12 is a central player during cardiac remodeling. We show that RhoGEF12 is required for stretch-induced RhoA activation and hypertrophic gene transcription in vitro and that its activation depends on integrin beta1 and heterotrimeric G proteins of the G12/13 family. In vivo, cardiomyocyte-specific deletion of RhoGEF12 protects mice from overload-induced hypertrophy, fibrosis, and development of heart failure. Importantly, in mice with preexisting hypertrophy, induction of RhoGEF12 deficiency protects from cardiac decompensation, resulting in significantly increased long-term survival. Collectively, RhoGEF12 acts as an integrator of stretch-induced signaling cascades in cardiomyocytes and is an interesting new target for therapeutic intervention in patients with pressure overload-induced heart failure.
Free Keywords:Animals; Cardiomegaly/genetics/metabolism/pathology; Cells, Cultured; Fibrosis; GTP-Binding Protein alpha Subunits, G12-G13/genetics/*metabolism; Guanine Nucleotide Exchange Factors/genetics/*metabolism; Heart Failure/genetics/metabolism/pathology; Integrins/genetics/*metabolism; Mice; Mice, Knockout; Muscle Proteins/genetics/*metabolism; Myocardium/*metabolism/pathology; Myocytes, Cardiac/*metabolism; Rho Guanine Nucleotide Exchange Factors; *Signal Transduction
External Publication Status:published
Document Type:Article
Communicated by:Svea Hümmer
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:ISSN:1540-9538 (Electronic) 0022-1007 (Linking) %R 10.1084/jem.20122126
URL:http://www.ncbi.nlm.nih.gov/pubmed/23530122
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