RhoA/Rho-Kinase as a Therapeutic Target in Asthma

Abstract

Rho-kinase is an effector molecule of RhoA, a monomeric GTP-binding protein, and causes Ca(2+) sensitization via inactivation of myosin phosphatase. The major physiological functions of Rho-kinase include contraction, migration, and proliferation in cells. These actions are thought to be related to the pathophysiological features of asthma, i.e., airflow limitation, airway hyperresponsiveness, beta-adrenergic desensitization, eosinophil recruitment and airway remodeling. Here, the roles of RhoA/Rho-kinase in the pathophysiology and treatment of asthma were investigated. In airway smooth muscle, pre-exposure to chemical mediators released from inflammatory cells markedly enhances methacholine-induced contraction without elevating intracellular concentrations of Ca(2+). This augmented responsiveness to methacholine involves the phosphorylation of myosin phosphatase targeting protein 1 (MYPT1) via Rho-kinase, however, it is attenuated by pre-treatment with Rho-kinase inhibitors such as Y-27632 and HA-1077. Airway smooth muscle contraction due to asthma-related substances such as contractile agonists and reactive oxygen species is suppressed by these Rho-kinase inhibitors. Reduced responsiveness to beta-adrenergic receptor agonists occurs via Ca(2+) sensitization, after exposure to lysophospholipids and proteases released from inflammatory cells. This beta-adrenergic desensitization is also attenuated in the presence of Y-27632. Furthermore, the proliferation of airway smooth muscle cells is elevated by Rho-kinase, however, it is markedly suppressed by Y-27632. Antigen challenges cause hyperresponsiveness and eosinophilia in the airways; however, these reactions are markedly suppressed by these Rho-kinase inhibitors. These findings indicate that RhoA/Rho-kinase is involved in the pathophysiology of asthma, and suggest that Rho-kinase inhibitors have therapeutic potential for prohibiting these features. In conclusion, RhoA/Rho-kinase is a novel target molecule for the treatment of asthma.

The effects of the small GTPase RhoA on the muscarinic contraction of airway smooth muscle result from its role in regulating actin polymerization

“…On the basis of its role in the regulation of airway smooth muscle contractility, RhoA has also been proposed as a potential target for asthma therapy (32). Our results suggest that downstream effectors in the RhoA pathway that regulate cytoskeletal dynamics may provide very effective targets for the mitigation of airway hyperresponsiveness with airway inflammation and asthma.…”

Induction of RhoA gene expression by interleukin-4 in cultured human bronchial smooth muscle cells

“…In these models of airway hyperresponsiveness, an increased contractility of isolated BSM to contractile agonists has also been found (Misawa and -518 to -510, -271 to -263, -191 to -183, and -78 to -70 bp) Chiba, 1993;Chiba and Misawa, 1995;Chiba et al, 2005;2008;2009a). The augmented BSM contraction induced by antigen exposure has reportedly been associated with an upregulation of RhoA (Chiba et al, 1999;2003;2005;2008;2009a;2009b;2009c), a small GTPase that is involved in the agonist-induced Ca 2+ sensitization of smooth muscle contraction (Somlyo and Somlyo 2003;Chiba and Misawa, 2004). The RhoA and its downstream Rho-kinases are now considered as a target of airway obstructive diseases such as asthma (Gosens et al, 2006;Kume, 2008;Schaafsma et al, 2008a;2008b).…”

“…In animal models of allergic bronchial asthma, an in vivo airway hyperresponsiveness accompanied by the increased IgE production and pulmonary eosinophilia has been demonstrated (Misawa and Chiba, 1993;Kato et al, 1999;Chiba et al, 2008). In these models of airway hyperresponsiveness, an increased contractility of isolated BSM to contractile agonists has also been found (Misawa and -518 to -510, -271 to -263, -191 to -183, and -78 to -70 bp) Chiba, 1993;Chiba and Misawa, 1995;Chiba et al, 2005;2008;2009a). The augmented BSM contraction induced by antigen exposure has reportedly been associated with an upregulation of RhoA (Chiba et al, 1999;2003;2005;2008;2009a;2009b;2009c), a small GTPase that is involved in the agonist-induced Ca 2+ sensitization of smooth muscle contraction (Somlyo and Somlyo 2003;Chiba and Misawa, 2004).…”

“…The augmented BSM contraction induced by antigen exposure has reportedly been associated with an upregulation of RhoA (Chiba et al, 1999;2003;2005;2008;2009a;2009b;2009c), a small GTPase that is involved in the agonist-induced Ca 2+ sensitization of smooth muscle contraction (Somlyo and Somlyo 2003;Chiba and Misawa, 2004). The RhoA and its downstream Rho-kinases are now considered as a target of airway obstructive diseases such as asthma (Gosens et al, 2006;Kume, 2008;Schaafsma et al, 2008a;2008b). Although the promoter of the human RhoA gene is not fully understood until now to our knowledge, IL-4 is known to share many functional properties with IL-13 (Hershey, 2003).…”

“…Recent studies demonstrated that the agonist-induced, RhoA/Rho-kinase-mediated Ca 2+ sensitization of bronchial smooth muscle (BSM) contraction is augmented in rats (Chiba et al, 1999) and mice (Chiba et al, 2005) with allergic bronchial asthma. An importance of the RhoA/Rho-kinase system has also been demonstrated in human BSM (Yoshii et al, 1999), and the signaling of RhoA and its downstream Rho-kinases are now considered as a therapeutic target for the treatment of airway hyperresponsiveness in asthma (Gosens et al, 2006;Kume, 2008;Schaafsma et al, 2008a;2008b).…”