{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:51:33Z","timestamp":1791312693956,"version":"4.3.1"},"reference-count":31,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,4,8]]},"abstract":"<jats:p>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 \u03b21 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\u2013induced heart failure.<\/jats:p>","DOI":"10.1084\/jem.20122126","type":"journal-article","created":{"date-parts":[[2013,3,25]],"date-time":"2013-03-25T23:28:39Z","timestamp":1364254119000},"page":"665-673","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["RhoGEF12 controls cardiac remodeling by integrating G protein\u2013 and integrin-dependent signaling cascades"],"prefix":"10.1084","volume":"210","author":[{"given":"Mikito","family":"Takefuji","sequence":"first","affiliation":[{"name":"Department of Pharmacology 1 and 2"},{"name":"Biomolecular Mass Spectrometry Group, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany 1 and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Kr\u00fcger","sequence":"additional","affiliation":[{"name":"Department of Pharmacology 1 and 2"},{"name":"Biomolecular Mass Spectrometry Group, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany 1 and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kishor K.","family":"Sivaraj","sequence":"additional","affiliation":[{"name":"Department of Pharmacology 1 and 2"},{"name":"Biomolecular Mass Spectrometry Group, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany 1 and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kozo","family":"Kaibuchi","sequence":"additional","affiliation":[{"name":"Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa, Nagoya, AICHI 466-8550, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Offermanns","sequence":"additional","affiliation":[{"name":"Department of Pharmacology 1 and 2"},{"name":"Biomolecular Mass Spectrometry Group, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany 1 and 2"},{"name":"Medical Faculty, Johann Wolfgang Goethe University Frankfurt, 60590 Frankfurt, Germany 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Wettschureck","sequence":"additional","affiliation":[{"name":"Department of Pharmacology 1 and 2"},{"name":"Biomolecular Mass Spectrometry Group, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany 1 and 2"},{"name":"Medical Faculty, Johann Wolfgang Goethe University Frankfurt, 60590 Frankfurt, Germany 4"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2013,3,25]]},"reference":[{"key":"2023072601320246500_bib1","doi-asserted-by":"publisher","first-page":"4053","DOI":"10.1128\/MCB.22.12.4053-4061.2002","article-title":"Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA","volume":"22","author":"Booden","year":"2002","journal-title":"Mol. 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