RhoGEF12 controls cardiac remodeling by integrating G protein- and integrindependent signaling cascades

Mikito Takefuji, Marcus Krüger, Kishor K. Sivaraj, Kozo Kaibuchi, Stefan Offermanns, Nina Wettschureck

研究成果: Article査読

17 被引用数 (Scopus)


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 β1 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 longterm 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.

ジャーナルJournal of Experimental Medicine
出版ステータスPublished - 2013

All Science Journal Classification (ASJC) codes

  • 免疫アレルギー学
  • 免疫学


「RhoGEF12 controls cardiac remodeling by integrating G protein- and integrindependent signaling cascades」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。