The Ras homolog gene family member A (RhoA) is the founding member of Rho GTPase superfamily originally studied in cancer cells where it was found to stimulate cell cycle progression and migration. RhoA acts as a master switch control of actin dynamics essential for maintaining cytoarchitecture of a cell. In the last two decades, however, RhoA has been coined and increasingly investigated as an essential molecule involved in signal transduction and regulation of gene transcription thereby affecting physiological functions such as cell division, survival, proliferation and migration. RhoA has been shown to play an important role in cardiac remodeling and cardiomyopathies; underlying mechanisms are however still poorly understood since the results derived from in vitro and in vivo experiments are still inconclusive. Interestingly its role in the development of cardiomyopathies or heart failure remains largely unclear due to anomalies in the current data available that indicate both cardioprotective and deleterious effects. In this review, we aimed to outline the molecular mechanisms of RhoA activation, to give an overview of its regulators, and the probable mechanisms of signal transduction leading to RhoA activation and induction of downstream effector pathways and corresponding cellular responses in cardiac (patho)physiology. Furthermore, we discuss the existing studies assessing the presented results and shedding light on the often-ambiguous data. Overall, we provide an update of the molecular, physiological and pathological functions of RhoA in the heart and its potential in cardiac therapeutics.

We and others have shown that LMCD1 expression levels are upregulated in various in vitro and in vivo models of hypertrophy and that LMCD1 is necessary and sufficient to induce cardiomyocyte hypertrophy in vitro . We successfully generated a new mouse line with a conditional cardiac knockout of LMCD1. We performed echocardiographic, morphometric, and molecular analysis in these LMCD1-deficient and appropriate control-mice under basic conditions as well as 14 days after transverse aortic banding (TAC)-induced left ventricular (LV) pressure overload. Our aim was to investigate the hypothesis of potential beneficial effects of LMCD1-downregulation in vivo . These knockout (KO)-mice revealed under basic conditions a significant reduction of LMCD1 in the heart to <10% on protein level compared to control (WT)-mice (females and males n=5 each, p<0.001), while anatomic and functional parameters of the heart as well as LMCD1 levels in all other tested organs remained unchanged. Sham-operated KO-mice also showed significantly reduced level of LMCD1 in the LV compared to Sham-operated WT-mice (protein level <20%, p<0.001, n=8). No significant increase of LMCD1 in TAC- compared to Sham-operated KO-mice was found. TAC-operated KO-mice showed no significant differences in heart anatomy and function when compared to TAC-operated WT-mice. However, we determined a consistent trend toward improved heart function (ejection fraction and fractional shortening). Furthermore, TAC-operated KO-mice showed reduced activation of the fetal gene program in LV-tissue compared to TAC-operated WT-mice: mRNA levels of the hypertrophic markers NppA, NppB, and Rcan1-4 were all decreased (WT-TAC n=8 vs. KO-TAC n=10: NppA 8.5±2.0 vs. 5.1±1.5, p<0.05; NppB 1.9±0.2 vs. 1.7±0.3, p=0.093; Rcan1-4 6.0±0.2 vs. 3.2 vs. 0.7, p<0.05), suggesting a protective role of LMCD1-knockout. The reduction of calcineurin (CnA)-responsive Rcan1-4 specifically suggests a protective role of LMCD1-knockout in CnA-dependent signaling. Taken together, our preliminary data reveals protective effects of LMCD1-knockout against TAC-induced hypertrophic signaling. Ongoing experiments focus on effects of LMCD1-knockout on apoptosis and fibrosis and its role in Angiotensin-induced hypertrophy.