RhoA/Rho-kinase as a therapeutic target in asthma.
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.
Kume
Hiroaki
H
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan. hkume@med.nagoya-u.ac.jp
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein