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RhoA Signaling in Immune Cell/Cardiac
One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases.
The immune system is based on two main complexes: (1) the innate immune system and (2) the adaptive immune system. The innate immune system is triggered by direct contact with pathogens or inflammatory/danger signals and includes non-cellular responses, i.e., the release of inflammatory cytokines, and cellular responses, i.e., infiltration of innate immune cells (macrophages, dendritic cells, and granulocytes) into affected tissue . The adaptive immune system also involves non-cellular (hormonal) and cellular responses (stimulation of B- and T-cells), but in contrast to the innate response, it builds up an “immunologic memory” by developing pathogen-specific receptors . RhoA (ras homolog family member A), an ubiquitously expressed small GTPase, acts as a molecular switch not only in the activation of cytoskeletal proteins but also in responding chemokines, cytokines, and growth factors released from both innate and adaptive immune cells . Furthermore, RhoA activation and RhoA-dependent signaling pathways in cardiomyocytes  and in immune cells  have been shown to mediate immune responses, which play an important role in pathogenesis and progression of cardiac dysfunction .
2. Links between Cardiac Hypertrophy, Heart Failure, and Immune Cell Activation
In the last decades, the role of the innate and adaptive immune response is being linked with a number of signaling molecules and pathways, including RhoA activation in cardiomyocytes . Furthermore, it has been illustrated that different cardiac diseases (e.g., ischemic, hypertensive, and genetic cardiomyopathies) converge in inducing a common immune response that contributes to disease progression .
Signals that trigger activation of innate immune cells and subsequent immune responses are pathogen-associated molecules or “danger-molecules” and other signals arising from damaged tissue . The main group of receptors for inflammatory signals consists of pattern recognition receptors (PRRs) . PRRs, which are generally upregulated in HF , are commonly expressed by immune cells, but have also been found in cardiac cells . Although PPRs are best known for their activation after contact with pathogens, it can also be activated by danger-associated molecular patterns (DAMPs) that are released by damaged or dying cells , e.g., injured myocardium. The activation of PPRs triggers the release of inflammatory cytokines  (e.g., interferones (IFN) and IL-1β) and thus accelerates immune responses  (Figure 1).
3. RhoA Activation and Signaling in Immune Cells
Recent studies demonstrate that RhoA plays an important role in immune responses, with its effects being highly dependent on the spatio-temporal regulation of RhoA activation in different innate and adaptive immune cells . On molecular level, the activation of RhoA in immune cells and cardiomyocytes depends on its change from a guanosine diphosphate (GDP)-bound “inactive” to a guanosine triphosphate (GTP)-bound “active” state and back . This cycle is regulated by regulatory proteins, namely guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), guanine nucleotide dissociation inhibitors (GDIs) and GDI dissociation factors (GDFs) . GEFs facilitate the dissociation of GDP from RhoA, thus accelerating the binding of GTP and allowing the activation of downstream effectors . GAPs catalyze the hydrolysis of GTP back to GDP and thus the release of the effector . GDIs disconnect RhoA from the plasma membrane, thus inhibiting the dissociation of GDP , while GDFs initiate the dissociation of GDIs from RhoA allowing the cycle to start again . A number of these regulators have been shown to be identical in immune cells and cardiomyocytes (e.g., LARG (leukemia-associated RhoGEF), GEF-H1/Lfc (Lbc’s first cousin), PDZ-RhoGEF, p190RhoGAP, and Vav1) , while others were found specifically in immune cells (e.g., RhoA-GAP, Myo9B, and Rho-GEF7) . Even some of the up- and downstream signaling pathways of RhoA described in cardiomyocytes have been proven to play an important role in immune cells, e.g., RhoA activation via Gα12/13-coupled membrane receptors  and RhoGEF or activation of the RhoA effector, ROCK .
RhoA activation has also been associated with activation of β2-adrenergic receptors (β2-AR), probably via p115RhoGEF . Hyperactivity of the sympathetic nervous system is one of the hallmarks of heart failure that involves catecholamine spillover, and is associated with pro-inflammatory signaling . Several studies have shown that infusion of isoprenaline—a synthetic catecholamine and β2-AR agonist—in mice induces cardiac inflammation and dysfunction , and infusion of noradrenalin, also a β2-AR agonist, induces cardiac hypertrophy and fibrosis in rats . However, β1-ARs have been shown to be ubiquitously expressed in rodent (ventricular) cardiomyocytes, while β2-ARs were only found in a very small percentage of these myocytes . In contrast, β2-ARs were found to be abundant in non-myocytes of rodent heart tissue , suggesting that endothelial cells, fibroblasts and/or immune cells in cardiac tissue likely express β2-ARs.
The entry is from 10.3390/cells10071681
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