The role of RhoA-mediated Ca2+ sensitization of bronchial smooth muscle contraction in airway hyperresponsiveness.
Smooth muscle contraction is mediated by Ca2+-dependent and Ca2+-independent pathways. The latter Ca2+-independent pathway, termed Ca2+ sensitization, is mainly regulated by a monomeric GTP binding protein RhoA and its downstream target Rho-kinase. Recent studies suggest a possible involvement of augmented RhoA/Rho-kinase signaling in the elevated smooth muscle contraction in several human diseases. An increased bronchial smooth muscle contractility, which might be a major cause of the airway hyperresponsiveness that is a characteristic feature of asthmatics, has also been reported in bronchial asthma. Here, we will discuss the role of RhoA/Rho-kinase-mediated Ca2+ sensitization of bronchial smooth muscle contraction in the pathogenesis of airway hyperresponsiveness. Agonist-induced Ca2+ sensitization is also inherent in bronchial smooth muscle. Since the Ca2+ sensitization is sensitive to a RhoA inactivator, C3 exoenzyme, and a Rho-kinase inhibitor, Y-27632, the RhoA/Rho-kinase pathway is involved in the signaling. It is of interest that the RhoA/Rho-kinase-mediated Ca2+ sensitization of bronchial smooth muscle contraction is markedly augmented in experimental asthma. Moreover, Y-27632 relaxes the bronchospasm induced by contractile agonists and antigens in vivo. Y-27632 also has an ability to inhibit airway hyperresponsiveness induced by antigen challenge. Thus, the RhoA/Rho-kinase pathway might be a potential target for the development of new treatments for asthma, especially in airway hyperresponsiveness.
Chiba
Yoshihiko
Y
Department of Pharmacology, School of Pharmacy, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan. chiba@hoshi.ac.jp
Misawa
Miwa
M
D000818:Animals; D001980:Bronchi / Q000502:physiology*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology*; D006801:Humans; D009130:Muscle, Smooth / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
D020742:rhoA GTP-Binding Protein; D002118:Calcium