| First Author | Takefuji M | Year | 2013 |
| Journal | J Exp Med | Volume | 210 |
| Issue | 4 | Pages | 665-73 |
| PubMed ID | 23530122 | Mgi Jnum | J:198220 |
| Mgi Id | MGI:5495871 | Doi | 10.1084/jem.20122126 |
| Citation | Takefuji M, et al. (2013) RhoGEF12 controls cardiac remodeling by integrating G protein- and integrin-dependent signaling cascades. J Exp Med 210(4):665-73 |
| abstractText | 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. |
