The role of RHOA-mediated signaling in heart failure

[Speaker] Mikito Takefuji:1
[Co-author] Stefan Offermanns:2, Kozo Kaibuchi:3, Toyoaki Murohara:1
1:Department of Cardiology, Nagoya University School of Medicine, Japan, 2:Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Germany, 3:Department of Cell Pharmacology, Nagoya University School of Medicine, Japan

 Heart failure is a severe disease in which the heart is unable to pump blood and maintain tissue perfusion. Although therapies in cardiovascular diseases such as hypertension and myocardial infarction have been developed in the last 20 years, heart failure remains a major clinical health problem with significant mortality and morbidity.
 Structural cardiac remodeling, including hypertrophy and fibrosis, plays a crucial role in the pathogenesis of heart failure. Various mechanisms have been suggested to translate mechanical stress into structural changes including the release of humoral factors such as angiotensin II and endothelin-1, which induce cardiac hypertrophy through activation of receptors coupled to the Gq/11 family of heterotrimeric G proteins. Although it is known that most Gq/11-coupled receptors can also activate G proteins of the G12/13 family, the role of G12/13 in cardiac remodeling is not understood. We have previously shown that inducible, cardiomyocyte-specific inactivation of the alpha subunit of G12/13 does not affect basal heart function but protects mice from pressure overload-induced hypertrophy and fibrosis. We also demonstrated that G12/13 controls agonist-induced expression of hypertrophy-specific genes through activation of the small GTPase RHOA. Furthermore, we identified Rho guanine nucleotide exchange factors (RhoGEFs) activated during cardiac pressure overload in vivo and show that RhoGEF12 is required for stretch-induced, G12/13-dependent RhoA activation and hypertrophic gene transcription. In addition, we showed that cardiomyocyte-specific deletion of RhoGEF12 protects mice from cardiac dysfunction. Collectively, our findings show that G12/13-RhoGEF12-RHOA signaling contributes to the development of heart failure.
 The Rho-associated coiled-coil containing kinase (ROCK also known as Rho-kinase), a downstream target of RHOA, has been studied to identify the molecular mechanisms underlying vascular diseases such as hypertension. Several preclinical and clinical studies in vascular diseases such as vasospasm have evaluated the potential applications of ROCK inhibitors in humans. In addition, RHOA also activates protein kinase N (PKN), but the role of PKN in cardiovascular diseases is not understood. Building on our emerging understanding of the role of RHOA signaling in cardiac remodeling and cardiovascular disease, we present our latest findings from in vitro and in vivo experiments illustrating a potential RHOA-PKN-mediated mechanism in heart failure.

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